Treatment Of Cocaine Dependence Research Articles

Predictors of cocaine use disorder treatment outcomes: a systematic review

BackgroundPsychosocial approaches are the first-line treatments for cocaine dependence, although they still present high dropout and relapse rates. Thus, there is a pressing need to understand which variables influence treatment outcomes to improve current treatments and prevent dropout and relapse rates. The aim of this study is to explore predictors of treatment retention and abstinence in CUD.MethodsThis systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We searched three databases—PubMed, PsychINFO and Web of Science—for randomized clinical trials (RCTs) published in English and Spanish from database inception through April 1, 2023. We selected all studies that met the inclusion criteria (adults aged ≥ 18, outpatient treatment, CUD as main addiction, and no severe mental illness) to obtain data for the narrative synthesis addressing cocaine abstinence and treatment retention as main outcome variables. After data extraction was completed, risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials (RoB-2).ResultsA total of 566 studies were screened, and, of those, 32 RCTs were included in the synthesis. Younger age, more years of cocaine use, and craving levels were significant predictors of relapse and treatment dropout. Fewer withdrawal symptoms, greater baseline abstinence, greater treatment engagement, and more self-efficacy were all predictors of longer duration of abstinence. The role of impulsivity as a predictor of CUD is unclear due to conflicting data, although the evidence generally suggests that higher impulsivity scores can predict more severe addiction and withdrawal symptoms, and earlier discontinuation of treatment.ConclusionCurrent evidence indicates which variables have a direct influence on treatment outcomes, including well-studied cocaine use-related variables. However, additional variables, such as genetic markers, appear to have a high impact on treatment outcomes and need further study.Systematic review registrationThis systematic review is registered at PROSPERO (ID: CRD42021271847). This study was funded by the Spanish Ministry of Science, Innovation and Universities, Instituto Carlos III (ISCIII) (FIS PI20/00929) and FEDER funds and Fundació Privada Hospital de la Santa Creu i Sant Pau (Pla d’acció social 2020).

Human Butyrylcholinesterase Mutants for (-)-Cocaine Hydrolysis: A Correlation Relationship between Catalytic Efficiency and Total Hydrogen Bonding Energy with an Oxyanion Hole.

A combined computational and experimental study has been carried out to explore and test a quantitative correlation relationship between the relative catalytic efficiency (RCE) of human butyrylcholinesrase (BChE) mutant-catalyzed hydrolysis of substrate (-)-cocaine and the total hydrogen bonding energy (tHBE) of the carbonyl oxygen of the substrate with the oxyanion hole of the enzyme in the modeled transition-state structure (TS1), demonstrating a satisfactory linear correlation relationship between ln(RCE) and tHBE. The satisfactory correlation relationship has led us to computationally predict and experimentally confirm new human BChE mutants that have a further improved catalytic activity against (-)-cocaine, including the most active one (the A199S/F227S/S287G/A328W/Y332G mutant) with a 2790-fold improved catalytic efficiency (kcat/KM = 2.5 × 109 min-1 M-1) compared to the wild-type human BChE. Compared to the reference mutant (the A199S/S287G/A328W/Y332G mutant) tested in the reported clinical development of an enzyme therapy for cocaine dependence treatment, this new mutant (with a newly predicted additional F227S mutation) has an improved catalytic efficiency against (-)-cocaine by ∼2.6-fold. The good agreement between the computational and experimental ln(RCE) values suggests that the obtained correlation relationship is robust for computational prediction. A similar correlation relationship could also be explored in studying BChE or other serine hydrolases/esterases with an oxyanion hole stabilizing the carbonyl oxygen in the rate-determining reaction step of the enzymatic hydrolysis of other substrates.

The Effect of Transcranial Direct Current Stimulation (tDCS) on Cocaine Addiction: A Narrative Review.

Cocaine addiction is a significant problem worldwide. The development of addiction involves a reward system, which consists of certain brain regions like the ventral tegmental area, nucleus accumbens, and prefrontal cortex. Currently, there are no approved medications for treating cocaine dependence, so researchers are actively searching for effective treatments that can impact the brain. One potential treatment under investigation is transcranial direct current stimulation (tDCS), a non-invasive method of stimulating the brain to modulate its activity. In this review, we explore the use of tDCS in treating cocaine addiction. We found nine relevant articles via a literature search, and the results indicate that applying tDCS to the right dorsolateral prefrontal cortex (DLPFC) holds promise for reducing drug cravings in individuals with cocaine addiction. The review also discusses the possible mechanisms by which tDCS works and provides recommendations for future research in this field.

