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Rationale: The newly emerging synthetic cannabinoids (SCs) 5F-EDMB-PICA, CUMYL-PEGACLONE, and NM-2201 have been observed to produce effects by activating cannabinoid type 1 (CB1) receptors. Nevertheless, the pharmacological effects and potential for abuse of these three substances remain to be studied. These substances have yet to be regulated in many countries., Objectives: We investigated the safety, pharmacological effects, rewarding effects, and cannabinoid withdrawal of 5F-EDMB-PICA, CUMYL-PEGACLONE, and NM-2201., Methods: This study evaluated the drug safety and the cannabinoid-specific pharmacological effects of the three substances through acute toxicity experiments (in which the LD 50 of each substance was obtained) and tetrad experiments (comprising assessments of hypothermia, analgesia, locomotion inhibition, and catalepsy). Furthermore, the conditioned place preference (CPP) experiments and withdrawal experiments were conducted to evaluate the rewarding effect and cannabinoid withdrawal potential of the substances in question., Results: The results demonstrated that all three drugs exhibited certain acute toxic effects and could potentially induce tetrad effects. The data were analyzed using non-linear regression, and the corresponding ED 50 values and 95% confidence intervals (CI) were obtained. The rank order of potency was determined to be CUMYL-PEGACLONE > 5F-EDMB-PICA > NM-2201. In the CPP experiments, it was demonstrated that 5F-EDMB-PICA significantly induced an increase in CPP score at a dose of 0.3 mg/kg, while NM-2201 caused an increase in CPP score and a significant aversion effect at a dose of 2 and 3 mg/kg, respectively. It is noteworthy that all three types of SCs were observed to produce a significant biphasic effect, indicating that CPP scores were biphasic for all compounds. Following the administration of the CB1 receptor antagonist rimonabant, a notable increase in head twitches and paw tremors was observed, indicating that these three SCs induce cannabinoid withdrawal through the mediation of CB1 receptors., Conclusions: The results of this study indicated that these SCs possess cannabinoid-specific pharmacological effects and abuse potential, which provides substantial experimental data to support the future regulation of these substances., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The persistent use of opioids leads to profound changes in neuroplasticity of the brain, contributing to the emergence and persistence of addiction. However, chronic opioid use disrupts the delicate balance of the reward system in the brain, leading to neuroadaptations that underlie addiction. Chronic cocaine usage leads to synchronized alterations in gene expression, causing modifications in the Nucleus Accumbens (NAc), a vital part of the reward system of the brain. These modifications assist in the development of maladaptive behaviors that resemble addiction. Neuroplasticity in the context of addiction involves changes in synaptic connectivity, neuronal morphology, and molecular signaling pathways. Drug-evoked neuroplasticity in opioid addiction and withdrawal represents a complicated interaction between environmental, genetic, and epigenetic factors. Identifying specific transcriptional and epigenetic targets that can be modulated to restore normal neuroplasticity without disrupting essential physiological processes is a critical consideration. The discussion in this article focuses on the transcriptional aspects of drug-evoked neuroplasticity, emphasizing the role of key transcription factors, including cAMP response element-binding protein (CREB), ΔFosB, NF-kB, Myocyte-enhancing factor 2 (MEF2), Methyl-CpG binding protein 2 (MeCP2), E2F3a, and FOXO3a. These factors regulate gene expression and lead to the neuroadaptive changes observed in addiction and withdrawal. Epigenetic regulation, which involves modifying gene accessibility by controlling these structures, has been identified as a critical component of addiction development. By unraveling these complex molecular processes, this study provides valuable insights that may pave the way for future therapeutic interventions targeting the mechanisms underlying addiction and withdrawal., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: People with tobacco addiction have deficits in cognition, in particular deficits in attention. It is not clear however, whether deficits are a cause or a consequence, or both, of chronic nicotine use. Here we set out a series of experiments in rats to address this question and, more specifically, to assess the effects of exposure to and withdrawal from chronic nicotine self-administration on attentional performance., Methods: Animals were trained in a 5-choice serial reaction time task to probe individual attentional performance and, then, were given access to a fixed versus increasing dose of intravenous nicotine for self-administration, a differential dose procedure known to induce two between-session patterns of nicotine intake: a stable versus escalation pattern. Attentional performance was measured daily before, during and also 24-h after chronic access to the differential dose procedure of nicotine self-administration., Conclusions: We found that pre-existing individual variation in attentional performance predicts individual vulnerability to develop escalation of nicotine intake. Moreover, while chronic nicotine self-administration increases attention, withdrawal from nicotine intake escalation