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• Psilocybin has shown promise for the treatment of psychiatric disorders. • Psilocybin was administered following extinction of cocaine self-administration. • Psilocybin had no effect on reinstatement in mice or rats. There are currently no pharmacological treatments for cocaine use disorder. Recently there has been a great deal of interest in the potential of psychedelic drugs such as psilocybin to treat psychiatric disorders. Human studies have indicated that a single administration of psilocybin can have long-lasting effects. Few preclinical studies have examined a role for psilocybin in addiction models. The goal of the current study was to determine whether psilocybin would enhance extinction following cocaine self-administration in male and female mice and rats and thus result in an attenuation of cue-induced drug-seeking. In experiments in mice, 16 female and 19 male mice underwent 8d of cocaine self-administration (0.5 mg/kg/infusion) and extinction training. Immediately following extinction trials, mice were injected with vehicle or 1.0 mg/kg psilocybin. Following the conclusion of extinction training, mice were tested for cue-induced reinstatement. In experiments in rats, 24 female and 23 male rats underwent 15d of cocaine self-administration (0.8 mg/kg/infusion) and extinction training. Immediately following extinction trials, rats were injected with vehicle, 1.0 mg/kg psilocybin, or 2.5 mg/kg psilocybin. Following the conclusion of extinction training, rats were tested for cue-induced reinstatement. Psilocybin administered following extinction trials had no effect, as both female and male mice and rats demonstrated significant cue-induced reinstatement. These data suggest that psilocybin is ineffective at altering cocaine-seeking behavior in the paradigm and doses used in the current study. It remains to be seen whether treatment with psilocybin under different conditions may be useful in the long-standing goal of finding pharmacotherapies to treat CUD. [ABSTRACT FROM AUTHOR]

Past research has illuminated pivotal roles of dopamine D 3 receptors (D 3 R) in the rewarding effects of cocaine and opioids. However, the cellular and neural circuit mechanisms that underlie these actions remain unclear. We employed Cre-LoxP techniques to selectively delete D 3 R from presynaptic dopamine neurons or postsynaptic dopamine D 1 receptor (D 1 R)–expressing neurons in male and female mice. We utilized RNAscope in situ hybridization, immunohistochemistry, real-time polymerase chain reaction, voltammetry, optogenetics, microdialysis, and behavioral assays (n ≥ 8 animals per group) to functionally characterize the roles of presynaptic versus postsynaptic D 3 R in cocaine and opioid actions. Our results revealed D 3 R expression in ∼25% of midbrain dopamine neurons and ∼70% of D 1 R-expressing neurons in the nucleus accumbens. While dopamine D 2 receptors (D 2 R) were expressed in ∼80% dopamine neurons, we found no D 2 R and D 3 R colocalization among these cells. Selective deletion of D 3 R from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked nucleus accumbens dopamine release. Conversely, deletion of D 3 R from D 1 R-expressing neurons attenuated locomotor responses to D 1 -like and D 2 -like agonists. Strikingly, deletion of D 3 R from either cell type reduced oxycodone self-administration and oxycodone-enhanced brain-stimulation reward. In contrast, neither of these D 3 R deletions impacted cocaine self-administration, cocaine-enhanced brain-stimulation reward, or cocaine-induced hyperlocomotion. Furthermore, D 3 R knockout in dopamine neurons reduced oxycodone-induced hyperactivity and analgesia, while deletion from D 1 R-expressing neurons potentiated opioid-induced hyperactivity without affecting analgesia. We dissected presynaptic versus postsynaptic D 3 R function in the mesolimbic dopamine system. D 2 R and D 3 R are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. Mesolimbic D 3 R are critically involved in the actions of opioids but not cocaine. [ABSTRACT FROM AUTHOR]

Identifying biomarkers that predict substance use disorder propensity may better strategize antiaddiction treatment. Melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus critically mediate interactions between sleep and substance use; however, their activities are largely obscured in surface electroencephalogram (EEG) measures, hindering the development of biomarkers. Surface EEG signals and real-time calcium (Ca2+) activities of lateral hypothalamus MCH neurons (Ca2+ MCH) were simultaneously recorded in male and female adult rats. Mathematical modeling and machine learning were then applied to predict Ca2+ MCH using EEG derivatives. The robustness of the predictions was tested across sex and treatment conditions. Finally, features extracted from the EEG-predicted Ca2+ MCH either before or after cocaine experience were used to predict future drug-seeking behaviors. An EEG waveform derivative—a modified theta-delta-theta peak ratio (EEG TDT ratio)—accurately tracked real-time Ca2+ MCH in rats. The prediction was robust during rapid eye movement sleep (REMS), persisted through vigilance states, sleep manipulations, and circadian phases, and was consistent across sex. Moreover, cocaine self-administration and long-term withdrawal altered EEG TDT ratio, suggesting shortening and circadian redistribution of synchronous MCH neuron activities. In addition, features of EEG TDT ratio indicative of prolonged synchronous MCH neuron activities predicted lower subsequent cocaine seeking. EEG TDT ratio also exhibited advantages over conventional REMS measures for the predictions. The identified EEG TDT ratio may serve as a noninvasive measure for assessing MCH neuron activities in vivo and evaluating REMS; it may also serve as a potential biomarker for predicting drug use propensity. [ABSTRACT FROM AUTHOR]

Experience-dependent functional adaptation of nucleus accumbens (NAc) circuitry underlies the development and expression of reward-motivated behaviors. Parvalbumin-expressing GABAergic (gamma-aminobutyric acidergic) interneurons (PVINs) within the NAc are required for this process. Perineuronal nets (PNNs) are extracellular matrix structures enriched around PVINs that arise during development and have been proposed to mediate brain circuit stability. However, their function in the adult NAc is largely unknown. Here, we studied the developmental emergence and adult regulation of PNNs in the NAc of male and female mice and examined the cellular and behavioral consequences of reducing the PNN component brevican in NAc PVINs. We characterized the expression of PNN components in mouse NAc using immunofluorescence and RNA in situ hybridization. We lowered brevican in NAc PVINs of adult mice using an intersectional viral and genetic method and quantified the effects on synaptic inputs to NAc PVINs and reward-motivated learning. PNNs around NAc PVINs were developmentally regulated and appeared during adolescence. In the adult NAc, PVIN PNNs were also dynamically regulated by cocaine. Transcription of the gene that encodes brevican was regulated in a cell type– and isoform-specific manner in the NAc, with the membrane-tethered form of brevican being highly enriched in PVINs. Lowering brevican in NAc PVINs of adult mice decreased their excitatory inputs and enhanced both short-term novel object recognition and cocaine-induced conditioned place preference. Regulation of brevican in NAc PVINs of adult mice modulates their excitatory synaptic drive and sets experience thresholds for the development of motivated behaviors driven by rewarding stimuli. [ABSTRACT FROM AUTHOR]

Antenatal substance misuse is a significant problem and the effects on the developing child can be long lasting. It is estimated that 20–30% of pregnant women smoke, 15% drink alcohol, 3–10% use cannabis and 0.5–3% use cocaine worldwide. Many parents make efforts to stop or cut down alcohol, cigarette and drug use during pregnancy. However, many pregnancies are unplanned and may be recognized late. Addicted parents may not be able to stop drug and alcohol use without support. Illicit drugs, nicotine and alcohol in the maternal blood stream cross to the foetus via the placenta and have a direct effect of the developing foetus. These effects can include poor fetal growth, increased risk of stillbirth, congenital malformations, and long-lasting impacts on development. The impact of these antenatal exposures might not become apparent until much later in childhood. Children who have been exposed to drugs and alcohol in utero may present to paediatricians at any stage in childhood with a range of health and developmental problems. This article will explore the immediate and long-term impact of exposure to these substances in pregnancy and consider how to obtain an accurate history of exposure to drugs and alcohol in pregnancy as part of standard paediatric history taking. [ABSTRACT FROM AUTHOR]

This national prospective multicohort study examined the relationship between US adolescents' use of stimulant therapy for attention-deficit/hyperactivity disorder (ADHD) and subsequent risk of nonmedical stimulant use (i.e., nonmedical use of prescription stimulants and cocaine use) during young adulthood, relative to nonstimulant therapy and population controls. Nationally representative multicohort panels of 11,905 US 12th-grade students were surveyed via self-administered questionnaires at baseline (age 18) and followed prospectively over six years into young adulthood (ages 19‒24). There were no statistically significant differences between adolescents who used stimulant therapy for ADHD compared to those who used only nonstimulant medications and population controls in their adjusted odds of nonmedical stimulant use incidence or prevalence during young adulthood, after adjusting for baseline covariates. The findings offer preliminary support that adolescents who use prescription stimulant or nonstimulant medications for ADHD when clinically indicated are not at greater risk for nonmedical stimulant use during young adulthood. [ABSTRACT FROM AUTHOR]

Chest pain (CP), a common presentation in the emergency department (ED) setting, is associated with significant morbidity and mortality if emergency clinicians miss the diagnosis of acute coronary syndrome (ACS). The HEART (History, Electrocardiogram, Age, Risk Factors, Troponin) score had been validated for risk-stratification patients who are at high risk for ACS and major adverse cardiac events (MACE). However, the use of cocaine as a risk factor of the HEART score was controversial. We hypothesized that patients with cocaine-positive (COP) would not be associated with higher risk of 30-day MACE than cocaine-negative (CON) patients. This retrospective study included adult patients who presented to 13 EDs of a University's Medical System between August 7, 2017 to August 19, 2021. Patients who had CP and prospectively calculated HEART scores and urine toxicology tests as part of their clinical evaluation were eligible. Areas Under The Receiver Operating Curve (AUROC) were calculated for the performance of HEART score and 30-day MACE for each group. This study analyzed 46,210 patients' charts, 663 (1.4%) were COP patients. Mean age was statistically similar between groups but there were fewer females in the COP group (26.2% vs 53.2%, p < 0.001). Mean (+/− SD) HEART score was 3.7 (1.4) comparing to 3.1 (1.8, p < 0.001) between COP vs CON groups, respectively. Although more COP patients (54%) had moderate HEART scores (4–6) vs. CON group (35.2%, p < 0.001), rates of 30-day MACE were 1.1% for both groups. HEART score's AUROC was 0.72 for COP and 0.78 for CON groups. AUROC for the Risk Factor among COP patients, which includes cocaine, was poor (0.54). This study, which utilized prospective calculated HEART scores, demonstrated that overall performance of the HEART score was reasonable. Specifically, our analysis showed that the rate of 30-day MACE was not affected by cocaine use as a risk factor. We would recommend clinicians to consider the HEART score for this patient group. [ABSTRACT FROM AUTHOR]

