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Dr. Pickens was remarkably productive during this time with more than 32 basic research papers on drug self-administration as well as 29 reviews and book chapters. In possibly the most influential of these papers, Pickens and Thompson ([6]) systematically studied the effects of cocaine dose and schedule of reinforcement on cocaine self-administration. Graph Roy W. Pickens died peacefully on May 25, 2022, at his home in Glen Allen, Virginia, where he and his wife Dace Svikis have lived since 1999. [Extracted from the article]

Background: In this paper, we reviewed translational studies concerned with environmental influences on the rewarding effects of heroin versus cocaine in rats and humans with substance use disorder. These studies show that both experienced utility ('liking') and decision utility ('wanting') of heroin and cocaine shift in opposite directions as a function of the setting in which these drugs were used. Briefly, rats and humans prefer using heroin at home but cocaine outside the home. These findings appear to challenge prevailing theories of drug reward, which focus on the notion of shared substrate of action for drug of abuse, and in particular on their shared ability to facilitate dopaminergic transmission. Aims: Thus, in the second part of the paper, we verified whether our findings could be accounted for by available computational models of reward. To account for our findings, a model must include a component that could mediate the substance-specific influence of setting on drug reward Results: It appears of the extant models that none is fully compatible with the results of our studies. Conclusions: We hope that this paper will serve as stimulus to design computational models more attuned to the complex mechanisms responsible for the rewarding effects of drugs in real-world contexts. [ABSTRACT FROM AUTHOR]

Rationale: Knowing how stress manifests in the lives of people with substance-use disorders could help inform mobile 'just in time' treatment. Objectives: The purpose of this paper is to examine discrete episodes of stress, as distinct from the fluctuations in background stress assessed in most EMA studies. Methods: For up to 16 weeks, outpatients on opioid-agonist treatment carried smartphones on which they initiated an entry whenever they experienced a stressful event (SE) and when randomly prompted (RP) three times daily. Participants reported the severity of stress and craving and the context of the report (location, activities, companions). Decomposition of covariance was used to separate within-person from between-person effects; r sizes below are within-person. Results: Participants (158 of 182; 87%) made 1787 stress-event entries. Craving for opioids increased with stress severity ( r = 0.50). Stress events tended to occur in social company (with acquaintances, 0.63, friends, 0.17, or on the phone, 0.41) rather than with family (spouse, −0.14; child, −0.18), and in places with more overall activity (bars, 0.32; outside, 0.28; walking, 0.28) and more likelihood of unexpected experiences (with strangers, 0.17). Being on the internet was slightly protective (−0.22). Our prior finding that being at the workplace protects against background stress in our participants was partly supported in these stressful-event data. Conclusions: The contexts of specific stressful events differ from those we have seen in prior studies of ongoing background stress. However, both are associated with drug craving. [ABSTRACT FROM AUTHOR]

Objective: This paper provides an overview of the role of type 2 metabotropic glutamate receptors (mGluR2) in addiction and behaviors reflecting addictive processes. Results: AZD8529, an mGluR2 positive allosteric modulator (PAM), failed to separate from placebo in a phase II schizophrenia trial. The demonstration by Athina Markou's laboratory that AZD8529 attenuated both nicotine self-administration and cue-induced reinstatement was a key factor in the decision to move this compound into a smoking cessation study. Conclusion: Here, we highlight Markou laboratory's contribution to this project, as well as several innovative features of the phase II clinical trial that has already completed enrollment with top line results expected in early 2017. [ABSTRACT FROM AUTHOR]