induces attentional deficits, a withdrawal effect that is dose-dependently reversed by acute nicotine. Together, these results suggest that pre-existing individual variation in attentional performance predicts individual vulnerability to develop escalation of nicotine intake, and that part of the motivation for using nicotine during escalation might be to alleviate withdrawal-induced attentional deficits., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Chronic amphetamine (AMPH) use leading to addiction results in adaptive changes within the central nervous system that persist well beyond the drug's elimination from the body and can precipitate relapse. Notably, alterations in glutamatergic neurotransmission play a crucial role in drug-associated behaviours., Objectives: This study aimed to identify changes induced by amphetamine in glutamate levels and the neuromodulators of glutamatergic neurotransmission (taurine and kynurenic acid) observable after 14 and 28 days of abstinence in key brain regions implicated in addiction: the cortex (Cx), nucleus accumbens (Acb), and dorsolateral striatum (CPu-L)., Methods: The rats were administered 12 doses of amphetamine (AMPH) intraperitoneally (i.p.) at 1.5 mg/kg. The behavioural response was evaluated through ultrasonic vocalizations (USV). High-performance liquid chromatography (HPLC) was used to measure the levels of glutamate, taurine, and kynurenic acid in the Cx, Acb, and CPu-L after 14 and 28 days of abstinence., Results: AMPH administration led to sensitisation towards AMPH's rewarding effects, as evidenced by changes in USV. There was a noticeable decrease in kynurenic acid levels and an increase in both taurine and glutamate in the CPu-L, along with an increase in glutamate levels in the Cx, 28 days following the final AMPH injection., Conclusions: The most significant changes in the tissue levels of glutamate, taurine, and kynurenic acid were seen in the CPu-L 28 days after the last dose of AMPH. The emergence of these changes exclusively after 28 days suggests that the processes initiated by AMPH use and subsequent abstinence take time to become apparent and may be enduring. This could contribute to the incubation of craving and the risk of relapse. Developing pharmacological strategies to counteract the reduction in kynurenic acid induced by psychostimulants may provide new avenues for therapy development., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Epidemiological studies and clinical observations suggest that nicotine, a major contributor of the global burden of disease, acts in a partially sex specific manner. Still, preclinical research has primarily been conducted in males. More research is thus required to define the effects displayed by nicotine on the female brain. To this end, female rats received 15 injections of either nicotine (0.36mg/kg) or saline, over a 3-week period and were then followed for up to 3 months. Behavioral effects of nicotine were assessed using locomotor activity measurements and elevated plus maze, while neurophysiological changes were monitored using ex vivo electrophysiological field potential recordings conducted in subregions of the dorsal and ventral striatum. Behavioral assessments demonstrated a robust sensitization to the locomotor stimulatory properties of nicotine, but monitored behaviors on the elevated plus maze were not affected during acute (24 h) or protracted (3 months) withdrawal. Electrophysiological recordings revealed a selective increase in excitatory neurotransmission in the nucleus accumbens shell and dorsomedial striatum during acute withdrawal. Importantly, accumbal neuroadaptations in nicotine-treated rats correlated with locomotor behavior, supporting a role for the nucleus accumbens in behavioral sensitization. While no sustained neuroadaptations were observed following 3 months withdrawal, there was an overall trend towards reduced inhibitory tone. Together, these findings suggest that nicotine produces selective transformations of striatal brain circuits that may drive specific behaviors associated with nicotine exposure. Furthermore, our observations suggest that sex-specificity should be considered when evaluating long-term effects by nicotine on the brain., (© 2023. The Author(s).)

Objectives: The need for prevention and management of medication-related osteonecrosis of the jaw (MRONJ) has increased with the growing number of patients using antiresorptive agents. The scope of this systematic review (SR) was to determine whether the withdrawal of antiresorptive agents is necessary for tooth extractions in patients receiving each of the antiresorptive medications., Materials and Methods: The searches were performed using the MEDLINE databases. We selected SRs, randomized controlled trials (RCTs), prospective and retrospective non-randomized clinical (observational) studies, and case reports/case series in this order of preference., Results: We included one SR, one RCT, five observational studies, and three case reports. Meta-analyses were not conducted because the RCT had an extremely small sample size and the observational studies had different definitions of intervention and comparison that could not be integrated across studies. In this SR, no studies showed a benefit (i.e., a reduction in the incidence of osteonecrosis of the jaw) of short-term withdrawal of antiresorptive agents for tooth extraction. Additionally, no studies examined the harm (i.e., an increase in femoral and vertebral fractures and skeletal-related events