Cocaine use has tended to increase over the past decade, particularly among younger populations. Cocaine is the second most commonly used illicit substance in France. Over the past few years, there has been an uptick in cocaine consumption in the country. The observed increase in consumption raises questions about the underlying motives. The goal of the present study is to construct and validate a questionnaire that explores the motivation behind cocaine use. This paper consists of two studies conducted on different data collections. In the first study, one thousand, one hundred and thirteen (n = 1113) individuals participated and six hundred and seventy (n = 670) individuals participated in the second study. All participants were current or former cocaine users. These participants completed an online sociodemographic questionnaire, a constructed questionnaire exploring motivations for cocaine use. This questionnaire was developed using the self-determination theory of (Deci & Ryan, 1985) and 11 semi-structured interviews with users. The purpose of these interviews was to explore the motivation for cocaine use, the expected benefits, and the negative consequences. From literature and the corpus of previously completed interviews, a first version of the questionnaire with 31 items was produced. The research respects the ethical recommendations of Helsinki and has received a favorable opinion from the research ethics committee. The data was collected anonymously and on a voluntary basis. In the first study, 574 (51.6%) men and 539 (48.4%) women participated. The mean age of the participants was 25.0 years (SD = 5.83) ranging from 18 to 65 years old. In the second study 310 (46.3%) men and 360 (53.7%) women participated. The mean age of the participants was 25.7 years (SD = 4.23) ranging from 18 to 48 years old. Initially, an exploratory factor analysis was carried out. This first analysis resulted in a 23-item questionnaire with a four-factor solution: pleasant sensations, social pressure and self-image, absence of motivation, and curiosity and experience. The psychometric indicators were quite satisfactory with X2 (465) = 15951, P < 0.001 for the Bartlett test and 0.91 for the KMO (Kaiser-Meyer-Olkin) test. In the second part of the research, the confirmatory factor analysis indicated a solution with three factors and 21 items. Psychometric indicators showed CFI (Comparative Fit Index) = 0.89, RMSEA (Root Mean Square Error of Approximation) = 0.06 and SRMR (Standardized Root Mean Square Residual) = 0.06. The three main factors for cocaine use were: pleasant and positive sensations, social pressure and self-esteem, and amotivation. This study laid the groundwork for the development of a valid questionnaire to explore and better understand the cocaine users' motivations, thereby enabling preventive and therapeutic measures to be adjusted accordingly. This questionnaire can also be used for future research on cocaine use, which is focused on mental health as well as family history and history of traumatic life events, as associated with cocaine use. We may also consider replicating this study on a clinical population with a cocaine-dependency diagnosis, potentially revealing additional motivations. [ABSTRACT FROM AUTHOR]

• A/G and G/G mice self-administered more oxycodone. • A/G and G/G mice self-administered more oxycodone when combined with cocaine. • A/G and G/G mice self-administered more cocaine. • Gene expression levels of Pdyn, Fkbp5, Oprk1 and Oprm1 changed after SA. The use of mu-opioid receptor (MOP-r) agonists such as oxycodone together with cocaine is prevalent, and deaths attributed to using these combinations have increased. Rationale: It is unknown if functional single nucleotide polymorphisms (SNPs), such as the OPRM1 (MOP-r gene) SNP A118G, can predispose individuals to more dual opioid and psychostimulant intake. The dual self-administration (SA) of MOP-r agonists and cocaine has not been thoroughly examined, especially with regard to neurobiological changes. Objectives: We examined oxycodone SA and subsequent dual oxycodone and cocaine SA in male and female A112G (A/G and G/G, heterozygote and homozygote, respectively) mice, models of human A118G carriers, versus wild-type (A/A) mice. Methods: Adult male and female A/G, G/G and A/A mice self-administered oxycodone (0.25 mg/kg/infusion, 4hr/session, FR 1.) for 10 consecutive days (sessions 1–10). Mice then self-administered cocaine (2 hr) following oxycodone SA (4 hr, as above) in each session for a further 10 consecutive days (sessions 11–20). Message RNA transcripts of 24 reward-related genes were examined in the dorsal striatum. Results: Male and female A/G and G/G mice had greater oxycodone SA than A/A mice did in the initial 10 days and in the last 10 sessions. Further, A/G and G/G mice showed greater cocaine intake than A/A mice. Dorsal striatal mRNA levels of Pdyn , Fkbp5 , Oprk1, and Oprm1 were altered following oxycodone and cocaine SA. Conclusions: These studies demonstrated that this functional genetic variation in Oprm1 affected dual opioid and cocaine SA and altered specific gene expression in the striatum. [ABSTRACT FROM AUTHOR]

Both psychostimulant use and engagement with probabilistic schedules of reward sensitize the mesocorticolimbic dopamine (DA) system. Such behaviors may act synergistically to explain the high comorbidity between stimulant use and gambling disorder. The salient audiovisual stimuli of modern electronic gambling may exacerbate the situation. To probe these interactions, we sensitized ventral tegmental area DA neurons via chronic chemogenetic stimulation while rats (n = 134) learned a rat gambling task in the presence or absence of casino-like cues. The same rats then learned to self-administer cocaine. In a separate cohort (n = 25), we confirmed that our chemogenetic methods sensitized the locomotor response to cocaine and potentiated phasic excitability of ventral tegmental area DA neurons through in vivo electrophysiological recordings. In the absence of cues, sensitization promoted risk taking in both sexes. When rewards were cued, sensitization expedited the development of a risk-preferring phenotype in males while attenuating cue-induced risk taking in females. While these results provide further confirmation that ventral tegmental area DA neurons critically modulate risky decision making, they also reveal stark sex differences in the decisional impact that dopaminergic signals exert when winning outcomes are cued. As previously observed, risky decision making on the cued rat gambling task increased as both males and females learned to self-administer cocaine. The combination of DA sensitization and win-paired cues while gambling led to significantly greater cocaine taking, but these rats did not show any increase in risky choice as a result. Therefore, cocaine and heavily cued gambles may partially substitute for each other once the DA system has been rendered labile through sensitization, thereby compounding addiction risk across modalities. [ABSTRACT FROM AUTHOR]

Opioid-involved deaths are continuing to increase across the United States, exceeding 100,000 for the first time in 2021. Contamination with, and intentional use of, synthetic opioids such as fentanyl are a major driver of this increase. Utilizing self-report substance use data of patients being treated in the emergency department (ED) can be useful to determine which substances patients are intentionally seeking. 1) Examine changes in self-reported illicit substance use (including fentanyl) over time; 2) Examine changes in the co-occurrence of self-reported fentanyl with other illicit substance use over time. All patients presenting to the study EDs that answered anything other than "never" on the National Institute on Drug Abuse Quick Screen and were seen by a peer recovery specialist in the ED between July 1, 2020 and December 31, 2022 were included for analysis. The substance of use as reported by each patient was recorded by the peer recovery specialist. Differences in substance use by type over time were examined using chi-squared tests of proportions. There were 7568 patients that met inclusion criteria. Self-reported fentanyl (1760%; p < 0.0001) and cocaine (82%; p = 0.034) use increased, whereas heroin use (16%; p < 0.0001) decreased. Self-reported fentanyl and cocaine use has increased significantly in South Carolina ED patients between 2020 and 2022. Given the high morbidity and mortality associated with fentanyl and fentanyl analog use, further measures to identify these patients and provide harm reduction and treatment from the ED setting are warranted. [ABSTRACT FROM AUTHOR]

Most efforts in addiction research have focused on the involvement of the medial prefrontal cortex, including the infralimbic, prelimbic, and anterior cingulate cortical areas, in cocaine-seeking behaviors. However, no effective prevention or treatment for drug relapse is available. We focused instead on the motor cortex, including both the primary and supplementary motor areas (M1 and M2, respectively). Addiction risk was evaluated by testing cocaine seeking after intravenous self-administration (IVSA) of cocaine in Sprague Dawley rats. The causal relationship between the excitability of cortical pyramidal neurons (CPNs) in M1/M2 and addiction risk was explored by ex vivo whole-cell patch clamp recordings and in vivo pharmacological or chemogenetic manipulation. Our recordings showed that on withdrawal day 45 (WD45) after IVSA, cocaine, but not saline, increased the excitability of CPNs in the cortical superficial layers (primarily layer 2, denoted L2) but not in layer 5 (L5) in M2. Bilateral microinjection of the GABA A (gamma-aminobutyric acid A) receptor agonist muscimol to the M2 area attenuated cocaine seeking on WD45. More specifically, chemogenetic inhibition of CPN excitability in L2 of M2 (denoted M2-L2) by the DREADD (designer receptor exclusively activated by designer drugs) agonist compound 21 prevented drug seeking on WD45 after cocaine IVSA. This chemogenetic inhibition of M2-L2 CPNs had no effects on sucrose seeking. In addition, neither pharmacological nor chemogenetic inhibition manipulations altered general locomotor activity. Our results indicate that cocaine IVSA induces hyperexcitability in the motor cortex on WD45. Importantly, the increased excitability in M2, particularly in L2, could be a novel target for preventing drug relapse during withdrawal. [ABSTRACT FROM AUTHOR]