Nonparametric Bayesian Q-learning for optimization of dynamic treatment regimes in the presence of partial compliance.

Existing methods for estimation of dynamic treatment regimes are mostly limited to intention-to-treat analyses-which estimate the effect of randomization to a particular treatment regime without considering the compliance behavior of patients. In this article, we propose a novel nonparametric Bayesian Q-learning approach to construct optimal sequential treatment regimes that adjust for partial compliance. We consider the popular potential compliance framework, where some potential compliances are latent and need to be imputed. The key challenge is learning the joint distribution of the potential compliances, which we accomplish using a Dirichlet process mixture model. Our approach provides two kinds of treatment regimes: (1) conditional regimes that depend on the potential compliance values; and (2) marginal regimes where the potential compliances are marginalized. Extensive simulation studies highlight the usefulness of our method compared to intention-to-treat analyses. We apply our method to the Adaptive Treatment for Alcohol and Cocaine Dependence (ENGAGE) study , where the goal is to construct optimal treatment regimes to engage patients in therapy.

Anti-cocaine Vaccine Development: Where Are We Now and Where Are We Going?

Cocaine is one of the oldest and most widely used illicit drugs in the world and is responsible for major worldwide medical and social problems. Drug addiction is a disease state where the body relies on a substance for normal functioning and develops a physical dependence leading to compulsive and repetitive use despite negative consequences to the user's health, mental state, or social life. The primary driver for the development of anti-cocaine vaccines has been the failure to develop effective pharmacological treatments to combat cocaine dependence. Despite several decades of research, no approved pharmacological treatments for cocaine dependence are available to assist addicts to overcome cocaine withdrawal or to prevent drug relapse. This Perspective highlights the challenges associated with anti-cocaine vaccines, including the current state of anti-cocaine vaccines and catalytic antibody research to aid in the fight against cocaine addiction.

Development of a Highly Efficient Long-Acting Cocaine Hydrolase Entity to Accelerate Cocaine Metabolism.

It is particularly challenging to develop a truly effective pharmacotherapy for cocaine use disorder (CUD) treatment. Accelerating cocaine metabolism via hydrolysis at cocaine benzoyl ester using an efficient cocaine hydrolase (CocH) is known as a promising pharmacotherapeutic approach to CUD treatment. Preclinical and clinical studies on our first CocH (CocH1), in its human serum albumin-fused form known as TV-1380, have demonstrated the promise of a general concept of CocH-based pharmacotherapy for CUD treatment. However, the biological half-life of TV-1380 (t1/2 = 8 h in rats, associated with t1/2 = 43-77 h in humans) is not long enough for practical treatment of cocaine dependence, which requires enzyme injection for no more than once weekly. Through protein fusion of a human butyrylcholinesterase mutant (denoted as CocH5) with a mutant (denoted as Fc(M6)) of Fc from human IgG1, we have designed, prepared, and tested a new fusion protein (denoted as CocH5-Fc(M6)) for its pharmacokinetic profile and in vivo catalytic activity against (-)-cocaine. CocH5-Fc(M6) represents the currently most efficient long-acting cocaine hydrolase with both the highest catalytic activity against (-)-cocaine and the longest elimination half-life (t1/2 = 229 ± 5 h) in rats. As a result, even at a single modest dose of 3 mg/kg, CocH5-Fc(M6) can significantly and effectively accelerate the metabolism of cocaine in rats for at least 60 days. In addition, ∼70 nM CocH5-Fc(M6) in plasma was able to completely block the toxicity and physiological effects induced by intraperitoneal injection of a lethal dose of cocaine (60 mg/kg).