during bone metastasis) of withdrawal for tooth extraction., Conclusions: We were unable to determine whether withdrawal before and after tooth extraction is necessary with a high certainty of evidence. Future systematic reviews including RCTs with larger samples are expected to provide such evidence., Clinical Relevance: This systematic review provides evidence-based information for multidisciplinary collaborations related to patients receiving antiresorptive agents., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Withdrawal from opioids involves a negative affective state that promotes maintenance of drug-seeking behavior and relapse. As such, understanding the neurobiological mechanisms underlying withdrawal from opioid drugs is critical as scientists and clinicians seek to develop new treatments and therapies. In this review, we focus on the neural systems known to mediate the affective and somatic signs and symptoms of opioid withdrawal, including the mesolimbic dopaminergic system, basolateral amygdala, extended amygdala, and brain and hormonal stress systems. Evidence from preclinical studies suggests that these systems are altered following opioid exposure and that these changes mediate behavioral signs of negative affect such as aversion and anxiety during withdrawal. Adaptations in these systems also parallel the behavioral and psychological features of opioid use disorder (OUD), highlighting the important role of withdrawal in the development of addictive behavior. Implications for relapse and treatment are discussed as well as promising avenues for future research, with the hope of promoting continued progress toward characterizing neural contributors to opioid withdrawal and compulsive opioid use., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Nicotine cessation is associated with increased consumption of highly palatable foods and body weight gain in most smokers. Concerns about body weight gain are a major barrier to maintaining long-term smoking abstinence, and current treatments for nicotine use disorder (NUD) delay, but do not prevent, body weight gain during abstinence. Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce food intake and are FDA-approved for treating obesity. However, the effects of GLP-1R agonist monotherapy on nicotine seeking and withdrawal-induced hyperphagia are unknown., Objectives: We screened the efficacy of the long-lasting GLP-1R agonist liraglutide to reduce nicotine-mediated behaviors including voluntary nicotine taking, as well as nicotine seeking and hyperphagia during withdrawal., Methods: Male and female rats self-administered intravenous nicotine (0.03 mg/kg/inf) for ~21 days. Daily liraglutide administration (25 μg/kg, i.p.) started on the last self-administration day and continued throughout the extinction and reinstatement phases of the experiment. Once nicotine taking was extinguished, the reinstatement of nicotine-seeking behavior was assessed after an acute priming injection of nicotine (0.2 mg/kg, s.c.) and re-exposure to conditioned light cues. Using a novel model of nicotine withdrawal-induced hyperphagia, intake of a high fat diet (HFD) was measured during home cage abstinence in male and female rats with a history of nicotine self-administration., Results: Liraglutide attenuated nicotine self-administration and reinstatement in male and female rats. Repeated liraglutide attenuated withdrawal-induced hyperphagia and body weight gain in male and female rats at a dose that was not associated with malaise-like effects., Conclusions: These findings support further studies investigating the translational potential of GLP-1R agonists to treat NUD., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Post-traumatic stress disorder (PTSD) and opioid use disorder (OUD) are comorbid in clinical populations. However, both pre-clinical and clinical studies of these co-occurring disorders have disproportionately represented male subjects, limiting the applicability of these findings. Our previous work has identified chronic escalating heroin administration and withdrawal can produce enhanced fear learning. This behavior is associated with an increase in dorsal hippocampal (DH) interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and glial fibrillary acidic protein (GFAP) immunoreactivity. Further, we have shown that these increases in IL-1β and TNF-α are mechanistically necessary for the development of enhanced fear learning. Although these are exciting findings, this paradigm has only been studied in males. The current studies aim to examine sex differences in the behavioral and neuroimmune effects of chronic heroin withdrawal and future enhanced fear learning. In turn, we determined that chronic escalating heroin administration can produce withdrawal in female rats comparable to male rats. Subsequently, we examined the consequence of heroin withdrawal on future enhanced fear learning and IL-1β, TNF-α, and GFAP immunoreactivity. Strikingly, we identified sex differences in these neuroimmune measures, as chronic heroin administration and withdrawal does not produce enhanced fear learning or immunoreactivity changes in females. Moreover, we determined whether heroin withdrawal produces short-term and long-term anxiety behaviors in both female and males. Collectively, these novel experiments are the first to test whether heroin withdrawal can sensitize future fear learning, produce neurobiological changes, and cause short-term and long-term anxiety behaviors in female rats., (© 2023. The Author(s).)