• Geospatial intelligence contributes to the formulation of public drug policies. • Concentrated individual cocaine seizures linked to specific geographical features. • News websites provide valuable insights into drug trafficking dynamics. • The identified routes and trends align with current literature on drug trafficking. • São Paulo: key node for Brazil's cocaine traffic and its international distribution. Cocaine trafficking threatens countries' national security and is a major public health challenge. Cocaine is transported from producer countries to consumer markets using various routes, methods, and transportation means. These routes develop in the geographical environment, are carefully planned and are geo-strategic objects that respond to the opportunities that drug trafficking organisations (DTOs) find to reduce the risks of interdiction. In this sense, individual drug seizure data (IDS) become essential indicators for identifying trends and understanding trafficking flows associated with drug trafficking routes. However, due to the illicit nature of DTOs, the availability of these data is considerably limited, hindering the ability to analyse and identify trends. This study presents a methodology for collecting and processing data from open-source information reported by Brazil's federal government news website. Using geospatial intelligence and natural language processing methods, we created a dataset with 939 records and 44 variables related to cocaine seizures in Brazil in 2022. We applied geospatial analysis techniques from this dataset to identify trends and potential cocaine trafficking flows. The results were broadly consistent with existing literature on drug trafficking. They demonstrated the potential of open-source information for environmental scanning and knowledge generation through geographic information science. The approach proposed in our research provides tools that can be used to complement drug trafficking monitoring and formulate public policies to strengthen prevention and enforcement strategies. [ABSTRACT FROM AUTHOR]

Opioid overdose deaths in 2021 were the highest ever, driven by fentanyl and polysubstance use. The aim of the study was to characterize drug use, assessed by urine drug screens (UDSs), in patients with untreated opioid use disorder (OUD) presenting to 28 emergency departments (EDs) nationally and by region. We analyzed UDSs from patients enrolled in the CTN-0099 ED-INNOVATION (Emergency Department-Initiated Buprenorphine Validation) trial between July 12, 2020 and March 9, 2022. Participants were adult ED patients with OUD not engaged in addiction treatment with a UDS positive for an opioid, but negative for methadone. Sites were divided into "East" and "West" regions. A UDS was available for all 925 enrolled participants, 543 from East and 382 from West. Fentanyl was in 702 specimens (76%) (n = 485 [89%] East vs. n = 217 [57%] West; p < 0.01) and was the only opioid in 269 (29%). After fentanyl, the most common opioids were morphine (presumably heroin; n = 411 [44%]; n = 192 [35%] East vs. n = 219 [57%] West; p < 0.01) and buprenorphine (n = 329 [36%]; n = 186 [35%] East vs. n = 143 [37%] West; p = 0.32). The most common drugs found with opioids were stimulants (n = 545 [59%]), tetrahydrocannabinol (n = 417 [45%]), and benzodiazepines (n = 151 [16%]). Amphetamine-type stimulants were more common in West (n = 209 [55%] vs. East (n = 125 [23%]). Cocaine was more common in East (n = 223 [41%]) vs. West (n = 82 [21%]). The presence of multiple drugs was common (n = 759 [82%]). Most participants had UDS specimens containing multiple substances; a high proportion had fentanyl, stimulants, and buprenorphine. Regional differences were noted. Given the increased risk of death with fentanyl and polysubstance use, ED providers should be providing risk reduction counseling, treatment, and referral. [ABSTRACT FROM AUTHOR]

[Display omitted] Despite significant advancements in our understanding of addiction at the neurobiological level, a highly effective extinction procedure for preventing relapse remains elusive. In this study, we report that bright light treatment (BLT) administered during cocaine withdrawal with extinction training prevents cocaine-driven reinstatement by acting through the thalamic-habenular pathway. We found that during cocaine withdrawal, the lateral habenula (LHb) was recruited, and inhibition of the LHb via BLT prevented cocaine-driven reinstatement. We also demonstrated that the effects of BLT were mediated by activating LHb-projecting neurons in the ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL) or by inhibiting postsynaptic LHb neurons. Furthermore, BLT was found to improve aversive emotional states induced by drug withdrawal. Our findings suggest that BLT administered during the cocaine withdrawal may be a promising strategy for achieving drug abstinence. [ABSTRACT FROM AUTHOR]

Unbalanced activity of medium spiny neurons (MSNs) of the direct and indirect pathways mediates reward-related behaviors induced by addictive drugs. Prelimbic (PL) input to MSNs in the nucleus accumbens core (NAcC) plays a key role in cocaine-induced early locomotor sensitization (LS). However, the adaptive plastic changes at PL-to-NAcC synapses underlying early LS remain unclear. Using transgenic mice and retrograde tracing, we identified NAcC-projecting pyramidal neurons (PNs) in the PL cortex based on the expression of dopamine receptor types (D1R or D2R). To examine cocaine-induced alterations in PL-to-NAcC synapses, we measured excitatory postsynaptic current amplitudes evoked by optostimulation of PL afferents to MSNs. Riluzole was chosen to test the effects of PL excitability on cocaine-induced changes of PL-to-NAcC synapses. NAcC-projecting PNs were segregated into D1R- and D2R-expressing PNs (D1- and D2-PNs, respectively), and their excitability was opposingly regulated by respective dopamine agonists. Both D1- and D2-PNs exhibited balanced innervation of direct MSNs and indirect MSNs in naïve animals. Repeated cocaine injections resulted in biased synaptic strength toward direct MSNs through presynaptic mechanisms in both D1- and D2-PNs, although D2R activation reduced the D2-PN excitability. Under group 1 metabotropic glutamate receptors coactivation, however, D2R activation enhanced the D2-PN excitability. The cocaine-induced rewiring accompanied LS, and both rewiring and LS were precluded by PL infusion of riluzole, which reduced the intrinsic excitability of PL neurons. These findings indicate that cocaine-induced rewiring of PL-to-NAcC synapses correlates well with early behavioral sensitization and that rewiring and LS can be prevented by riluzole-induced reduction of excitability of PL neurons. [ABSTRACT FROM AUTHOR]

The ability of neurons to respond to external stimuli involves adaptations of gene expression. Induction of the transcription factor ΔFOSB in the nucleus accumbens, a key brain reward region, is important for the development of drug addiction. However, a comprehensive map of ΔFOSB's gene targets has not yet been generated. We used CUT&RUN (cleavage under targets and release using nuclease) to map the genome-wide changes in ΔFOSB binding in the 2 main types of nucleus accumbens neurons—D1 or D2 medium spiny neurons—after chronic cocaine exposure. To annotate genomic regions of ΔFOSB binding sites, we also examined the distributions of several histone modifications. Resulting datasets were leveraged for multiple bioinformatic analyses. The majority of ΔFOSB peaks occur outside promoter regions, including intergenic regions, and are surrounded by epigenetic marks indicative of active enhancers. BRG1, the core subunit of the SWI/SNF chromatin remodeling complex, overlaps with ΔFOSB peaks, a finding consistent with earlier studies of ΔFOSB's interacting proteins. Chronic cocaine use induces broad changes in ΔFOSB binding in both D1 and D2 nucleus accumbens medium spiny neurons of male and female mice. In addition, in silico analyses predict that ΔFOSB cooperatively regulates gene expression with homeobox and T-box transcription factors. These novel findings uncover key elements of ΔFOSB's molecular mechanisms in transcriptional regulation at baseline and in response to chronic cocaine exposure. Further characterization of ΔFOSB's collaborative transcriptional and chromatin partners specifically in D1 and D2 medium spiny neurons will reveal a broader picture of the function of ΔFOSB and the molecular basis of drug addiction. [ABSTRACT FROM AUTHOR]

Drug use is prevalent in patients with schizophrenia spectrum disorders (SSD) but there is limited knowledge about the influence of drug use on the effectiveness of antipsychotic medication. This secondary explorative study compared the effectiveness of three antipsychotics in patients with SSD, with and without drug use. The BeSt InTro multi-centre, head to head, rater-blinded randomised study compared amisulpride, aripiprazole and olanzapine over a 1-year follow-up period. All patients (n = 144) were aged ≥18 years and met the ICD-10 criteria for SSD (F20–29). Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). The primary outcome was reduction of a PANSS positive subscale score. At baseline, 38% of all patients reported drug use in the last 6 months before inclusion, with cannabis as the main drug (85%), followed by amphetamine-type stimulants (45%), sedatives (26%), hallucinogens (19%), cocaine (13%), opiates (4%), GHB (4%), solvents (4%), analgesics (4%) and anabolic steroids (2%). The predominant pattern was the use of several drugs. There were no significant overall differences in the PANSS positive subscale score reduction for the three studied antipsychotics among patients either with or without drug use. In the drug use group, older patients treated with amisulpride showed a greater PANSS positive subscale score reduction during the treatment period compared to younger patients. The current study showed that drug use does not appear to affect the overall effectiveness of amisulpride, aripiprazole and olanzapine in patients with SSD. However, amisulpride may be a particularly suitable choice for older patients with drug use. [ABSTRACT FROM AUTHOR]