Rationale: Given that many patients being treated for opioid-use disorder continue to use drugs, identifying clusters of patients who share similar patterns of use might provide insight into the disorder, the processes that affect it, and ways that treatment can be personalized. Objectives and methods: We applied hierarchical clustering to identify patterns of opioid and cocaine use in 309 participants being treated with methadone or buprenorphine (in a buprenorphine–naloxone formulation) for up to 16 weeks. A smartphone app was used to assess stress and craving at three random times per day over the course of the study. Results: Five basic patterns of use were identified: frequent opioid use, frequent cocaine use, frequent dual use (opioids and cocaine), sporadic use, and infrequent use. These patterns were differentially associated with medication (methadone vs. buprenorphine), race, age, drug-use history, drug-related problems prior to the study, stress-coping strategies, specific triggers of use events, and levels of cue exposure, craving, and negative mood. Craving tended to increase before use in all except those who used sporadically. Craving was sharply higher during the 90 min following moderate-to-severe stress in those with frequent use, but only moderately higher in those with infrequent or sporadic use. Conclusions: People who share similar patterns of drug-use during treatment also tend to share similarities with respect to psychological processes that surround instances of use, such as stress-induced craving. Cluster analysis combined with smartphone-based experience sampling provides an effective strategy for studying how drug use is related to personal and environmental factors. [ABSTRACT FROM AUTHOR]

Rationale: The mesolimbic dopamine (DA) system is considered a principal site for nicotine-cocaine interactions., Objectives and Methods: The aim of this paper is to study the effects of local perfusions (through the microdialysis cannula) of nicotinic acetylcholine receptor (nAChR) antagonists in the ventral tegmental area (VTA, where mesolimbic DA cell bodies are located) or nucleus accumbens (nAc, where mesolimbic DA nerve terminals project) on cocaine-elicited increase in DA levels in the nAc of mice using intracerebral microdialysis., Results: Intra-nAc perfusion of mecamylamine (a nonselective central nicotinic antagonist) or coperfusion of methyllycaconitine (MLA, 10 nM) and dihydro-beta-erythroidine (DHbetaE, 10-100 muM) decreased cocaine-elicited increase in DA perfusate levels. In contrast, intra-nAc perfusion of MLA alone (a relatively selective antagonist of alpha7 subunit-containing nAChRs) increased, while DHbetaE (a relatively selective antagonist of heteromeric nAChR subtypes) did not alter, cocaine-elicited increase in DA perfusate levels. Intra-VTA perfusion of MLA (100 nM) or DHbetaE (100 micro M) significantly increased the cocaine-elicited increase of DA levels in the nAc or VTA, whereas DHbetaE and MLA coperfusion or mecamylamine perfusion had no significant effect., Conclusions: These results show that intra-nAc and intra-VTA perfusion of nAChR antagonists differentially affect cocaine-elicited increase in DA levels in a region and subtype-specific manner. This suggests that multiple cholinergic/nicotinic pathways influence the effects of cocaine on mesolimbic DA neurons in complex, and sometimes opposing, patterns.

Relapse to drug use in humans can be induced by exposure to drug-associated cues. The ability of drug cues to provoke ‘relapse’ has been studied in laboratory animals using a reinstatement model in which resumption of drug seeking is assessed after extinction of drug-reinforced responding. In this model, there are no adverse consequences of drug-seeking behavior. However, in humans, abstinence is often self-imposed, and relapse episodes likely involve making a choice between the desire for the drug and the negative consequences of pursuing it (a conflict situation). In this paper, we describe a conflict model of cue-induced relapse in rats that approximate the human condition. Rats were trained to lever press for cocaine; infusions were paired with a discrete light cue. An ‘electric barrier’ was then introduced by electrifying the floor area near the levers. Responding decreased over days with increasing shock intensities, until the rats did not approach the levers for 3 days. Subsequently, the effect of intermittent noncontingent light-cue presentations on resumption of lever responding (relapse) was assessed in extinction tests, with the electric barrier remaining activated; during testing, lever presses led to contingent light-cue presentations. Noncontingent cue exposure led to resumption of lever presses during the relapse tests in 14 of the 24 rats. Surprisingly, 24 h later, 11 of the 24 rats resumed lever responding in a subsequent post -noncontingent cue test under similar extinction conditions. Large individual differences in responding were observed during both tests. At its current stage of development, the conflict relapse model appears particularly suitable for studying individual differences in cue-induced relapse to cocaine seeking or factors that promote this relapse. [ABSTRACT FROM AUTHOR]