Growing use of valproic acid in substance use disorders

IntroductionValproic acid is an antiepileptic drug used in different fields of Psychiatry. It is known mostly for its use in managing patients with bipolar affective disorder. In psychiatry of addiction, there is still no approved indications for its usage, but it is widely prescribed in treating alcohol and cocaine abuse, due to the existence of studies in these addictions.ObjectivesThis review aims to clarify the relation between valproic acid and dependences, particularly cocaine.MethodsNon-systematic literature review using a PubMed search, using the following key words: “valproate”; “cocaine use”.ResultsCocaine dependence can decrease GABA levels in humans. Valproic acid has multiple mechanisms that favour the synthesis of GABA, potentiating its release and postsynaptic GABAergic response. Because of this, valproic acid was found effective in promoting abstinence and in reducing the use of cocaine. There are studies that support the valproic acid’s use in alcohol and cocaine dependences. Valproic acid has been shown to be promising in relapse prevention. It has also showed efficacy in the management of impulsivity and irritability, what makes it useful in managing patients with borderline personality disorder – patients at higher risk for alcohol or substance use disorders.ConclusionsCocaine addiction involves different phenomena and may respond to distinct pharmacologic approaches. Although some studies need to be confirmed by larger clinical trials, valproic acid seems a promising agent as one of some potential treatments for cocaine dependence. Further studies are required in this field to come to more reliable conclusions.DisclosureNo significant relationships.

Machine Learning Analysis of Cocaine Addiction Informed by DAT, SERT, and NET-Based Interactome Networks.

Cocaine addiction is a psychosocial disorder induced by the chronic use of cocaine and causes a large number of deaths around the world. Despite decades of effort, no drugs have been approved by the Food and Drug Administration (FDA) for the treatment of cocaine dependence. Cocaine dependence is neurological and involves many interacting proteins in the interactome. Among them, the dopamine (DAT), serotonin (SERT), and norepinephrine (NET) transporters are three major targets. Each of these targets has a large protein-protein interaction (PPI) network, which must be considered in the anticocaine addiction drug discovery. This work presents DAT, SERT, and NET interactome network-informed machine learning/deep learning (ML/DL) studies of cocaine addiction. We collected and analyzed 61 protein targets out of 460 proteins in the DAT, SERT, and NET PPI networks that have sufficiently large existing inhibitor datasets. Utilizing autoencoder (AE) and other ML/DL algorithms, including gradient boosting decision tree (GBDT) and multitask deep neural network (MT-DNN), we built predictive models for these targets with 115 407 inhibitors to predict drug repurposing potential and possible side effects. We further screened their absorption, distribution, metabolism, and excretion, and toxicity (ADMET) properties to search for leads having potential for developing treatments for cocaine addiction. Our approach offers a new systematic protocol for artificial intelligence (AI)-based anticocaine addiction lead discovery.

Moderation of buprenorphine therapy for cocaine dependence efficacy by variation of the Prodynorphin gene.

The aim of this secondary analysis was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP). Cocaine-dependent participants (N = 302) were randomly assigned to a platform of injectable, extended-release naltrexone (XR-NTX) and one of three daily medication arms: 4mg BUP (BUP4), 16mg BUP (BUP16), or placebo (PLB) for 8weeks (Parent Trial Registration: Protocol ID: NIDA-CTN-0048, Clinical Trials.gov ID: NCT01402492). DNA was obtained from 277 participants. Treatment response was determined from weeks 3 to 7 over each 1-week period by the number of cocaine-positive urines per total possible urines. In the cross-ancestry group, the PLB group had more cocaine-positive urines than the BUP16 group (P = 0.0021). The interactions of genetic variant × treatment were observed in the rs1022563 A-allele carrier group where the BUP16 group (N = 35) had fewer cocaine-positive urines (P = 0.0006) than did the PLB group (N = 26) and in the rs1997794 A-allele carrier group where the BUP16 group (N = 49) had fewer cocaine-positive urines (P = 0.0003) than did the PLB group (N = 58). No difference was observed in the rs1022563 GG or rs1997794 GG genotype groups between the BUP16 and PLB groups. In the African American-ancestry subgroup, only the rs1022563 A-allele carrier group was associated with treatment response. These results suggest that PDYN variants may identify patients who are best suited to treatment with XR-NTX plus buprenorphine for cocaine use disorder pharmacotherapy.

Bayesian set of best dynamic treatment regimes: Construction and sample size calculation for SMARTswithbinary outcomes.