There are indications that drug conditioned stimuli (CS) may activate neurochemical systems of memory modulation that are activated by the drugs themselves. To directly test this hypothesis, a cholinergic nicotinic receptor antagonist (mecamylamine; MEC: 0, 10 or 30 µg/side) and a dopamine D2 receptor antagonist (l -741,626: 0, 0.63, 2.5 µg/side) were infused in the perirhinal cortex (PRh) to block modulation of object recognition memory consolidation induced by 0.4 mg/kg nicotine, 20 mg/kg cocaine, or their CSs. To establish these CSs, male Sprague-Dawley rats were confined for 2 h in a chamber, the CS+, after injections of 0.4 mg/kg nicotine, or 20 mg/kg cocaine, and in another chamber, the CS−, after injections of vehicle. This was repeated over 10 days (5 drug/CS+ and 5 vehicle/CS− pairings in total). It was found that the memory enhancing action of post-sample nicotine was blocked by intra-PRh infusions of both MEC doses, and 30 µg/side MEC also blocked the memory enhancing action of the nicotine CS. Interestingly, intra-PRh MEC did not block the memory enhancing effect of cocaine, nor that of the cocaine CS. In contrast, the memory enhancing action of post-sample cocaine administration was blocked by both l -741,626 doses, and 2.5 µg/side also blocked the effect of the cocaine CS, but not the memory effects of nicotine or of the nicotine CS. This functional double dissociation strongly indicates that drug CSs modulate memory consolidation by activating neural systems that are activated by the drugs themselves. [ABSTRACT FROM AUTHOR]

Over the course of chronic drug use, brain transcriptional neuroadaptation is thought to contribute to a change in drug use behavior over time. The function of the transcription factor CREB (cAMP response element binding protein) within the nucleus accumbens (NAc) has been well documented in opposing the rewarding properties of many classes of drugs, yet the gene targets through which CREB causally manifests these lasting neuroadaptations remain unknown. Here, we identify zinc finger protein 189 (Zfp189) as a CREB target gene that is transcriptionally responsive to acute and chronic cocaine use within the NAc of mice. To investigate the role of the CREB- Zfp189 interaction in cocaine use, we virally delivered modified clustered regularly interspaced short palindromic repeats (CRISPR)/dCas9 constructs capable of selectively localizing CREB to the Zfp189 gene promoter in the NAc of mice. We observed that CREB binding to the Zfp189 promoter increased Zfp189 expression and diminished the reinforcing responses to cocaine. Furthermore, we showed that NAc Zfp189 expression increased within D1 medium spiny neurons in response to acute cocaine but increased in both D1- and D2-expressing medium spiny neurons in response to chronic cocaine. CREB-mediated induction of Zfp189 potentiated electrophysiological activity of D1- and D2-expressing medium spiny neurons, recapitulating the known effect of CREB on these neurons. Finally, targeting CREB to the Zfp189 promoter within NAc Drd2- expressing neurons, but not Drd1- expressing neurons, was sufficient to diminish cocaine-conditioned behaviors. Together, these findings point to the CREB- Zfp189 interaction within the NAc Drd2+ neurons as a molecular signature of chronic cocaine use that is causal in counteracting the reinforcing effects of cocaine. [ABSTRACT FROM AUTHOR]

Although hyperthermia is described after cocaine intoxication, the two hyperthermic cases discussed were unusual in severity and duration for cocaine alone. Synephrine was found in biological samples of these patients in high concentrations and was suspected to be an adulterant in illicitly obtained drugs. Two patients presented to a tertiary care university hospital within 2 days of each other after recreational drug use with delayed and protracted hyperthermia. Synephrine was later found in high concentrations in biological samples as an unexpected drug adulterant. The first patient's presentation came with delayed recognition of hyperthermia and implementation of aggressive cooling measures; he entered multisystem organ failure with prolonged intensive care unit stay and significant morbidity. The second patient's hyperthermia was recognized promptly, and she received early, aggressive cooling, including deep sedation and ice water submersion. She left against medical advice from the hospital at her baseline 3 days after presentation. Synephrine is a suspected adulterant that may be associated with profound hyperthermia. Early recognition of drug overdose and working knowledge of common adulterants can facilitate early targeted management, such as aggressive cooling measures, which may prevent morbidity and mortality. [ABSTRACT FROM AUTHOR]

[Display omitted] • Exposure to morphine and cocaine induces changes in the transcriptome of zebrafish embryos. • Pathways related to lipid metabolism appear to be overrepresented for both treatments. • Other deregulated pathways are detoxification, response to chemicals and calcium signalling. • Morphine and cocaine modify global DNA methylation. Morphine and other opioid analgesics are the drugs of election to treat moderate-to-severe pain, and they elicit their actions by binding to the opioid receptors. Cocaine is a potent inhibitor of dopamine, serotonin, and noradrenaline reuptake, as it blocks DAT, the dopamine transporter, causing an increase in the local concentration of these neurotransmitters in the synaptic cleft. The molecular effects of these drugs have been studied in specific brain areas or nuclei, but the systemic effects in the whole organism have not been comprehensively analyzed. This study aims to analyze the transcriptomic changes elicited by morphine (10 uM) and cocaine (15 uM) in zebrafish embryos. An RNAseq assay was performed with tissues extracts from zebrafish embryos treated from 5 hpf (hours post fertilization) to 72 hpf, and the most representative deregulated genes were experimentally validated by qPCR. We have found changes in the expression of genes related to lipid metabolism, chemokine receptor ligands, visual system, hemoglobins, and metabolic detoxification pathways. Besides, morphine and cocaine modified the global DNA methylation pattern in zebrafish embryos, which would explain the changes in gene expression elicited by these two drugs of abuse. [ABSTRACT FROM AUTHOR]

In 2014, we proposed that orexin signaling transformed motivationally relevant states into adaptive behavior directed toward exploiting an opportunity or managing a threat, a process we referred to as motivational activation. Advancements in animal models since then have permitted higher-resolution measurements of motivational states; in particular, the behavioral economics approach for studying drug demand characterizes conditions that lead to the enhanced motivation that underlies addiction. This motivational plasticity is paralleled by persistently increased orexin expression in a topographically specific manner—a finding confirmed across species, including in humans. Normalization of orexin levels also reduces drug motivation in addiction models. These new advancements lead us to update our proposed framework for the orexin function. We now propose that the capacity of orexin neurons to exhibit dynamic shifts in peptide production contributes to their role in adaptive motivational regulation and that this is achieved via a pool of reserve orexin neurons. This reserve is normally bidirectionally recruited to permit motivational plasticity that promotes flexible, adaptive behavior. In pathological states such as addiction, however, we propose that the orexin system loses capacity to adaptively adjust peptide production, resulting in focused hypermotivation for drug, driven by aberrantly and persistently high expression in the orexin reserve pool. This mechanistic framework has implications for the understanding and treatment of several psychiatric disorders beyond addiction, particularly those characterized by motivational dysfunction. [ABSTRACT FROM AUTHOR]

Social experiences influence susceptibility to substance use disorder. The adolescent period is associated with the development of social reward and is exceptionally sensitive to disruptions to reward-associated behaviors by social experiences. Social isolation (SI) during adolescence alters anxiety- and reward-related behaviors in adult males, but little is known about females. The medial amygdala (meA) is a likely candidate for the modulation of social influence on drug reward because it regulates social reward, develops during adolescence, and is sensitive to social stress. However, little is known regarding how the meA responds to drugs of abuse. We used adolescent SI coupled with RNA sequencing to better understand the molecular mechanisms underlying meA regulation of social influence on reward. We show that SI in adolescence, a well-established preclinical model for addiction susceptibility, enhances preference for cocaine in male but not in female mice and alters cocaine-induced protein and transcriptional profiles within the adult meA particularly in males. To determine whether transcriptional mechanisms within the meA are important for these behavioral effects, we manipulated Crym expression, a sex-specific key driver gene identified through differential gene expression and coexpression network analyses, specifically in meA neurons. Overexpression of Crym, but not another key driver that did not meet our sex-specific criteria, recapitulated the behavioral and transcriptional effects of adolescent SI. These results show that the meA is essential for modulating the sex-specific effects of social experience on drug reward and establish Crym as a critical mediator of sex-specific behavioral and transcriptional plasticity. [ABSTRACT FROM AUTHOR]

Persistent sleep disruptions following withdrawal from abused drugs may hold keys to battle drug relapse. It is posited that there may be sleep signatures that predict relapse propensity, identifying which may open new avenues for treating substance use disorders. We trained male rats (approximately postnatal day 56) to self-administer cocaine. After long-term drug withdrawal (approximately postnatal day 100), we examined the correlations between the intensity of cocaine seeking and key sleep features. To test for causal relationships, we then used behavioral, chemogenetic, or optogenetic methods to selectively increase rapid eye movement sleep (REMS) and measured behavioral and electrophysiological outcomes to probe for cellular and circuit mechanisms underlying REMS-mediated regulation of cocaine seeking. A selective set of REMS features was preferentially associated with the intensity of cue-induced cocaine seeking after drug withdrawal. Moreover, selectively increasing REMS time and continuity by environmental warming attenuated a withdrawal time-dependent intensification of cocaine seeking, or incubation of cocaine craving, suggesting that REMS may benefit withdrawal. Warming increased the activity of lateral hypothalamic melanin-concentrating hormone (MCH) neurons selectively during prolonged REMS episodes and counteracted cocaine-induced synaptic accumulation of calcium-permeable AMPA receptors in the nucleus accumbens—a critical substrate for incubation. Finally, the warming effects were partly mimicked by chemogenetic or optogenetic stimulations of MCH neurons during sleep, or intra-accumbens infusions of MCH peptide during the rat's inactive phase. REMS may encode individual vulnerability to relapse, and MCH neuron activities can be selectively targeted during REMS to reduce drug relapse. [ABSTRACT FROM AUTHOR]