Abstract Rationale: Repeated exposure to stimulant drugs, such as the indirect dopaminergic agonists amphetamine or cocaine, results in increased sensitivity to their effects on behavior and dopaminergic function. Neuroadaptations initiated in the ventral tegmental area (VTA), a cell body region of midbrain dopaminergic neurons, and dependent on glutamatergic transmission, underlie the development of this persistent drug-induced sensitization. How precisely drug actions in the VTA initiate long-lasting changes in dopaminergic function, and how glutamate participates in these events is not clear. Objective: To discuss the idea that neurotrophic, neuroprotective factors are involved. Results: We review the few studies that have been concerned with a role for neurotrophic factors in the changing response to stimulant drugs and present a summary of those conducted in our laboratory on basic fibroblast growth factor (bFGF), a neurotrophic factor produced by astrocytes. Conclusion: We argue that repeated exposure to stimulant drugs increases the demands on dopaminergic cell functioning, and, by stimulating glutamate release, recruits neurotrophic and neuroprotective substances such as bFGF. We propose that the actions of these factors, in turn, give rise to long-lasting neuronal adaptations that underlie sensitized responding to further drug exposure. Possible mechanisms whereby bFGF participates in the development of sensitization, including interactions with other neurotrophic factors, are discussed. In addition, we show how the evidence reviewed in this paper provides further support for the idea that repeated treatment with stimulant drugs induces synaptic plasticity. [ABSTRACT FROM AUTHOR]

Background: Individuals with schizophrenia have high rates of comorbid substance use problems. One potential explanation for this comorbidity is similar neuropathophysiology in substance use and schizophrenia, which may arise from shared genetic risk factors between the two disorders. Here we investigated if genetic risk for schizophrenia could affect drug reward and reinforcement for cocaine in an established mouse model of genetic risk for schizophrenia, the neuregulin 1 transmembrane domain heterozygous (Nrg1 TM HET) mouse. Methods: We examined drug-induced locomotor sensitization and conditioned place preference for several cocaine doses (5, 10, 20, 30 mg/kg) in male adult Nrg1 TM HET and wild-type-like (WT) littermates. We also investigated intravenous self-administration of and motivation for cocaine (doses 0.1, 0.5, 1 mg/kg/infusion), as well as extinction and cue-induced reinstatement of cocaine. In a follow-up experiment, we examined self-administration, extinction and cue-induced reinstatement of a natural reward, oral sucrose. Results: Cocaine preference was similar between Nrg1 TM HET mice and WT littermates at all doses tested. Locomotor sensitization to cocaine was not affected by Nrg1 genotype at any dose. Although self-administration and motivation for cocaine was unaffected, extinction of cocaine self-administration was impaired in Nrg1 TM HET compared to WT controls, and cue-induced reinstatement was greater in Nrg1 mutants in the middle of the reinstatement session. Sucrose self-administration and extinction thereof was not affected by genotype, but inactive lever responding was elevated during cue-induced reinstatement for operant sucrose in Nrg1 TM HET mice compared to WTs. Discussion: These results suggest impaired response inhibition for cocaine in Nrg1 TM HET mice and suggests Nrg1 mutation may contribute to behaviours which can limit control over cocaine use. [ABSTRACT FROM AUTHOR]

Abstract This paper attempts to summarize the evidence for the hypothesis that psychostimulant-like neurotransmitter processes within certain regions of the limbic system induce the positive effects of antidepressant sleep deprivation (SD). Preclinical and human studies indicate similar neurobiological effects of psychostimulants such as amphetamines, cocaine and SD. In clinical use, SD and psychostimulants have similar characteristics and behavioral effects. Furthermore, acute psychostimulant challenge decreases limbic metabolism in imaging studies, and SD decreases elevated limbic metabolism in SD responders, indicating that psychostimulant-like neurotransmitter release could decrease limbic metabolism in SD responders. Most antidepressant pharmacotherapies change the reactivity of the dopamine system, and a decrease of presynaptic dopamine or postsynaptic availability can induce depression. Sleep is accompanied by a reduction of catecholamine release and those processes which are increased by psychostimulants. It is concluded that a proposed regional postsynaptic deficit in catecholaminergic neurotransmission can be overcome either acutely by enhanced release during SD or psychostimulant use, or chronically by changes in receptor sensitivity or gene expression due to antidepressant therapies. A postsynaptic deficit in these areas becomes evident if presynaptic release is reduced in conditions such as sleep. Therefore, sleep is depressiogenic for predisposed individuals and the reduction of sleep avoids understimulation of subsensitive postsynaptic processes, which are enhanced by psychostimulants. [ABSTRACT FROM AUTHOR]