Sequential, multiple assignment, randomized trials (SMARTs) compare sequences of treatment decision rules called dynamic treatment regimes (DTRs). In particular, the Adaptive Treatment for Alcohol and Cocaine Dependence (ENGAGE) SMART aimed to determine the best DTRs for patients with a substance use disorder. While many authors have focused on a single pairwise comparison, addressing the main goal involves comparisons of >2 DTRs. For complex comparisons, there is a paucity of methods for binary outcomes. We fill this gap by extending the multiple comparisons with the best (MCB) methodology to the Bayesian binary outcome setting. The set of best is constructed based on simultaneous credible intervals. A substantial challenge for power analysis is the correlation between outcome estimators for distinct DTRs embedded in SMARTs due to overlapping subjects. We address this using Robins' G-computation formula to take a weighted average of parameter draws obtained via simulation from the parameter posteriors. We use non-informative priors and work with the exact distribution of parameters avoiding unnecessary normality assumptions and specification of the correlation matrix of DTR outcome summary statistics. We conduct simulation studies for both the construction of a set of optimal DTRs using the Bayesian MCB procedure and the sample size calculation for two common SMART designs. We illustrate our method on the ENGAGE SMART. The R package SMARTbayesR for power calculations is freely available on the Comprehensive R Archive Network (CRAN) repository. An RShiny app is available at https://wilart.shinyapps.io/shinysmartbayesr/.

Bupropion use for the treatment of cocaine dependence

Bupropion use for the treatment of cocaine dependence

Hypericum perforatum L. prevents the acquisition of and promotes resilience against stress-induced reinstatement of the conditioned place preference induced by cocaine

Cocaine use disorder is a serious problem worldwide, and there are no approved medications for its treatment. A novel approach to the treatment of drug addiction is the use of natural products, and, in this context, preclinical evidence suggests that Hypericum perforatum L. (Hypericum) is effective against alcohol and other substance use disorders. We hypothesised that Hypericum could also be useful as a treatment for cocaine use disorder, and so we set out to test its effectiveness in a mice model of cocaine addiction. In the first experiment we evaluated its effects on the acquisition of cocaine-induced conditioned place preference (CPP). Adult male mice were conditioned with cocaine (25 mg/kg), cocaine with Hypericum (75, 150 or 300 mg/kg) or the plant extract alone (300 mg/kg). In the second experiment, we tested the effects of Hypericum on stress-induced reinstatement of cocaine CPP. All the mice were conditioned with cocaine (25 mg/kg) and, after extinction of CPP, the reinstating effects of social defeat (alone or with 75, 150 or 300 mg/kg of Hypericum) were evaluated. All the doses of Hypericum prevented the acquisition of cocaine-induced CPP. Furthermore, the plant extract dose-dependently reduced the reinstating effects of social defeat. Therefore, Hypericum is effective in reducing the rewarding effects of cocaine and prevents the stress-induced reinstatement of cocaine CPP in mice. The mechanisms underlying these positive effects of Hypericum perforatum L. need to be determined by future research. Our results endorse Hypericum as a natural treatment for cocaine dependence.

Sex differences in behavioral traits related with high sensitivity to the reinforcing effects of cocaine

Cocaine is the most prevalent illegal stimulant drug in Europe among the adult population. Its abuse is characterized by a faster substance abuse disorder (SUD) development than other drugs, with high vulnerability to relapse. However, there does not exist an effective treatment for cocaine dependence. Sex differences have been reported in psychological disorders including SUD. For this reason, it is essential to identify risk factors that predict susceptibility or resilience to cocaine addiction for the development of effective prevention strategies considering sex differences. In the present study, the main objective was to determine more sensitive phenotypes to the conditioned reinforcing effects of cocaine in both sexes. Anxiety-like behavior and the locomotor response to novelty were evaluated in the elevated plus maze, and despair in the tail suspension test, as well as vulnerability traits linked with a high sensitivity to the reinforcing effects of a subthreshold dose of cocaine (1 mg/kg) in the conditioned place preference (CPP) paradigm in male and female mice. Our results indicated that only female mice with high anxiety, low locomotor response to novelty or low despair levels acquired CPP induced by cocaine, while male mice with low anxiety, high locomotor response to novelty or high despair levels presented a higher susceptibility to the rewarding effects of cocaine than others. These sex differences in the results reveal an opposite pattern in males and females on the relationship between anxiety- and depressive-like behaviors and cocaine vulnerability, demonstrating the need to include female mice in preclinical studies.