Rationale: Regular consumption of gamma-hydroxybutyrate (GHB) may result in a dependence syndrome that can lead to withdrawal symptoms. There are limited data on medications to manage GHB withdrawal., Objectives: To examine characteristics associated with delirium and discharge against medical advice (DAMA), in the context of implementing a GHB withdrawal management protocol at an inner-city hospital in 2020., Methods: We retrospectively reviewed records (01 January 2017-31 March 2021), and included admissions that were ≥ 18 years of age, admitted for GHB withdrawal, and with documented recent GHB use. Admissions were assessed for demographics, medications administered, features of delirium, ICU admission, and DAMA. Exploratory analyses were conducted to examine factors associated (p < 0.2) with features of delirium and DAMA., Results: We identified 135 admissions amongst 91 patients. Medications administered included diazepam (133 admissions, 98.5%), antipsychotics (olanzapine [70 admissions, 51.9%]), baclofen (114 admissions, 84%), and phenobarbital (8 admissions, 5.9%). Features of delirium were diagnosed in 21 (16%) admissions. Delirium was associated with higher daily GHB consumption prior to admission, while duration of GHB use, time from presentation to first dose of diazepam, and concomitant methamphetamine use were inversely associated with delirium. DAMA occurred amongst 41 (30%) admissions, and was associated with a longer time from presentation to first dose of baclofen, while being female and receiving a loading dose of diazepam were inversely associated., Conclusions: This study adds to the literature in support of the safety and feasibility of diazepam and baclofen for the management of GHB withdrawal. Prospective, randomised trials are required., (© 2022. The Author(s).)

Rationale: Chronic intermittent ethanol (CIE) vapor inhalation is a widely used model of alcohol dependence, but the impact of CIE on cue-elicited alcohol seeking is poorly understood., Objective: Here, we assessed the effects of CIE on alcohol-seeking elicited by cues paired with alcohol before or after CIE vapor inhalation., Methods: In experiment 1, male and female Long-Evans rats were trained in a discriminative stimulus (DS) task, in which one auditory cue (the DS) predicts the availability of 15% ethanol and a control cue (the NS) predicts no ethanol. Rats then underwent CIE or served as controls. Subsets of each group received access to oral ethanol twice a week during acute withdrawal. After CIE, rats were presented with the DS and NS cues under extinction and retraining conditions to determine whether they would alter their responses to these cues. In experiment 2, rats underwent CIE prior to training in the DS task., Results: CIE enhanced behavioral responses to cues previously paired with alcohol, but only in rats that received access to alcohol during acute withdrawal. When CIE occurred before task training, male rats were slower to develop cue responses and less likely to enter the alcohol port, even though they had received alcohol during acute withdrawal., Conclusions: These results suggest that CIE vapor inhalation alone does not potentiate the motivational value of alcohol cues but that an increase in cue responses requires alcohol experience during acute withdrawal. Furthermore, under some conditions, CIE may disrupt responses to alcohol-paired cues., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Synthetic opioids like fentanyl are contributing to the rise in rates of opioid use disorder and drug overdose deaths. Sleep dysfunction and circadian rhythm disruption may worsen during opioid withdrawal and persist during abstinence. Severe and persistent sleep and circadian alterations are putative factors in opioid craving and relapse. However, very little is known about the impact of fentanyl on sleep architecture and sleep-wake cycles, particularly opioid withdrawal. Further, circadian rhythms regulate sleep-wake cycles, and the circadian transcription factor, neuronal PAS domain 2 (NPAS2) is involved in the modulation of sleep architecture and drug reward. Here, we investigate the role of NPAS2 in fentanyl-induced sleep alterations., Objectives: To determine the effect of fentanyl administration and withdrawal on sleep architecture, and the role of NPAS2 as a factor in fentanyl-induced sleep changes., Methods: Electroencephalography (EEG) and electromyography (EMG) was used to measure non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS) at baseline and following acute and chronic fentanyl administration in wild-type and NPAS2-deficient male mice., Results: Acute and chronic administration of fentanyl led to increased wake and arousal in both wild-type and NPAS2-deficient mice, an effect that was more pronounced in NPAS2-deficient mice. Chronic fentanyl administration led to decreased NREMS, which persisted during withdrawal, progressively decreasing from day 1 to 4 of withdrawal. The impact of fentanyl on NREMS and arousal was more pronounced in NPAS2-deficient mice., Conclusions: Chronic fentanyl disrupts NREMS, leading to a progressive loss of NREMS during subsequent days of withdrawal. Loss of NPAS2 exacerbates the impact of fentanyl on sleep and wake, revealing a potential role for the circadian transcription factor in opioid-induced sleep changes., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The trajectory of the use of dopamine replacement therapy (DRT) in Parkinson's disease (PD) is variable and doses may need to be increased, but also tapered. The plan for dose adjustment is usually done as per drug information recommendations from the licensing bodies, but there are no clear guidelines with regards to the best practice regarding the tapering off schedule given sudden dose reductions of drugs such as dopamine agonists may have serious adverse consequences. A systematic literature search was, therefore, performed to derive recommendations and the data show that there are no controlled studies or evidence-based recommendations how to taper or discontinue PD medication in a systematic manner. Most of the data were available on the dopamine