The original article can be found online at https://doi.org/10.1007/s00213-021-06033-0. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. [Extracted from the article]

Rationale: Compared to obesity-resistant rats, obesity-prone rats consume more food, work harder to obtain food, show greater motivational responses to food-cues, and show greater striatal plasticity in response to eating sugary/fatty foods. Therefore, it is possible that obesity-prone rats may also be more sensitive to the motivational properties of cocaine and cocaine-paired cues, and to plasticity induced by cocaine. Objective: To examine baseline differences in motivation for cocaine and effects of intermittent access (IntA) cocaine self-administration on cocaine motivation, neurobehavioral responsivity to cocaine-paired cues, and locomotor sensitization in male obesity-prone vs obesity-resistant rats. Methods: Intravenous cocaine self-administration was used to examine drug-taking and drug-seeking in males. Motivation for cocaine was measured using a within session threshold procedure. Cue-induced c-Fos expression in mesocorticolimbic regions was measured. Results: Drug-taking and drug-seeking, cue-induced c-Fos, locomotor sensitization, and preferred level of cocaine consumption (Q0) were similar between obesity-prone and obesity-resistant groups. Maximal responding during demand testing (Rmax) was lower in obesity-prone rats. IntA experience enhanced motivation for cocaine (Pmax) in obesity-prone rats. Conclusions: The results do not support robust inherent differences in motivation for cocaine, cue-induced cocaine seeking, or neurobehavioral plasticity induced by IntA in obesity-prone vs obesity-resistant rats. This contrasts with previously established differences seen for food and food cues in these populations and shows that inherent enhancements in motivation for food and food-paired cues do not necessarily transfer to drugs and drug-paired cues. [ABSTRACT FROM AUTHOR]

Rationale: Cocaine use disorder (CUD) is a highly heritable form of substance use disorder, with genetic variation accounting for a substantial proportion of the risk for transitioning from recreational use to a clinically impairing addiction. With repeated exposures to cocaine, psychomotor and incentive sensitization are observed in rodents. These phenomena are thought to model behavioral changes elicited by the drug that contribute to the progression into addiction, but little is known about how genetic variation may moderate these consequences. Objectives: Here, we describe the use of two Collaborative Cross (CC) recombinant inbred mouse strains that either exhibit high (CC018/UncJ) or no (CC027/GeniUncJ) psychomotor sensitization in response to cocaine to measure phenotypes related to incentive sensitization after repeated cocaine exposures; given the relationship of incentive motivation to nucleus accumbens core (NAc) dopamine release and reuptake, we also assessed these neurochemical mechanisms. Methods: Adult male and female CC018/UncJ and CC027/GeniUncJ mice underwent Pavlovian conditioning to associate a visual cue with presentation of a palatable food reward, then received five, every-other-day injections of cocaine or vehicle. Following Pavlovian re-training, they underwent testing acquisition of a new operant response for the visual cue, now serving as a conditioned reinforcer. Subsequently, electrically evoked dopamine release was assessed using fast-scan cyclic voltammetry from acute brain slices containing the NAc. Results: While both strains acquired the Pavlovian association, only CC018/UncJ mice showed conditioned reinforcement and incentive sensitization in response to cocaine, while CC027/GeniUncJ mice did not. Voltammetry data revealed that CC018/UncJ, compared to CC027/GeniUnc, mice exhibited higher baseline dopamine release and uptake. Moreover, chronic cocaine exposure blunted tonic and phasic dopamine release in CC018/UncJ, but not CC027/GeniUncJ, mice. Conclusions: Genetic background is a moderator of cocaine-induced neuroadaptations in mesolimbic dopamine signaling, which may contribute to both psychomotor and incentive sensitization and indicate a shared biological mechanism of variation. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: The prefrontal cortex is critical for execution and inhibition of reward seeking. Neural manipulation of rodent medial prefrontal cortex (mPFC) subregions differentially impacts execution and inhibition of cocaine seeking. Dorsal, or prelimbic (PL), and ventral, or infralimbic (IL) mPFC are implicated in cocaine seeking or extinction of cocaine seeking, respectively. This differentiation is not seen across all studies, indicating that further research is needed to understand specific mPFC contributions to drug seeking. Methods: We recorded neuronal activity in mPFC subregions during cocaine self-administration, extinction, and cue- and cocaine-induced reinstatement of cocaine seeking. Results: Both PL and IL neurons were phasically responsive around lever presses during cocaine self-administration, and activity in both areas was reduced during extinction. During both cue- and, to a greater extent, cocaine-induced reinstatement, PL neurons exhibited significantly elevated responses, in line with previous studies demonstrating a role for the region in relapse. The enhanced PL signaling in cocaine-induced reinstatement was driven by strong excitation and inhibition in different groups of neurons. Both of these response types were stronger in PL vs. IL neurons. Finally, we observed tonic changes in activity in all tasks phases, reflecting both session-long contextual modulation as well as minute-to-minute activity changes that were highly correlated with brain cocaine levels and motivation associated with cocaine seeking. Conclusions: Although some differences were observed between PL and IL neuron activity across sessions, we found no evidence of a go/stop dichotomy in PL/IL function. Instead, our results demonstrate temporally heterogeneous prefrontal signaling during cocaine seeking and extinction in both PL and IL, revealing novel and complex functions for both regions during these behaviors. This combination of findings argues that mPFC neurons, in both PL and IL, provide multifaceted contributions to the regulation of drug seeking and addiction. [ABSTRACT FROM AUTHOR]