Use of sustained release dextroamphetamine for the treatment of stimulant use disorder in the setting of injectable opioid agonist treatment in Canada: a case report

BackgroundFor people with opioid use disorder who are not responding to oral opioid agonist treatment, evidence supports the effectiveness of injectable opioid agonist treatment with injectable hydromorphone (an opioid analgesic) and diacetylmorphine (pharmaceutical grade heroin). While this treatment is effective at reducing illicit opioid use, concurrent cocaine use is prevalent. Dextroamphetamine (a central nervous system stimulant) has been found to be a safe and effective treatment for cocaine dependence among people receiving injectable opioid agonist treatment in Europe. We present the first report of dextroamphetamine prescribing offered for the treatment of stimulant use disorder among a patient receiving iOAT outside of a clinical trial. This case report can be used to inform clinical practice in the treatment of cocaine use disorder, an area where interventions are currently lacking.Case presentationDextroamphetamine was prescribed to a 51-year-old male who was diagnosed with concurrent opioid and stimulant use disorder in an injectable opioid agonist treatment clinic in Vancouver, Canada. He reported smoking crack cocaine daily for more than two decades and was experiencing health consequences associated with this use. He presented to his routine physician visit with the goal of reducing his cocaine use and was prescribed dextroamphetamine for the treatment of stimulant use disorder. After 4-weeks the patient was tolerating the medication with no observed adverse events and was achieving his therapeutic goal of reducing his cocaine use.ConclusionsDextroamphetamine can be prescribed to support patients with stimulant use disorder to reduce or stop their use of cocaine. The case demonstrated that when dextroamphetamine was prescribed, a significant reduction in cocaine use was experienced among a patient that had been regularly using cocaine on a daily basis for many years. Daily contact with care for the opioid medication promoted adherence to the stimulant medication and allowed for monitoring of dose and tolerance. Settings where patients are in regular contact with care such as oral and injectable opioid agonist treatment clinics serve as a suitable location to integrate dextroamphetamine prescribing for patients that use illicit stimulants to reduce use and associated harms.

Effective connectivity predicts cognitive empathy in cocaine addiction: a spectral dynamic causal modeling study.

Social cognition plays a crucial role in the development and treatment of cocaine dependence. However, studies investigating social cognition, such as empathy and its underlying neural basis, are lacking. To explore the neural interactions among reward and memory circuits, we applied effective connectivity analysis on resting-state fMRI data collected from cocaine-dependent subjects. The relationship between effective connectivity within these two important circuits and empathy ability - evaluated with the Interpersonal Reactivity Index (IRI) - was assessed by machine learning algorithm using multivariate regression analysis. In accordance with the neurocircuitry disruptions of cocaine addiction, the results showed that cocaine-dependent subjects relative to healthy controls had altered resting state effective connectivity between parts of the memory and reward systems. Furthermore, effective connectivity between the memory and reward system could predict the fantasy empathy (FE) subscale scores in cocaine dependence. Overall, our findings provide further evidence for the neural substrates of social cognition in cocaine-dependent patients. These new insights could be useful for the development of new treatment programs for this substance dependency disorder.

Clinical potential of a rationally engineered enzyme for treatment of cocaine dependence: Long-lasting blocking of the psychostimulant, discriminative stimulus, and reinforcing effects of cocaine

It is a grand challenge to develop a truly effective treatment of substance use disorder (SUD), particularly for cocaine and other drugs without an FDA-approved treatment available, because a truly effective therapy must effectively block the drug's physiological and reinforcing effects during the entire period of treatment in order to achieve the long-time abstinence required by the FDA. Whether a biologic, such as monoclonal antibody, vaccine, or therapeutic enzyme, can be truly effective for SUD treatment or not has been the subject of extensive debate. The main debate question is whether a biologic, particularly an exogenous enzyme, can effectively block the drug's reinforcing effect. In this report, we demonstrate that a modest dose of a recently redesigned long-acting cocaine hydrolase, CocH3-Fc(M6), can be used to effectively block the psychostimulant, discriminative stimulus, and reinforcing effects of cocaine for a sufficiently long period of time. For example, a dose of 3 mg/kg CocH3-Fc(M6) completely blocked the discriminative stimulus and reinforcing effects for 24/25 days and continued to significantly attenuate/decrease the cocaine effects for at least 29 days in rats. All the animal data consistently suggest that the long-acting cocaine hydrolase is a truly promising candidate of enzyme therapy for treatment of cocaine use disorder.