To understand the influence of phenotypic characteristics, such as stress, on substance use treatment outcomes, measures must function equivalently across groups to allow for interpretable comparisons of effects. The present study evaluated measurement invariance of the Perceived Stress Scale (PSS) across race, sex, and time, examined its association with cocaine use disorder (CUD) treatment outcomes, and tested whether associations were moderated by race and/or sex. Data from four clinical trials evaluating behavioral and/or pharmacological treatments for cocaine use were combined providing a total sample of 302 participants with DSM-IV cocaine abuse/dependence (57.6 % Black, 42.4 % White, 43.7 % females, M age = 40.22 years, SD = 9.26). Factor analyses support a two-factor model (i.e., general stress, self-efficacy to cope with stressors) that demonstrated configural, metric, and scalar invariance across race and sex and configural and metric invariance across time. End-of-treatment stress and coping were both related to treatment outcomes, but not treatment retention. Interactions between baseline and end-of-treatment stress and coping self-efficacy with race and sex predicting treatment retention and outcomes were not significant. Results support the utility of the PSS to examine between-group differences among individuals with CUD and suggest that sociodemographic groups differ in the extent to which stress and self-efficacy to cope influence treatment outcomes. • Two factors reflecting stress and self-efficacy to cope with stress had best fit. • The PSS was invariant across race and sex, and partially invariant across time. • End-of-treatment stress and coping and changes in coping influenced outcomes. [ABSTRACT FROM AUTHOR]

To guide improvements in treatment for pregnant persons with substance use disorders within the criminal legal system, treatment programs must first determine the primary substances of concern for this population. The objective of this study is to compare trends in specific substance use upon admission to treatment in pregnancy, based upon whether referrals originated from the criminal legal system or from another referral source. This research accessed data on perinatal substance use (1995–2021) and referral sources from the Treatment Episode Data Set-Admissions (TEDS-A). Analyses use multiple logistic regressions to evaluate trends in primary substance use leading to treatment admission during pregnancy. Approximately 1 % (N = 536,948) of all substance use treatment admissions in TEDS-A were for pregnant people. Between 1995 and 2021, the percentage of treatment admissions increased for primary methamphetamine use (10 % to 27 %), primary opioid use (21 % to 38 %), and primary cannabis use (9 % to 18 %), and decreased for primary cocaine use (32 % to 6 %) and primary alcohol use (26 % to 11 %). By 2021, treatment admissions referred from criminal legal agencies were more likely to primarily be for primary methamphetamine use (33 % vs 25 %) and less likely to be for primary opioid use (22 % vs 42 %) compared to other referral sources. Trends in substance use treatment during pregnancy have changed substantially over the past few decades and emphasize the unique needs of patients referred to treatment by the criminal legal system. Treatment programs must therefore adapt to fluctuating trends in perinatal substance use. In particular, it is important to expand programs that prioritize treatment of methamphetamine use disorder for pregnant people referred through criminal legal agencies. • Trends in substance use treatment during pregnancy changed in the last 2.5 decades. • Methamphetamine use is greater in pregnant patients referred by the criminal legal system. • Opioid use is greater in pregnant patients referred to treatment by public sources. • Treatment programs need to accommodate different patient needs by referral type. [ABSTRACT FROM AUTHOR]

In addition to cocaine's addictive properties, cocaine use may lead to heightened risk-taking behavior. The disruptive effects of cocaine on aversive memory formation may underlie this behavior. The present study investigated the effects of cocaine on fear memory using a cued fear conditioning paradigm in female Sprague Dawley rats, and further determined the role of D2 receptors in modulating the effect of cocaine on cued fear expression. Animals received six evenly spaced shocks preceded by a tone. The following day, rats were returned to the fear chamber where tones, but no shocks, were delivered. In Experiment 1, separate or concurrent administrations of cocaine (15 mg/kg; i.p.) and the D2 receptor antagonist eticlopride (0.1 mg/kg; i.p.) were given immediately after conditioning trials. It was determined that cocaine administration during the consolidation period diminished the expression of cued fear during the subsequent test day. Concurrent eticlopride administration attenuated this effect, indicating the involvement of D2 receptors in the deleterious effects of cocaine on fear memory consolidation. In Experiment 2, eticlopride (0.05 μg) was infused directly into the ventral hippocampus (VH) after fear conditioning and before cocaine administration. Cocaine continued to disrupt consolidation of cued and contextual fear memory, and concurrent intra-VH eticlopride blocked this effect, thereby demonstrating that VH D2 receptors mediate cocaine-induced impairment of fear memory consolidation. Overall, the present study provides evidence that acute cocaine administration impairs aversive memory formation and establishes a potential circuit through which cocaine induces its detrimental effects on fear memory consolidation. • Immediate post-training administration of cocaine disrupted expression of cued fear memory in female rats. • The D2 receptor antagonist eticlopride, when administered systemically and concurrently with cocaine, recovered the expression of cued fear memory. • Eticlopride, when infused directly into the ventral hippocampus, blocked the deleterious effect of post-training cocaine on fear memory consolidation suggesting the role of D2 receptors in the ventral hippocampus in modulating this effect. [ABSTRACT FROM AUTHOR]

• This paper examines the connection between exposure to drug trafficking and school truancy in Costa Rica. • We use a unique microdata set that merges information on cocaine seizures and socioeconomic characteristics of Costa Rican districts with student and school data from the Programme for International Student Assessment (PISA). • Results show that students in districts with higher exposure to drug trafficking are more prone to school truancy. Exposure to crime and violence associated with drug trafficking has been shown to have negative consequences on students' health, peer relationships, and educational outcomes. However, little attention has been devoted to analyzing the effects of exposure to drug trafficking on students' truancy behavior, a critical outcome with a high cost at an individual and societal level. This study investigates the connection between exposure to drug trafficking (an increasingly common form of chronic crime and subsequent violence in Latin America) and school truancy in Costa Rica. To do so, we use a unique and comprehensive microdata set that merges detailed information on a specific measure of exposure to drug trafficking (cocaine seizures) and socioeconomic characteristics of Costa Rican districts with student and school data from the Programme for International Student Assessment (PISA). In total, we obtain a sample of 4,584 students in secondary education attending 195 schools in 147 districts. Using logistic regression, we find that students in districts with higher exposure to drug trafficking (measured by cocaine seizure rate) are more prone to school truancy. This finding suggests that strategies to tackle school truancy should consider a neighborhood context perspective. [ABSTRACT FROM AUTHOR]

Concurrent use of heroin and cocaine (known as the "speedball") prevails among substance use disorder populations, especially in opioid-dependent individuals, with severe consequences and a high fatality rate. Little is known about the patterns and correlations of the concurrent use of heroin and cocaine. It is vital to investigate such a polydrug use in both humans and animals to uncover concomitant toxicity and the cause of fatal overdose (death). In this study, we aimed to shed some light on the role of cocaine in the etiology of heroin-related deaths in the context of molecular pharmacokinetics (PK). For the purpose, a high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of heroin, cocaine, and their metabolites in whole blood was developed and fully validated in accordance with the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. Then, this method was used to analyze heroin, cocaine, and their metabolites in blood from the rats intraperitoneally administered non-lethal 10 mg/kg heroin or 20 mg/kg cocaine alone, or their combination that is lethal with a proximal mortality of 33 %. The obtained results from the rats that experienced the lethal toxicity revealed that the concurrent use of heroin and cocaine significantly increased the risk of fatality from overdose. Heroin significantly slowed down the elimination of cocaine and its main metabolites in blood, while cocaine significantly enhanced heroin metabolism from 6-monoacetylmorphine (6-MAM) to morphine. Similar elimination half-lives for other heroin metabolites were observed. These findings are reported for the first time in this study, facilitating our understanding of the polysubstance metabolism and severe consequences produced by the polydrug use. • The PKs of heroin and cocaine co-use were investigated by using a LC-MS/MS method. • Simultaneous use of heroin and cocaine increased the risk of fatality from overdose. • Heroin delayed and inhibited metabolism of cocaine. • Cocaine affected two main steps of heroin metabolism inconsistently. [ABSTRACT FROM AUTHOR]

Synaptic plasticity in the mesolimbic dopamine (DA) system contributes to the neural adaptations underlying addictive behaviors and relapse. However, the specific behavioral relevance of glutamatergic excitatory drive onto dopamine D1 receptor (D1R)-expressing neurons in mediating the reinforcing effect of cocaine remains unclear. Here, we investigated how midbrain AMPAR and NMDAR function modulate cocaine reward-related behavior using mutant mouse lines lacking the glutamate receptor genes Gria1 or Grin1 in D1R-expressing neurons (GluA1 D1CreERT2 or GluN1 D1CreERT2 , respectively). We found that conditional genetic deletion of either GluA1 or GluN1 within this neuronal sub-population did not impact the ability of acute cocaine injection to increase intracranial self-stimulation (ICSS) ratio or reduced brain reward threshold compared to littermate controls. Additionally, our data demonstrate that deletion of GluA1 and GluN1 receptor subunits within D1R-expressing neurons did not affect cocaine reinforcement in an operant self-administration paradigm, as mutant mice showed comparable cocaine responses and intake to controls. Given the pivotal role of glutamate receptors in mediating relapse behavior, we further explored the impact of genetic deletion of AMPAR and NMDAR onto D1R-expressing neurons on cue-induced reinstatement following extinction. Surprisingly, deletion of AMPAR and NMDAR onto these neurons did not impair cue-induced reinstatement of cocaine-seeking behavior. These findings suggest that glutamatergic activity via NMDAR and AMPAR in D1R-expressing neurons may not exclusively mediate the reinforcing effects of cocaine and cue-induced reinstatement. • Glutamatergic activity in D1R neurons is not crucial for mediating acute cocaine reward. • GluA1 and GluN1 receptor subunits in D1R neurons are not essential for cocaine self-administration. • Deletion of AMPA and NMDA receptors in D1R neurons does not affect cue-induced reinstatement of cocaine-seeking behavior. [ABSTRACT FROM AUTHOR]

