The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

Structural brain changes associated with cocaine use and digital cognitive behavioral therapy in cocaine use disorder treatment.

Background: Few studies have investigated changes in brain structure and function associated with recovery from cocaine use disorder (CUD), and fewer still have identified brain changes associated with specific CUD treatments, which could inform treatment development and optimization. Methods: In this longitudinal study, T1-weighted magnetic resonance imaging scans were acquired from 41 methadone-maintained individuals with CUD (15 women) at the beginning of and after 12 weeks of outpatient treatment. As part of a larger randomized controlled trial, these participants were randomly assigned to receive (or not) computer-based training for cognitive behavioral therapy (CBT4CBT), and galantamine (or placebo). Results: Irrespective of treatment condition, whole-brain voxel-based morphometry analyses revealed a significant decrease in right caudate body, bilateral cerebellum, and right middle temporal gyrus gray matter volume (GMV) at post-treatment relative to the start of treatment. Subsequent region of interest analyses found that greater reductions in right caudate and bilateral cerebellar GMV were associated with higher relative and absolute levels of cocaine use during treatment, respectively. Participants who completed more CBT4CBT modules had a greater reduction in right middle temporal gyrus GMV. Conclusions: These results extend previous findings regarding changes in caudate and cerebellar GMV as a function of cocaine use and provide the first evidence of a change in brain structure as a function of engagement in digital CBT for addiction. These data suggest a novel potential mechanism underlying how CBT4CBT and CBT more broadly may exert therapeutic effects on substance-use-related behaviors through brain regions implicated in semantic knowledge.

Changes in dorsomedial striatum activity during expression of goal-directed vs. habit-like cue-induced cocaine seeking.

A preclinical model of cue exposure therapy, cue extinction, reduces cue-induced cocaine seeking that is goal-directed but not habit-like. Goal-directed and habitual behaviors differentially rely on the dorsomedial striatum (DMS) and dorsolateral striatum (DLS), but the effects of cue extinction on dorsal striatal responses to cue-induced drug seeking are unknown. We used fiber photometry in rats trained to self-administer cocaine paired with an audiovisual cue to examine how dorsal striatal intracellular calcium and extracellular dopamine activity differs between goal-directed and habit-like cue-induced cocaine seeking and how it is impacted by cue extinction. After minimal fixed-ratio training, rats showed enhanced DMS and DLS calcium responses to cue-reinforced compared to unreinforced lever presses. After rats were trained on goal-promoting fixed ratio schedules or habit-promoting second-order schedules of reinforcement, different patterns of dorsal striatal calcium and dopamine responses to cue-reinforced lever presses emerged. Rats trained on habit-promoting second-order schedules showed reduced DMS calcium responses and enhanced DLS dopamine responses to cue-reinforced lever presses. Cue extinction reduced calcium responses during subsequent drug seeking in the DMS, but not in the DLS. Therefore, cue extinction may reduce goal-directed behavior through its effects on the DMS, whereas habit-like behavior and the DLS are unaffected.

Co-stimulation of muscarinic M1 and M4 acetylcholine receptors prevents later cocaine reinforcement in male and female mice, but not place-conditioning.

Acute stimulation of M1 or M4 muscarinic cholinergic receptors reduces cocaine abuse-related effects in mice and rats. The combined activation of these receptor subtypes produces synergistic effects on some behavioural endpoints in mice. M1 and M1 + M4 receptor stimulation in a cocaine vs. food choice assay in rats and microdialysis in rats showed delayed and lasting "anticocaine effects". Here, we tested whether these putative lasting neuroplastic changes are sufficient to occlude the reinforcing effects of cocaine at the behavioural level in mice. Mice were pre-treated with the M1 receptor partial agonist VU0364572, M4 receptor positive allosteric modulator VU0152100, or VU0364572 + VU0152100 two weeks prior to acquisition of cocaine intravenous self-administration (IVSA). Male C57BL/6JRj mice received vehicle, VU0364572, VU0152100, or VU0364572 + VU0152100. Female mice were tested with two VU0364572 + VU0152100 dose combinations or vehicle. To attribute potential effects to either reduced rewarding effects or increased aversion to cocaine, we tested VU0364572 alone and VU0364572 + VU0152100 in acquisition of cocaine-conditioned place preference (CPP) in male mice using an unbiased design. The acquisition of cocaine IVSA was drastically reduced and/or slowed in male and female mice receiving VU0364572 + VU0152100, but not either drug alone. Food-maintained operant behaviour was unaffected, indicating that the treatment effects were cocaine-specific. No treatment altered the acquisition of cocaine-CPP, neither in the post-test, nor in a challenge 14 days later. The cocaine IVSA findings confirm unusual long-lasting "anticocaine" effects of muscarinic M1 + M4 receptor stimulation. Thus, in mice, simultaneous stimulation of both receptor subtypes seems to produce potential neuroplastic changes that yield lasting effects.