agonist withdrawal syndrome (DAWS) and we found only two instructions on how to reduce pramipexole and rotigotine published by the EMA. We suggest that based on the available data, levodopa, dopamine agonists (DA), and amantadine should not be discontinued abruptly. Abrupt or sudden reduction of DA or amantadine in particular can lead to severe life-threatening withdrawal symptoms. Tapering off levodopa, COMT inhibitors, and MAO-B inhibitors may worsen motor and non-motor symptoms. Based on our clinical experience, we have proposed how to reduce PD medication and this work will form the basis of a future Delphi panel to define the recommendations in a consensus., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Synthetic cannabinoid receptor agonists (SCRAs) may be used as an alternative to natural cannabis; however, they may carry a greater risk of problematic use and withdrawal. This study aimed to characterise the withdrawal symptom profile of SCRAs and compare their profile of effect with high-potency herbal cannabis. Global Drug Survey data (2015 and 2016) were used to access a clinically relevant sample of people reporting use of SCRAs >10 times in the past 12-months, a previous SCRA quit attempt, and lifetime use of high-potency herbal cannabis. Participants completed an 11-item SCRA withdrawal symptom checklist and compared SCRAs and high-potency herbal cannabis on their onset and duration of effects, speed of the development of tolerance, severity of withdrawal, and difficulty with dose titration. Participants (n = 284) reported experiencing a mean of 4.4 (95% CI: 4.1, 4.8) withdrawal symptoms after not using SCRAs for >1 day; most frequently reported were sleep issues (59.2%), irritability (55.6%), and low mood (54.2%). Withdrawal symptoms were significantly associated with frequency (>51 vs. 11-50 times per year: IRR = 1.43, 95% CI: 1.16, 1.77, p = 0.005) and quantity (grams per session: IRR = 1.13, 95% CI: 1.05, 1.22, p = 0.001) of SCRA use. Compared to high-potency herbal cannabis, SCRAs were rated as having a faster onset and shorter duration of effects, faster development of tolerance, and more severe withdrawal (p's < 0.001). In conclusion, SCRA withdrawal symptoms are more likely to occur after greater SCRA exposure. The effects of SCRA indicate a more severe withdrawal syndrome and a greater risk of problematic use than natural cannabis., (© 2021. The Author(s).)

Objective: Stimulant use instigates abstinence syndrome in humans. miRNAs are a critical component for the pathophysiology of stimulant abstinence. Here we sought to identify a miRNA marker of methamphetamine abstinence in the circulating extracellular vesicles (cEVs)., Methods: miR-137 in the cEVs was quantified by qPCR in thirty-seven patients under methamphetamine abstinence and thirty-five age-matched healthy controls recruited from 2014 to 2016 from the general adult population in a hospital setting, Seoul, South Korea. Diagnostic power was evaluated by area under curve in the receiver-operating characteristics curve and other multiple statistical parameters., Results: Patients under methamphetamine abstinence exhibited a significant reduction in cEV miR-137. Overall, cEV miR-137 had high potential as a blood-based marker of methamphetamine abstinence. cEV miR-137 retained the diagnostic power irrespective of the duration of methamphetamine abstinence or methamphetamine use. Interestingly, cEV miR-137 interacted with age: Control participants displayed an aging-dependent reduction of cEV miR-137, while methamphetamine-abstinent patients showed an aging-dependent increase in cEV miR-137. Accordingly, cEV miR-137 had variable diagnostic power depending on age, in which cEV miR-137 more effectively discriminated methamphetamine abstinence in the younger population. Duration of methamphetamine use or abstinence, cigarette smoking status, depressive disorder, or antidepressant treatment did not interact with the methamphetamine abstinence-induced reduction of cEV miR-137., Conclusion: Our data collectively demonstrated that miR-137 in the circulating extracellular vesicles held high potential as a stable and accurate diagnostic marker of methamphetamine abstinence syndrome., (© 2022. The Author(s).)

Introduction: Caffeine is frequently consumed to boost goal-directed attention. These procognitive effects may occur due to the adenosine-mediated enhancement of monoamines, such as dopamine, after caffeine administration. As such, caffeine's beneficial effects may be altered in conditions such as Parkinson's disease (PD). However, whether caffeine improves cognition, and at what cost, has not been experimentally established in patients with neurodegenerative disease., Methods: Single-dose trials to probe cognitive effects of caffeine are often confounded by short-term caffeine abstinence which conflates caffeine's effects with treatment of withdrawal. Using a placebo controlled, blinded, randomised trial design, we assessed the effect of 100 mg of caffeine across well-established tasks (Choice reaction time, Stroop Task and Rapid Serial Visual Presentation Task; RSVP) that probe different aspects of attention in PD patients (n = 24) and controls (n = 44). Critically, participants withdrew from caffeine for a week prior to testing to eliminate the possibility that withdrawal reversal explained any cognitive benefit., Results: Caffeine administration was found to reduce the overall number of errors in patients and controls on the Stroop (p = .018, η 2 p  = .086) and Choice reaction time (p < . 0001, η 2 p  = .588) tasks, but there was no specific effect of caffeine on ignoring irrelevant information in the Stroop task. On the RSVP task, caffeine improved dual item accuracy (p = .037) but impaired single item accuracy (p = .044). Across all tasks, there was little evidence that caffeine has different effects in PD participants and controls., Conclusion: When removing withdrawal effects as a factor, we demonstrate caffeine has beneficial effects on selective attention but is a double-edge sword for visual temporal attention and would need careful targeting to be clinically useful., (© 2022. Crown.)