Substance use disorder (SUD) is a heterogeneous disorder, where severity, symptoms, and patterns of use vary across individuals. Yet, when rats self-administer cocaine under short-access conditions, their behavior tends to be well-regulated, though individual differences can emerge with long- or intermittent-access. In contrast, significant individual differences emerge when rats self-administer 3,4-methylenedioxypyrovalerone (MDPV), even under short-access conditions, wherein ~30 % of rats exhibit high levels of drug-taking. This study assessed SUD-like phenotypes of male and female rats self-administering MDPV or cocaine by comparing level of drug intake, responding during periods of signaled drug unavailability, and sensitivity to footshock punishment to determine whether: (1) under short-access conditions, rats that self-administer MDPV will exhibit a more robust SUD-like phenotype than rats that self-administer cocaine; (2) female rats will have a more severe phenotype than male rats; and (3) compared to short-access, long- and intermittent-access to MDPV or cocaine self-administration will result in a more robust SUD-like phenotype. Compared to cocaine, rats that self-administered MDPV exhibited a more severe phenotype, even under short-access conditions. Long- and intermittent-access to cocaine and MDPV temporarily altered drug-taking patterns but did not systematically change SUD-like phenotypes. Behavioral and quantitative autoradiography studies suggest phenotypic differences are not due to expression of dopamine transporter, dopamine D 2 or D 3 receptors, or 5-HT 1B , 5-HT 2A , or 5-HT 2C receptors. This study suggests individuals who use synthetic cathinones may be at greater risk for developing a SUD, and short-access MDPV self-administration may provide a useful method to study the transition to disordered substance use in humans. • MDPV resulted in a more severe substance use disorder-like phenotype than cocaine. • Long and intermittent access only produced short-term changes in drug-taking patterns. • Differences in phenotypes were not explained by changes in receptor expression. • Synthetic cathinones may be useful for studying problematic stimulant use. [ABSTRACT FROM AUTHOR]

Post-mortem toxicology constantly deals with the research of reliable alternative matrices to be applied in case of highly damaged corpses (such us carbonized, skeletonized, human remains, etc.). Teeth represent a promising alternative matrix since dental tissues are endowed by different features, resistance and stability after death. Since scant literature reported on the pharmacokinetics and mechanism of incorporation of xenobiotics into dental tissues, this pilot research aims to investigate whether in the pulp can be detected the same substances found in blood in drug related death cases. Secondly, the study is addressed to disclose the possible deposit of drugs in dental hard tissues (dentine and/or enamel), thus contributing to reconstruct the drug abuse history (timing, e.g.). The study experimented with a novel method to separately analyse dental enamel, dentin, and pulp, applied to 10 teeth collected during autopsies of drug-related deaths along with blood and hair samples for classic toxicological analyses. Each tooth was prepared by "pulverization technique" and then analysed by gas chromatography paired with mass spectrometry (GC-MS) and ultra high performance liquid chromatography coupled to high resolution mass spectrometry (UHPLC/HR-MS) for searching cocaine, opiates, and metabolites. The results were then compared with those obtained from blood and hair samples. Preliminary results demonstrated that teeth differ from any other classic matrix (blood and hairs) since the qualitative correspondence of the detected substances between pulp and blood as well as dental hard tissues and hair suggests that they can be useful in post-mortem evaluation as a unique matrix for both acute and chronic assumptions of drugs. The mechanism of accumulation of substances in mineralized dental tissues emerged the most significant result, being influenced by the type of molecule and the method of assumption. The main limitation of this study is the limited availability of the sample and the absence of anamnestic information of the time, rates and method of drug assumption during life. Further research is necessary to systematically investigate the distribution of different substances within the different tissues of the tooth. • Post-mortem toxicology deals with reliable alternative matrices. • Teeth represent a promising alternative matrix. • Teeth show the qualitative correspondence of substances with blood or hair. • Teeth can be a useful matrix for both acute and chronic assumptions of drugs. • The mechanism of adsorption in teeth is influenced by the method of assumption. [ABSTRACT FROM AUTHOR]

Rearing rats in environmental enrichment produces a protective effect when exposed to stimulants, as enriched rats display attenuated cocaine seeking during reinstatement. However, less is known about what changes in the brain are responsible for this protective effect. The current study investigated differences in Fos protein expression following reinstatement of cocaine seeking in differentially reared rats. Rats were reared in either enriched (EC) or impoverished (IC) conditions for 30 days, after which rats self-administered cocaine in 2-h sessions. Following self-administration, rats underwent extinction and cue-induced or cocaine-primed reinstatement of cocaine seeking, brains were extracted, and Fos immunohistochemistry was performed. IC rats sought cocaine significantly more than EC rats during cue-induced reinstatement, and cocaine seeking was positively correlated with Fos expression in the nucleus accumbens core and ventral pallidum. IC rats displayed greater Fos expression than EC rats in the accumbens and ventral pallidum, suggesting a role of these areas in the enrichment-induced protective effect. • Enrichment rearing produces a protective effect as enriched rats reinstate to cues at lower levels than impoverished rats • Enriched rats display blunted fos expression in the accumbal-pallidal glutamatergic circuit compared to impverished rats • Fos expression in enriched rats was positively correlated with active lever pressing during reinstatement. [ABSTRACT FROM AUTHOR]

Street cocaine is often mixed with various substances that intensify its harmful effects. This paper proposes a framework to identify attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) intervals that best predict the concentration of adulterants in cocaine samples. Wavelengths are ranked according to their relevance through ReliefF and mRMR feature selection approaches, and an iterative process removes less relevant wavelengths based on the ranking suggested by each approach. Gaussian Process (GP) regression models are constructed after each wavelength removal and the prediction performance is evaluated using RMSE. The subset balancing a low RMSE value and a small percentage of retained wavelengths is chosen. The proposed framework was validated using a dataset consisting of 345 samples of cocaine with different amounts of levamisole, caffeine, phenacetin, and lidocaine. Averaged over the four adulterants, the GP regression coupled with the mRMR retained 1.07 % of the 662 original wavelengths, outperforming PLS and SVR regarding prediction performance. • A new framework for predicting cocaine adulterant concentration • Two feature selection approaches integrated to Gaussian Process are tested • Predictions were substantially improved when using reduced regions of the spectra • The proposed framework was validated in four adulterants [ABSTRACT FROM AUTHOR]

Individual differences in drug use emerge soon after initial exposure, and only a fraction of individuals who initiate drug use go on to develop a substance use disorder. Variability in vulnerability to establishing drug self-administration behavior is also evident in preclinical rodent models. Latent characteristics that underlie this variability and the relationship between early drug use patterns and later use remain unclear. Here, we attempt to determine whether propensity to establish cocaine self-administration is related to subsequent cocaine self-administration behavior in male Sprague-Dawley rats (n = 14). Prior to initiating training, we evaluated basal locomotor and anxiety-like behavior in a novel open field test. We then trained rats to self-administer cocaine in daily 3 h cocaine (0.75 mg/kg/infusion) self-administration sessions until acquisition criteria (≥30 active lever presses with ≥70 % responding on the active lever in one session) was met and divided rats into Early and Late groups by median-split analysis based on their latency to meet acquisition criteria. After each rat met acquisition criteria, we gave them 10 additional daily cocaine self-administration sessions. We then conducted a progressive ratio, cocaine-induced locomotor sensitivity test, and non-reinforced cocaine seeking test after two weeks of forced abstinence. Early Learners exhibited significantly less locomotion after an acute injection of cocaine, but the groups did not differ in any other behavioral parameter examined. These results indicate that cocaine self-administration acquisition latency is not predictive of subsequent drug-taking behavior, but may be linked to physiological factors like drug sensitivity that can predispose rats to learn the operant task. [ABSTRACT FROM AUTHOR]

During the COVID-19 pandemic, one of Australia's biggest cities, Melbourne, experienced three major isolation ("lockdown") periods in 2020 (160 days) and in 2021 (111 days) which makes it one of the most locked down cities world-wide. This study assessed how the pandemic affected temporal trends in methamphetamine, MDMA and cocaine consumption using wastewater-based epidemiology. Daily samples were collected for most of 2020 and 2021 (n = 660 days). Concentrations were measured using direct-injection LC-MS/MS and back-calculated to consumption estimates. Results indicate that methamphetamine use was increasing before the first lockdown and decreased after the end of the first lockdown in 2020. Methamphetamine trends appeared to have remained steady throughout the second lockdown period before increasing steeply after it ended. For most of 2020, cocaine use remained steady, with an increase after the second lockdown. MDMA use decreased after the start of the first lockdown and remained steady throughout most of 2020 and 2021. In comparison to 2020, trends in 2021 were less variable and stimulant use did not appear to be as associated with COVID-19 restrictions. Overall, this study was able to show the impact of lockdown periods and the related social restrictions on illicit stimulant use. Illicit drugs are hazardous chemicals, of concern both to humans and the environment. While studies have been undertaken to understand their temporal trends, this work utilizes wastewater-based epidemiology and daily sampling to provide a comprehensive understanding of the impact of the COVID-19 pandemic on the use of methamphetamine, MDMA and cocaine on one of the most locked-down cities in the world. Understanding the consequences of this significant intervention on illicit drug use could provide valuable insights into its potential environmental impact. [Display omitted] • First study to examine daily wastewater samples for illicit drugs across a two-year period. • MDMA, methamphetamine and cocaine analysed in a city with significant lockdowns. • COVID-19 restrictions in 2021 had less impact on illicit drug use than those in 2020. [ABSTRACT FROM AUTHOR]