Apomorphine (10 mg/kg, s.c.) does not induce in mice a compulsion to gnaw, but pretreatment with cocaine (10-40 mg/kg, i.p.) caused gnawing activity. This effect of cocaine was inhibited by pretreatment with α-methyl- p-tyrosine, haloperidol, and physostigmine, but not with FLA-63, phenoxybenzamine and tetrabenazine. These findings would suggest that dopaminergic mechanism plays a significant role in the potentiation of apomorphine gnawing activity by cocaine and also support the view that inhibition of dopamine uptake is responsible for the stimulatory action of cocaine. [ABSTRACT FROM AUTHOR]

Rationale: Stimulant use, including cocaine, often occurs in a social context whose influence is important to understand to decrease intake and reduce associated harms. Although the importance of social influence in the context of drug addiction is known, there is a need for studies assessing its neurobiological substrate and for translational research. Objectives: Here, we explored the influence of peer presence and familiarity on cocaine intake and its neurobiological basis. Given the regulatory role of the subthalamic nucleus (STN) on cocaine intake and emotions, we investigated its role on such influence of social context on cocaine intake. Methods: We first compared cocaine consumption in various conditions (with no peer present or with peers with different characteristics: abstinent peer or drug-taking peer, familiar or not, cocaine-naive or not, dominant or subordinate) in rats (n = 90). Then, with a translational approach, we assessed the influence of the social context (alone, in the group, in a dyad with familiar or non-familiar peers) on drug intake in human drug users (n = 77). Results: The drug consumption was reduced when a peer was present, abstinent, or drug-taking as well, and further diminished when the peer was non-familiar. The presence of a non-familiar and drug-naive peer represents key conditions to diminish cocaine intake. The STN lesion by itself reduced cocaine intake to the level reached in presence of a non-familiar naive peer and affected social cognition, positioning the STN as one neurobiological substrate of social influence on drug intake. Then, the human study confirmed the beneficial effect of social presence, especially of non-familiar peers. Conclusion: Our results indirectly support the use of social interventions and harm reduction strategies and position the STN as a key cerebral structure to mediate these effects. [ABSTRACT FROM AUTHOR]