Rationale: Kratom (Mitragyna speciosa Korth), a native medicinal plant of Southeast Asia, is proposed to exhibit potential therapeutic value as an opioid substitute. However, studies of its negative emotional states resulting from withdrawal particularly of its main psychoactive compound, mitragynine (MG), are limited., Objectives: Using the pentylenetetrazol (PTZ) discrimination assay, this study aims to investigate the effects of MG in responding to the PTZ stimulus and to assess the generalisation effects of withdrawal from MG to the PTZ stimulus., Methods: Rats (n = 20) were trained on a tandem (FR-10, VI-15) schedule of food reinforcement to press one lever after administration of the anxiogenic compound PTZ (16 mg/kg, i.p.) and an alternate lever after vehicle. Following acute tests, training was suspended, and rats were chronically treated with MG or morphine at 8-h intervals for 9 days and withdrawal was precipitated on the tenth day using naloxone (1 mg/kg, i.p.). The rats were tested for generalisation to PTZ at 2, 8 and 24 h after the last dose of MG or morphine administration., Results: Unlike morphine that produced dose-related PTZ-like stimulus, MG at 3, 10, 30 and 45 mg/kg doses showed no substitution to the PTZ discriminative stimulus. In contrast to morphine which produced a time-dependent generalisation to the PTZ stimulus, naloxone did not precipitate withdrawal effects in MG-treated rats as they selected the vehicle lever at three withdrawal time points., Conclusion: These results demonstrate that MG produces a very different response to morphine withdrawal that is not associated with anxiogenic-like subjective symptoms. These characteristics of MG may provide further support for use as a novel pharmacotherapeutic intervention for managing opioid use disorder., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Cannabidiol (CBD) reduces craving in animal models of alcohol and cocaine use and is known to modulate nicotinic receptor function, suggesting that it may alleviate symptoms of nicotine withdrawal. However, preclinical evaluation of its efficacy is still lacking., Objectives: The goal of this study was to test the preclinical efficacy of a chronic CBD treatment in reducing nicotine dependence using measures of withdrawal symptoms including somatic signs, hyperalgesia, and weight gain during acute and protracted abstinence., Methods: Male and female Wistar rats were made dependent on nicotine using osmotic minipumps (3.15 mg/kg/day) for 2 weeks, after which minipumps were removed to induce spontaneous withdrawal. Three groups received CBD injections at doses of 7.5, 15, and 30 mg/kg/day for 2 weeks, starting 1 week into chronic nicotine infusion. The control groups included rats with nicotine minipumps that received vehicle injections of sesame oil instead of CBD; rats implanted with saline minipumps received sesame oil injections (double vehicle) or the highest dose of CBD 30 mg/kg/day. Throughout the experiment, serum was collected for determination of CBD and nicotine concentrations, mechanical sensitivity threshold and withdrawal scores were measured, and body weight was recorded., Results: CBD prevented rats from exhibiting somatic signs of withdrawal and hyperalgesia during acute and protracted abstinence. There was no dose-response observed for CBD, suggesting a ceiling effect at the doses used and the potential for lower effective doses of CBD. The saline minipump group did not show either somatic signs of withdrawal or hyperalgesia during acute and protracted abstinence, and the highest dose of CBD used (30 mg/kg/day) did not alter these results., Conclusions: This preclinical study suggests that using CBD as a strategy to alleviate the withdrawal symptoms upon nicotine cessation may be beneficial., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: The emergence of the consumption of highly potent synthetic cannabinoid receptor agonists (spice drugs) that produce important neurological symptoms has prompted the research on the consequences of acute and chronic use of these new psychoactive substances. Most studies on cannabinoid dependence have been performed in male animals, and there is a need of studies using female subjects., Objectives: In the present study, we evaluated only in female animals the role of dopamine D1 receptors in the behavioral responses induced by acute and repeated stimulation of cannabinoid CB1 receptors, including the development of physical dependence, since cannabinoid CB1 receptors are co-localized with dopamine D1 receptors on GABAergic neurons projecting to the substantia nigra., Methods: To this end, female dopamine D1 receptor-deficient mice and wild-type littermates were treated with HU-210, a potent synthetic cannabinoid agonist., Results: Mutant mice displayed an enhanced response to acute motor and hypothermic effects to HU-210 when compared with wild-type females. The administration of SR141716A precipitated behavioral signs of withdrawal in mice treated subchronically with HU-210. Severity of cannabinoid withdrawal syndrome was potentiated in dopamine D1-deficient female mice. Indeed, 4 of 6 abstinence signs were increased in mutant mice., Conclusions: These results support for a role of dopamine D1 receptors in the acute, chronic, and withdrawal actions of spice drugs.