Effects of Cebranopadol on Cocaine-induced Hyperactivity and Cocaine Pharmacokinetics in Rats

Cebranopadol is known as a highly potent analgesic. Recent studies also demonstrated that administration of cebranopadol significantly decreased cocaine self-administration and significantly reduced cue-induced cocaine-seeking behaviors in rats. However, it was unclear whether these interesting behavioral observations are related to any potential effects of cebranopadol on cocaine pharmacokinetics or cocaine-induced hyperactivity. In principle, a promising therapeutic candidate for cocaine dependence treatment may alter the cocaine pharmacokinetics and/or attenuate cocaine-induced reward and hyperactivity and, thus, decrease cocaine self-administration and reduce cue-induced cocaine-seeking behaviors. In this study, we examined possible effects of cebranopadol on cocaine pharmacokinetics and cocaine-induced hyperactivity for the first time. According to our animal data in rats, cebranopadol did not significantly alter the pharmacokinetics of cocaine. According to our more extensive locomotor activity testing data, cebranopadol itself also dose-dependently induced hyperactivity in rats at doses higher than 50 µg/kg. Cebranopadol at a low dose of 25 µg/kg (p.o.) did not induce significant hyperactivity itself, but significantly potentiated cocaine-induced hyperactivity on Days 4 to 7 after the repeated daily dosing of the drug.

Cebranopadol reduces cocaine self-administration in male rats: Dose, treatment and safety consideration

As a novel first-in-class potent analgesic acting as an agonist of multiple opioid receptors, cebranopadol showed high efficacy and good tolerability in a broad range of preclinical models and clinical trials related to pain. In the present study, to evaluate the efficacy and safety of cebranopadol as a potential treatment of cocaine dependence, we tested the effects of cebranopadol with single and repeated doses (25, 50, 75, or 100 μg/kg, oral gavage) using rat models of cocaine fixed-ratio (FR) self-administration (SA), cocaine progressive-ratio (PR) SA, and sucrose pellet SA. In single-dosing treatment paradigm, cebranopadol significantly and dose-dependently reduced cocaine SA under FR and PR schedules and suppressed food intake under FR schedule without causing apparent side effects. In repeated-dosing treatment scheme, i.e. daily administration of 25, 50, 75, or 100 μg/kg cebranopadol for a week, the similar reduction in cocaine intake was detected, while non-negligible complications/side effects were observed at repeated high doses (75 and 100 μg/kg). The observed side effects were similar to the common toxic signs elicited by heroin at high doses, although cebranopadol did not fully substitute heroin's discriminative stimulant effects in our drug discriminative tests. These results demonstrated that the most appropriate oral dose of cebranopadol to balance the efficacy and safety is 50 μg/kg. Collectively, although cebranopadol may serve as a new treatment for cocaine dependence, more consideration, cautiousness, and a clear optimal dose window to dissociate its therapeutic effects from opioid side effects/complications in male and female subjects will be necessary to increase its practical clinical utility.

AJP Editors Select Best of Journal’s 2019 Studies

<i>AJP</i> Editors Select Best of Journal’s 2019 Studies

Potent and selective NOP receptor activation reduces cocaine self-administration in rats by lowering hedonic set point.

Developing new medications for the treatment of cocaine dependence continues to be a research priority. Compelling evidence indicates that mixed opioid receptor agonists, particularly bifunctional compounds that target nociceptin/orphanin FQ peptide (NOP) and mu opioid receptors, may be useful for the treatment of cocaine addiction. Here, we verify that potent and selective pharmacological activation of NOP receptors is sufficient to reduce relevant facets of cocaine addiction in animal models. Accordingly, we determined whether systemic injections of the small molecule AT-312 (0, 1, 3 mg/kg) could reduce operant cocaine self-administration, motivation for cocaine, and vulnerability to cocaine relapse in rats. Results indicate that a potent and selective NOP receptor agonist was equally efficacious in reducing the number of cocaine infusions in short (1-hour), as well as long (6-hour) access sessions. When tested on an economic-demand reinforcement schedule, AT-312 reduced Q0 , the parameter that describes the amount of drug consumed at zero price, while leaving the parameter α, a measure of motivation for drug consumption, unaltered. Furthermore, AT-312 successfully reduced conditioned reinstatement of cocaine seeking. In contrast, the NOP receptor agonist did not modify food self-administration. Blockade of the NOP receptor with the antagonist SB-612111 prevented the effect of AT-312 in decreasing cocaine-reinforced responding under a 2-hour fixed ratio 1 schedule, suggesting a NOP receptor-mediated mechanism. This work demonstrates that potent and selective activation of NOP receptors is sufficient to decrease cocaine taking and seeking behaviors in rats.