Prospective memory (PM) impairment in recreational drug users has been documented in recent years. However, most studies on the effects of drugs on PM contain several methodological challenges, such as small sample size (< 100 participants), unrepresentative sample type (e.g., student or patient), short abstinence period (< 7 days), and lack of control of potential confounds (e.g., sleep and IQ). The present study investigated the possible consequences of recreational drug use on prospective memory, using self-report and lab-based prospective memory measures while overcoming the methodological challenges. The sample was composed of 47 non-users (27 females, age range from 18 to 50 +) and 53 drug users (21 females, age range from 18 to 50 +). Recreational drug users reported significantly more deficits in the long-term episodic, short-term habitual, and internally cued PM failures subscales of the Prospective Memory Questionnaire. However, these deficits were eliminated after controlling for covariates (e.g., age, sleep quality, general health, alcohol usage). Recreational drug users also performed worse than non-users in the short-term, long-term, event-based, and time-based PM subscales of the Royal Prince Alfred Prospective Memory Test. These results remained significant after controlling for the covariates. Drug users demonstrated greater impairments on time-based and long-term PM tasks thought to be linked with executive functioning. Taken together, the present study provides further support for recreational drug-related deficits in PM and highlights a dissociation between self-report and lab-based PM measures. [ABSTRACT FROM AUTHOR]

Rationale: Risk factors for drug addiction include genetics, environment, and behavioral traits such as impulsivity and novelty preference (NP), which have been related to deficits in striatal dopamine (DA) D2/3-receptors (D2/3R) and heightened amphetamine (AMPH)-induced DA release. However, the influence of the early rearing environment on these behavioral and neurochemical variables is not clear. Objectives: We investigated the influence of early rearing environment on striatal D2/3R availabilities and AMPH-induced DA release in relation to impulsivity, NP, and propensity to drug self-administration (SA) in "addiction-prone" Roman high- (RHA) and "addiction-resistant" Roman low-avoidance (RLA) rats. Methods: Animals were reared post-weaning in either environmental enrichment (EE) or impoverishment (EI) and were assessed at adulthood for impulsivity, NP, and propensity to cocaine SA. EE and EI rats were also scanned using single-photon emission computed tomography to concurrently measure in vivo striatal D2/3R availability and AMPH-induced DA release. Results: EE vs. EI was associated with heightened impulsivity and a lack of NP in both rat lines. Higher dorsal striatal D2/3R densities were found in RHA EE and higher AMPH-induced DA release in RLA EE. Both impulsivity and NP were negatively correlated to dorsal striatal D2/3R availabilities and positively correlated with AMPH-induced DA release in EI but not in EE. EE vs. EI was related to a faster rate of cocaine intake and elevated active timeout responses in RHAs. Conclusion: Our results suggest non-monotonic, environment-dependent, relationships between impulsivity, NP, and D2/3R-mediated signaling, and suggest that EI vs. EE may decrease the reinforcing effects of psychostimulants in predisposed individuals. [ABSTRACT FROM AUTHOR]

Rationale and objectives: Recent studies reported that when given a mutually exclusive choice between cocaine and palatable food, most rats prefer the non-drug reward over cocaine. However, these studies used rat strains with limited genetic and behavioral diversity. Here, we used a unique outbred strain of rats (Heterogeneous Stock, HS) that mimic the genetic variability of humans. Methods: We first identified individual differences in addiction-like behaviors (low and high). Next, we tested choice between cocaine and palatable food using a discrete choice procedure. We characterized the individual differences using an addiction score that incorporates key features of addiction: escalated intake, highly motivated responding (progressive ratio), and responding despite adverse consequences (footshock punishment). We assessed food versus cocaine choice at different drug-free days (without pre-choice cocaine self-administration) during acquisition of cocaine self-administration or after escalation of cocaine self-administration. We also assessed drug versus food choice immediately after 1-, 2-, or 6-h cocaine self-administration. Results: Independent of the addiction score, without pre-choice cocaine (1 or more abstinence days), HS rats strongly preferred the palatable food over cocaine, even if the food reward was delayed or its size was reduced. However, rats with high but not low addiction score modestly increased cocaine choice immediately after 1-, 2-, or 6-h cocaine self-administration. Conclusions: Like other strains, HS rats strongly prefer palatable food over cocaine. Individual differences in addiction score were associated with increased drug choice in the presence but not absence (abstinence) of cocaine. The HS strain may be useful in studies on mechanisms of addiction vulnerability. [ABSTRACT FROM AUTHOR]