Controls on essential/precursor chemicals from commercial companies have been associated with many large downturns in illicit drug markets and attendant problems. My colleagues and I brought this to light in the studies that are the subject of Giommoni's review. McKetin et al. in an earlier review considered several of our studies on chemical controls for methamphetamine, all centered in North America. Giommoni discusses not only those studies but also our later work on chemical controls for cocaine and heroin. This later work evaluates US essential/precursor chemical policies targeting illicit drug producers outside of North America, and it examines impacts on illicit drug availability and use (the studies reviewed by McKetin et al. predominantly focused on outcomes such as drug-related hospitalizations, arrests, and treatment). Giommoni's review is a new resource that will help make the varied topics in essential/precursor chemical control research more accessible to many readers. After noting this, I discuss some common methodological misconceptions about our studies. For example, our studies generally used multi-replication interrupted time series analysis, a research design among the most powerful of all quasi-experimental designs. Authors, however, typically discuss the studies as if they used single-intervention interrupted time series analysis, a less powerful design. Multi-replication and single-intervention interrupted time series analyses also differ regarding likely confounders; awareness of this is critical to accurately assessing our findings and critiquing alternative explanations. Finally, I note that commercial chemical companies function as the silent, albeit usually unwitting, partners in the large-scale production of several illicit drugs, including fentanyl. And many governments are implementing essential/precursor chemical controls to help stymie this partnership. But they are doing so largely without evaluation and study—a poor policy practice. To remedy this, I suggest establishing multi-disciplinary applied research teams to help assess, guide and improve essential/precursor chemical control efforts. [ABSTRACT FROM AUTHOR]

The main urinary cocaine metabolites are benzoylecgonine and ecgonine methyl ester. These molecules possess two chemical functional groups that can be charged within the conventional pH range, this is the tertiary amine group (both) and the carboxylic group (benzoylecgonine). We have found that in the pH range from 2 to 6 (for benzoylecgonine) and pH from 2 to 4 (for ecgonine methyl ester) both molecules can be detected at the electrified liquid-liquid interface (eLLI) by following the interfacial ion transfer reactions triggered in the presence of the concerned metabolites in the aqueous phase. The presence of the benzene ring in the benzoylecgonine structure increases its hydrophobicity (on the formal Galvani potential difference scale) by around 200 mV as compared with ecgonine methyl ester which transfer is overlaid with the inorganic cations crossing the LLI at the positive end of the potential window. Macroscopic eLLI was used during physicochemical ecgonine methyl ester and benzoylecgonine characterization as we have defined their diffusion coefficients, ion partition, and concentration fraction diagrams (only for the latter). The miniaturized platform was used during electroanalytical studies focused on benzoylecgonine giving a few µM limit of detection. For this purpose, we have used the fused silica capillary as the eLLI support. All our findings allowed us to use this system first to develop the electroanalytical protocol for benzoylecgonine quantification to finally detect it in the spiked urine sample with nearly 100 % recovery. [Display omitted] • Benzoylecgonine and ecgonine methyl ester are active at the ITIES. • Benzoylecgonine and ecgonine methyl ester signals can be separated. • Detection was performed at microscopic ITIES with 5 µL of the organic phase. • Both cocaine metabolites limits of detection are equal to a few µM. • Only benzoylecgonine can be detected in urine samples. [ABSTRACT FROM AUTHOR]

A systematic review of functional neuroimaging studies on drug (self-) administration in rodents is lacking. Here, we summarized effects of acute or chronic drug administration of various classes of drugs on brain function and determined consistency with human literature. We performed a systematic literature search and identified 125 studies on in vivo rodent resting-state functional magnetic resonance imaging (n = 84) or positron emission tomography (n = 41) spanning depressants (n = 27), opioids (n = 23), stimulants (n = 72), and cannabis (n = 3). Results primarily showed alterations in the striatum, consistent with the human literature. The anterior cingulate cortex and (nonspecific) prefrontal cortex were also frequently implicated. Upregulation was most often found after shorter administration and downregulation after long chronic administration, particularly in the striatum. Importantly, results were consistent across study design, administration models, imaging method, and animal states. Results provide evidence of altered resting-state brain function in rodents upon drug administration, implicating the brain's reward network analogous to human studies. However, alterations were more dynamic than previously known, with dynamic adaptation depending on the length of drug administration. • Rodent brain function upon drug administration implicates the reward network. • Upregulation of brain function was consistently seen after short drug administration. • Long chronic administration resulted in downregulation, particularly in the striatum. • Results highlight the utility of preclinical models for neuroimaging substance use. [ABSTRACT FROM AUTHOR]

L'objectif de ce travail est de déterminer la fréquence des symptômes psychotiques induits par les psychostimulants, dont les nouveaux produits de synthèse (NPS), leurs caractéristiques cliniques, leur évolution et leurs traitements. Une revue de documents sélectionnés est effectuée suivant les principes de recherche systématique dans le Medline. La recherche retrouve 41 articles portant sur les psychostimulants hors NPS et 9 articles portant sur les NPS. Les symptômes psychotiques induits par les psychostimulants, y compris NPS, sont fréquents, présentent des caractéristiques typiques avec d'importants signes positifs malgré un insight en partie conservé, une possible évolution sur un mode chronique et répondent à des traitements comme les benzodiazépines et les antipsychotiques. Un récapitulatif des implications pratiques est proposé. Les symptômes psychotiques induits par les psychostimulants pourraient constituer un trouble à part ou une vulnérabilité qui devraient faire l'objet d'une prise en charge intégrée portant à la fois sur les consommations et la symptomatologie psychiatrique. Psychostimulants such as cocaine, amphetamines and their derivatives, methamphetamine or novel synthetic drugs such as cathinones are known to cause psychotic symptoms. The objective of this study is to determine the frequency of psychotic symptoms induced by psychostimulants, including novel psychoactive substances (NPS), their clinical characteristics, their evolution, and their treatments. A review of selected documents was carried out following the principles of systematic research in Medline from 02/12/2017 to 02/12/2022. We included articles in French or English dealing with psychotic symptoms, episodes and disorders induced by psychostimulants in humans, and excluded articles dealing with animal models, those not distinguishing between substances other than psychostimulants, and NPS and non-NPS psychostimulants, and articles focusing exclusively on individuals with previously diagnosed schizophrenia. The data was input in a table for non-NPS psychostimulants and another table for NPS psychostimulants. The search found 41 articles on non-NPS psychostimulants and 9 articles on NPS. Psychotic symptoms induced by psychostimulants, including NPS, are frequent in a population of medicalized consumers: 18 to 80% according to studies. Psychotic symptoms show typical features with prominent positive symptoms, especially persecutory delirium, auditory, visual and tactile hallucinations, less negative, and cognitive symptoms. We noted more agitation, even auto-aggressiveness or hetero-aggressiveness. The clinical presentation is frequently accompanied by signs of toxic impregnation, in particular tachycardia, palpitations, hypertension, sweating or mydriasis. The data suggest a possible evolution in a chronic presentation. Psychostimulant-induced psychotic symptoms appear to be improved by treatments such as benzodiazepines for agitation and antipsychotics. The data was less rich regarding NPS but broadly consistent with the findings presented above. A summary of practical implications is provided. The psychotic symptoms induced by psychostimulants present specific, although not exclusive, characteristics. They should be the subject of particular attention, in especially looking for urinary toxins, although certain substances such as cathinones are not detected by current laboratory practices. They may be subject to a specific treatment depending on their severity and duration. In some cases, they could evolve into a chronic presentation and constitute a separate disorder or a vulnerability that should be the subject of integrated care covering both consumptions and psychiatric symptoms. [ABSTRACT FROM AUTHOR]

• Cocaine dependence (CD) is a common comorbidity of HIV infection. • The effect of former cocaine dependence on brain integrity in HIV+ individuals was explored. • Higher caudate volume was observed in abstinent CD participants. • HIV identified as the primary driver of reduced cognitive performance on neurocognitive testing. • No interactions between HIV and CD history were identified. Evidence from animal research, postmortem analyses, and magnetic resonance imaging (MRI) investigations indicate substantial morphological alteration in brain structure as a function of human immunodeficiency virus (HIV) or cocaine dependence (CD). Although previous research on HIV+ active cocaine users suggests the presence of deleterious morphological effects in excess of either condition alone, a yet unexplored question is whether there is a similar deleterious interaction in HIV+ individuals with CD who are currently abstinent. To this end, the combinatorial effects of HIV and CD history on regional brain volume, cortical thickness, and neurocognitive performance was examined across four groups of participants in an exploratory study: healthy controls (n = 34), HIV-negative individuals with a history of CD (n = 21), HIV+ individuals with no history of CD (n = 20), HIV+ individuals with a history of CD (n = 15). Our analyses revealed no statistical evidence of an interaction between both conditions on brain morphometry and neurocognitive performance. While descriptively, individuals with comorbid HIV and a history of CD exhibited the lowest neurocognitive performance scores, using Principle Component Analysis of neurocognitive testing data, HIV was identified as the primary driver of neurocognitive impairment. Higher caudate volume was evident in CD+ participants relative to CD− participants. Findings indicate no evidence of compounded differences in neurocognitive function or structural measures of brain integrity in HIV+ individuals in recovery from CD relative to individuals with only one condition. [ABSTRACT FROM AUTHOR]

• Physical aggressiveness sub score was negatively correlated with the C allele of −819 C/T (IL-10). • T allele of the SNP −786T/C of the ENOS gene positively predicts traits of physical aggressiveness. • GA genotype and the A allele of −308 G/A SNP of the TNFA were positively correlated with aggressiveness physical. • GA genotype was positively correlated with aggressiveness verbal. Cytokines and nitric oxide have been associated with impulsive and aggressive personality traits. We conducted the first study that investigated the role of SNPs in cytokines and nitric oxide genes and the influence in the progression of aggressive and impulsive behavior in 107 of cocaine and crack users. In this case-control, IL-10 (−819C/T), TNFA (−308G/A) and ENOS (−786T/C) polymorphisms were determined by Real-Time PCR. In addition, the relationship between these polymorphisms and Impulsivity and Aggression was determined. We found that the physical aggressiveness sub score was negatively correlated with the C allele of −819C/T polymorphism of the IL-10 (b = −0.14; p = 0.04). The T allele of the SNP −786T/C of the ENOS gene positively predicts traits of physical aggressiveness (b = 0.14; p = 0.04). The GA genotype (b = 0.22; p = 0.01) and the A allele (b = 0.15; p = 0.02) of −308 G/A polymorphism of the TNFA were positively correlated with aggressiveness physical. The GA genotype (b = 0.20; p = 0.03) was positively correlated with aggressiveness verbal. IL-10 (−819C/T), TNFA (−308G/A) and ENOS (−786T/C) polymorphisms might be associated with high risk of aggressive and impulsive behavior. [ABSTRACT FROM AUTHOR]