Rationale: Methamphetamine is a highly abused psychostimulant drug and its use remains a major public health concern worldwide with limited effective treatment options. Accumulative evidence reveals the influence of gut microbiota on the brain, behavior, and health as a part of the gut-brain axis but its involvement in modulating this substance use disorder remains poorly understood., Objective: We sought to determine whether methamphetamine exposure and cessation or withdrawal alter the intestinal gut microbiota as well as characterize cessation-induced behavioral changes., Methods: Male, Sprague-Dawley rats were administered methamphetamine (2 mg/kg; s.c.) or vehicle (n = 8 per group) twice per day for 14 consecutive days. On various days before, during, and after administration, fecal samples were collected and tests of anxiety- and depressive-like behaviors were conducted., Results: Methamphetamine administration and cessation did not alter the relative abundance of bacteria but significantly changed the composition of gut bacteria through 16S rRNA sequencing. These changes were normalized after 7 days of methamphetamine cessation. Moreover, acute methamphetamine cessation induced depressive-like behavior, with an increase in immobility in the forced swim test but did not alter anxiety-like behaviors in tests of open field test or elevated plus maze., Conclusions: These findings provide direct evidence that methamphetamine and its cessation cause gut dysbiosis and that the latter associates with depressive-like behavior in rodents. Our observation will contribute to a better understanding of the function of gut microbiota in the process of substance use disorders and guide the choice of target therapeutics.

Converging evidence suggests opioid abuse can increase the incidence and severity of post-traumatic stress disorder (PTSD) in clinical populations. Interestingly, opioid withdrawal alone can produce symptoms similar to those of PTSD. Despite this association, the neural mechanisms underlying the relationship of opioid abuse, withdrawal, and PTSD is poorly understood. Our laboratory has investigated the neurobiological underpinnings of stress-enhanced fear learning (SEFL), an animal model of PTSD-like symptoms. We have previously shown that, in SEFL, a severe footshock induces an increase in dorsal hippocampal (DH) interleukin-1β (IL-1β), and subsequent fear learning is blocked by DH IL-1 receptor antagonism (IL-1RA). Given that opioids and stress engage similar neuroimmune mechanisms, the present experiments investigate whether the same mechanisms drive heroin withdrawal to induce a PTSD-like phenotype. First, we tested the effect of a chronic escalating heroin dose and withdrawal regimen on fear learning and found it produces enhanced future fear learning. Heroin withdrawal also induces a time-dependent, region-specific increase in IL-1β and glial fibrillary acidic protein (GFAP) immunoreactivity within the dentate gyrus of the DH. IL-1β was significantly colocalized with GFAP, indicating astrocytes may be involved in increased IL-1β. Moreover, intra-DH infusions of IL-1RA 0, 24, and 48 h into heroin withdrawal prevents the development of enhanced fear learning but does not alter withdrawal-induced weight loss. Collectively, our data suggests heroin withdrawal is sufficient to produce enhanced fear learning, astrocytes may play a role in heroin withdrawal-induced IL-1β, and DH IL-1 signaling during withdrawal mediates the development of heroin withdrawal-enhanced fear learning.

Rationale: Understanding factors contributing to individual differences in vulnerability to opioid addiction is essential for developing more effective preventions and treatments, yet few reliable behavioral predictors of subsequent opioid self-administration have been identified in rodents. Sensitivity to the acute effects of initial drug exposure predicts later addiction vulnerability in both humans and animals, but the relationship between sensitivity to withdrawal from initial drug exposure and later drug use vulnerability is unclear., Objective: The goal of the current study was to evaluate whether the degree of anhedonia experienced during withdrawal from early opioid exposure predicts subsequent vulnerability to opioid self-administration., Methods: Rats were first tested for withdrawal sensitivity following acute injections of morphine (i.e., "acute dependence"), measured as elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior) during naloxone-precipitated and spontaneous withdrawal. Rats were then tested for addiction-like behavior using various measures of i.v. morphine self-administration (MSA) including acquisition, demand, extinction, and reinstatement induced by morphine, stress, and/or drug-associated cues., Results: Greater naloxone-precipitated withdrawal across repeated morphine injections and greater peak spontaneous withdrawal severity following a single morphine injection were associated with lower addiction-like behavior on multiple MSA measures. Withdrawal-induced anhedonia predicted a wider range of MSA measures than did any individual measure of MSA itself., Conclusions: Our data establish WIA as one of the first behavioral measures to predict individual differences in opioid SA in rodents. This model promises to be useful for furthering our understanding of behavioral and neurobiological mechanisms underlying vulnerability to opioid addiction.