• Cocaine-fed larvae developed less in length and weight than the control. • Heroin-fed larvae had a more sluctuating development than the control. • Combination-fed larvae seemed to favour the effects of cocaine rather than heroin. • Cocaine and combination-fed larvae increased second and third instar stages, but shorten pupation and accelerate eclosion. • Heroin increases second instar stage and pupation. Insects present on or near decomposing bodies are collected by forensic entomologists and used to estimate the post-mortem interval. Drugs metabolized by a person before death may affect the rate of development of insects feeding on the corpse. This study aimed to determine the effects of cocaine and heroin main metabolites on the development rate of the Calliphora vomitoria (Diptera: Calliphoridae) and their implications on minimum post-mortem interval determination. Groups of 250 eggs each were placed into four separate pots of 150 g of minced pork meat being either un-spiked, or spiked with benzoylecgonine, morphine, or a combination of both. Larval length (mm) and weight (mg) measurements were taken twice daily and the rate of development of the insects' life cycle was monitored until eclosion. Results show that cocaine-fed larvae developed less in length and weight than the control group. Heroin-fed larvae showed a more fluctuating pattern, being smaller and lighter than the control group for most of their larval cycle, but overtaking them in both parameters towards pupation. Combination-fed larvae seemed to favour the effects of cocaine. The three conditions also had a significant impact on the length of the insects' life cycle. Cocaine and drug combination treatments increased the length of the second and third instar stages, but led to the shortening of pupation and accelerated eclosion. Conversely, heroin treatment led to lengthier pupation. Interestingly, the effects of the drug combination seemed to mirror more precisely those of cocaine. These findings indicate that both cocaine and heroin, singularly and in combination, have sizable effects on blowflies' development rates, potentially biasing post-mortem interval estimations. [ABSTRACT FROM AUTHOR]

Among patients presenting with acute myocardial infarction (AMI), the proportion of young individuals has increased in recent years. Although coronary atherosclerosis is less extensive in young patients with AMI, with higher prevalence of single-vessel disease and rare left main involvement, the long-term prognosis is not benign. Young patients with AMI with obstructive coronary artery disease have similar risk factors as older patients except for higher prevalence of smoking, lipid disorders, and family history of premature coronary artery disease, and lower prevalence of diabetes mellitus and hypertension. Smoking cessation is by far the most effective secondary preventive measure. Myocardial infarction with nonobstructive coronary arteries is a relatively common clinical entity (10%-20%) among young patients with AMI, with intravascular and cardiac magnetic resonance imaging being key for diagnosis and potentially treatment. Spontaneous coronary artery dissection is a frequent pathogenetic mechanism of AMI among young women, requiring a high degree of suspicion, especially in the peripartum period. [ABSTRACT FROM AUTHOR]

Cocaine-associated environments (i.e., contexts) evoke persistent memories of cocaine reward and thereby contribute to the maintenance of addictive behavior in cocaine users. From a therapeutic perspective, enhancing inhibitory control over cocaine-conditioned responses is of pivotal importance but requires a more detailed understanding of the neural circuitry that can suppress context-evoked cocaine memories, e.g., through extinction learning. The ventral medial prefrontal cortex (vmPFC) and dorsal medial prefrontal cortex (dmPFC) are thought to bidirectionally regulate responding to cocaine cues through their projections to other brain regions. However, whether these mPFC subregions interact to enable adaptive responding to cocaine-associated contextual stimuli has remained elusive. We used antero- and retrograde tracing combined with chemogenetic intervention to examine the role of vmPFC-to-dmPFC projections in extinction of cocaine-induced place preference in mice. In addition, electrophysiological recordings and optogenetics were used to determine whether parvalbumin-expressing inhibitory interneurons and pyramidal neurons in the dmPFC are innervated by vmPFC projections. We found that vmPFC-to-dmPFC projecting neurons are activated during unreinforced re-exposure to a cocaine-associated context, and selective suppression of these cells impairs extinction learning. Parvalbumin-expressing inhibitory interneurons in the dmPFC receive stronger monosynaptic excitatory input from vmPFC projections than local dmPFC pyramidal neurons, consequently resulting in disynaptic inhibition of pyramidal neurons. In line with this, we show that chemogenetic suppression of dmPFC parvalbumin-expressing inhibitory interneurons impairs extinction learning. Our data reveal that vmPFC projections mediate extinction of a cocaine-associated contextual memory through recruitment of feed-forward inhibition in the dmPFC, thereby providing a novel neuronal substrate that promotes extinction-induced inhibitory control. [ABSTRACT FROM AUTHOR]

The mechanisms through which drug-cue–induced negative affective states are involved in relapse have not been defined. We tested the hypothesis that in individuals having developed a dorsolateral striatum (DLS)–dependent cue-controlled cocaine-seeking habit, the loss of the opportunity to enact the drug-seeking response during abstinence results in an urge to act that exacerbates relapse severity mediated by negative urgency. Eighty-seven male Sprague Dawley rats were trained to seek cocaine under the influence of the conditioned reinforcing properties of drug-paired cues or not. We investigated whether the tendency to relapse depended on the aversive state of withdrawal or instead on the loss of opportunity to perform the ingrained drug-seeking response after periods of abstinence. The striatal locus of control over cocaine seeking at baseline and relapse was investigated using in situ hybridization of the cellular activity marker C -fos and assessment of the sensitivity of instrumental drug seeking to dopamine receptor blockade in the dorsomedial striatum–dependent goal-directed and DLS-dependent habit systems. The development of a DLS-dependent cue-controlled cocaine-seeking habit prior to abstinence resulted in a marked increase in drug seeking at relapse, which was not motivated by a cocaine withdrawal state and was no longer dependent on the DLS habit system. Instead, it reflected the emergence of negative urgency caused by the prevention of the performance of the habit during abstinence and underpinned by transient engagement of the goal-directed system. These results show that ingrained cue-controlled drug-seeking habits increase the pressure to relapse. [ABSTRACT FROM AUTHOR]

Substance use disorder is conceptualized as a form of maladaptive learning, whereby drug-associated memories, elicited by the presence of stimuli related to drug contexts or cues, contribute to the persistent recurrence of craving and the reinstatement of drug-seeking behavior. Hence, use of pharmacology or non-pharmacology way to disrupt drug-related memory holds promise to prevent relapse. Several studies have shown that memories can be unstable and susceptible to modification during the retrieval reactivation phase, termed the "reconsolidation time window". In this study, we use the classical conditioned place preference (CPP) model to investigate the role of aversive counterconditioning on drug-related memories during reconsolidation. Specifically, we uncovered that reconditioning drug cues through counterconditioning with LiCl-induced aversive outcomes following drug memory retrieval reduces subsequent drug-seeking behavior. Notably, the recall of cocaine- or morphine-CPP was eliminated when LiCl-induced aversive counterconditioning was performed 10 min, but not 6 h (outside the reconsolidation time window) after cocaine or morphine memory retrieval. In addition, the effect of LiCl-induced aversive counterconditioning could last for about 14 days. These results suggest that aversive counterconditioning during the reconsolidation of cocaine or morphine memory can prevent the re-seeking of cocaine or morphine, presumably by updating or replacing cocaine or morphine memories with aversive information. • A novel procedure to inhibit the craving and relapse of both cocaine and morphine. • The LiCl-induced counterconditioning performed after memory reactivation disrupts the reconsolidation process. • Counterconditioning is both time- and retrieval-dependent. [ABSTRACT FROM AUTHOR]

Dopamine signaling in the amygdala is known to play a role in associative learning and memory, including the process of learning to associate environmental cues with the reinforcing properties of drugs like cocaine. Evidence suggests that the ventral tegmental area (VTA) dopamine (DA) projection specifically to the basolateral amygdala (BLA) participates in establishing cocaine-cue associations that can promote later craving- and relapse-like responses to the cue alone. In order to further investigate the specific role of VTA-BLA projections in cocaine-reinforced learning, we used chemogenetics to manipulate VTA DA inputs to the BLA during cocaine self-administration, cue- and cocaine-primed reinstatement, and conditioned place preference. We found inhibiting DA input to the BLA during cocaine self-administration inhibited acquisition and weakened the ability of the previously cocaine-paired cue to elicit cocaine-seeking, while acutely inhibiting the pathway on the day of cue-induced reinstatement testing had no effect. Conversely, exciting the projection during self-administration boosted the salience of the cocaine-paired cue as indicated by enhanced responding during cue-induced reinstatement. Importantly, interfering with DA input to the BLA had no impact on the ability of cocaine to elicit a place preference or induce reinstatement in response to a priming cocaine injection. Overall, we show that manipulation of projections underlying DA signaling in the BLA may be useful for developing therapeutic interventions for substance use disorders. • Inhibition of dopamine inputs to the BLA impairs acquisition of cocaine self-administration. • Inhibition of dopamine inputs to the BLA does not disrupt cocaine conditioned place preference. • Chemogenetic activation of dopamine inputs to the BLA potentiates later cue-induced reinstatement. • Inhibiton of locus coeruleus inputs to the BLA does not alter cocaine self-administration. [ABSTRACT FROM AUTHOR]