Rationale: With repeated administration, the psychomotor activating effects of drugs such as cocaine or amphetamine can change in very different ways-showing sensitization or tolerance-depending on whether they are administered more or less intermittently. This behavioral plasticity is thought to reflect, at least in part, changes in dopamine (DA) neurotransmission, and therefore, may provide insights into the development of substance use disorders. Indeed, the most widely used preclinical model of cocaine addiction, which involves Long Access (LgA) self-administration procedures, is reported to produce tolerance to cocaine's psychomotor activating effects and effects on DA activity. In contrast, Intermittent Access (IntA) cocaine self-administration is more effective than LgA in producing addiction-like behavior, but sensitizes DA neurotransmission. There is, however, very little information concerning the effects of IntA experience on the psychomotor activating effects of cocaine., Objective: The objective of this study was to determine whether IntA experience produces psychomotor sensitization with similar characteristics to that produced by the intermittent, noncontingent administration of cocaine., Results: IntA to cocaine did indeed produce psychomotor sensitization that (1) was greater after a long (30 days) vs. short (1 day) period of withdrawal, (2) was greater in females than males, and (3) resulted in cross-sensitization to another psychomotor stimulant drug, amphetamine., Conclusion: The tolerance sometimes associated with LgA cocaine self-administration has been cited in support of the idea that, in addiction, drug-seeking and drug-taking is motivated to overcome a DA deficiency and associated anhedonia. In contrast, the neurobehavioral sensitization associated with IntA cocaine self-administration favors an incentive-sensitization view.

Rationale: Non-contingent chronic nicotine exposure procedures have evolved rapidly in recent years, culminating in electronic nicotine delivery systems (ENDS or e-cigarettes) to deliver vaporized drugs to rodents in standard housing chambers., Objectives: The aim of the current work was to use ENDS to test concentration-dependent effects of nicotine e-cigarette vapor inhalation on blood-nicotine concentrations, blood-cotinine concentrations, and somatic withdrawal signs over time in rats., Methods: Male Wistar rats were exposed to vapor containing various concentrations of nicotine (20, 40, 80 mg/mL) for 11 days through ENDS, and blood concentrations of nicotine and cotinine, the major proximate metabolite of nicotine, as well as spontaneous and precipitated somatic withdrawal signs, were measured over time (across days of exposure and over hours after termination of vapor exposure)., Results: Exposing male Wistar rats to non-contingent nicotine vapor inhalation through ENDS produces somatic withdrawal symptoms and measurable blood-nicotine and blood-cotinine levels that change according to (1) concentration of nicotine in vape solution, (2) number of days of nicotine vapor exposure, (3) time since termination of nicotine vapor exposure, and (4) relative to the withdrawal signs, whether withdrawal was spontaneous or precipitated (by mecamylamine)., Conclusions: The data presented here provide parameters that can be used as a reasonable starting point for future work that employs ENDS to deliver non-contingent nicotine vapor in rats, although many parameters can and should be altered to match the specific goals of future work.

Rationale: Kratom is proposed to exhibit therapeutic potential as an opium substitute, but little is known about its dependence-producing profile, particularly of its main psychoactive compound, mitragynine (MG)., Objectives: This study examined the dependence-producing effects of MG using operant-scheduled behaviour in rats and investigated the potential therapeutic effect of MG by comparing effects to buprenorphine in morphine-dependent rats using the same schedule-controlled behavioural task., Methods: The effects of acutely administered MG and morphine were determined in rats trained to respond under fixed-ratio (FR) 10 schedule of food reinforcement. Next, the rats were administered MG and morphine twice daily for 14 consecutive days to determine if physiological dependence would develop by examining cessation of drug treatment and following antagonist-precipitated withdrawal. The study then examined the effects of MG substitution to suppress naloxone-precipitated morphine withdrawal effects on scheduled responding., Results: Acute doses of MG did not produce dose-related decreases on FR schedules of responding compared to morphine. Unlike morphine, MG-treated rats showed no suppression of response rates following cessation of MG treatment. However, withdrawal effects were evident for MG after precipitation by either naloxone or SR141716A (rimonabant), similar to morphine-treated rats. MG in higher doses (10 and 30 mg/kg) attenuated the naloxone-precipitated morphine withdrawal effects while smaller doses of buprenorphine (0.3 and 1.0 mg/kg) were necessary to alleviate these effects., Conclusion: The findings suggest that MG does not induce physiological dependence but can alleviate the physical symptoms associated with morphine withdrawal which represent the desired characteristics of novel pharmacotherapeutic interventions for managing opioid use disorder (OUD).