Disrupted dynamic brain functional connectivity in male cocaine use disorder: Hyperconnectivity, strongly-connected state tendency, and links to impulsivity and borderline traits.

Cocaine use is a major public health problem with serious negative consequences at both the individual and societal levels. Cocaine use disorder (CUD) is associated with cognitive and emotional impairments, often manifesting as alterations in brain functional connectivity (FC). This study employed resting-state functional magnetic resonance imaging (rs-fMRI) to examine dynamic FC in 38 male participants with CUD and 31 matched healthy controls. Using group spatial independent component analysis (group ICA) combined with sliding window approach, we identified two recurring distinct connectivity states: the strongly-connected state (state 1) and weakly-connected state (state 2). CUD patients exhibited significant increased mean dwell and fraction time in state 1, and increased transitions from state 2 to state 1, demonstrated significant strongly-connected state tendency. Our analysis revealed abnormal FC patterns that are state-dependent and state-shared in CUD patients. This study observed hyperconnectivity within the default mode network (DMN) and between DMN and other networks, which varied depending on the state. Furthermore, after adjustment for multiple comparisons, we found significant correlations between these altered dynamic FCs and clinical measures of impulsivity and borderline personality disorder. The disrupted FC and repetitive effects of precuneus and angular gyrus across correlations suggested that they might be the important hub of neural circuits related behaviorally and mentally in CUD. In summary, our study highlighted the potential of these disrupted FC as neuroimaging biomarkers and therapeutic targets, and provided new insights into the understanding of the neurophysiologic mechanisms of CUD.

Gaussian process regression coupled with mRMR to predict adulterant concentration in cocaine.

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

How omics is revealing new roles for glia in addiction.

Experiments to study the biology of addiction have historically focused on the mechanisms through which drugs of abuse drive changes in the functioning of neurons and neural circuits. Glia have often been ignored in these studies, however, and this has left many questions in the field unanswered, particularly, surrounding how glia contribute to changes in synaptic plasticity, regulation of neuroinflammation, and functioning of neural ensembles given massive changes in signaling across the CNS. Omics methods (transcriptomics, translatomics, epigenomics, proteomics, metabolomics, and others) have expanded researchers' abilities to generate hypotheses and carry out mechanistic studies of glial cells during acquisition of drug taking, intoxication, withdrawal, and relapse to drug seeking. Here, we present a survey of how omics technological advances are revising our understanding of astrocytes, microglia, oligodendrocytes, and ependymal cells in addiction biology.

Analysis of MicroRNA Cargo in Circulating Extracellular Vesicles from HIV-Infected Individuals with Pulmonary Hypertension.

The risk of developing pulmonary hypertension (PH) in people living with HIV is at least 300-fold higher than in the general population, and illicit drug use further potentiates the development of HIV-associated PH. The relevance of extracellular vesicles (EVs) containing both coding as well as non-coding RNAs in PH secondary to HIV infection and drug abuse is yet to be explored. We here compared the miRNA cargo of plasma-derived EVs from HIV-infected stimulant users with (HIV + Stimulants + PH) and without PH (HIV + Stimulants) using small RNA sequencing. The data were compared with 12 PH datasets available in the GEO database to identify potential candidate gene targets for differentially altered miRNAs using the following functional analysis tools: ingenuity pathway analysis (IPA), over-representation analysis (ORA), and gene set enrichment analysis (GSEA). MiRNAs involved in promoting cell proliferation and inhibition of intrinsic apoptotic signaling pathways were among the top upregulated miRNAs identified in EVs from the HIV + Stimulants + PH group compared to the HIV + Stimulants group. Alternatively, the downregulated miRNAs in the HIV + Stimulants + PH group suggested an association with the negative regulation of smooth muscle cell proliferation, IL-2 mediated signaling, and transmembrane receptor protein tyrosine kinase signaling pathways. The validation of significantly differentially expressed miRNAs in an independent set of HIV-infected (cocaine users and nondrug users) with and without PH confirmed the upregulation of miR-32-5p, 92-b-3p, and 301a-3p positively regulating cellular proliferation and downregulation of miR-5571, -4670 negatively regulating smooth muscle proliferation in EVs from HIV-PH patients. This increase in miR-301a-3p and decrease in miR-4670 were negatively correlated with the CD4 count and FEV1/FVC ratio, and positively correlated with viral load. Collectively, this data suggest the association of alterations in the miRNA cargo of circulating EVs with HIV-PH.

Differential effects of deep brain stimulation on reinstatement of cocaine seeking in male and female rats.

There are currently no FDA-approved treatments for cocaine use disorder. Recent preclinical and clinical studies showed that deep brain stimulation (DBS) in limbic regions reduced drug seeking behavior. Our previous work indicated that DBS of the nucleus accumbens shell attenuated reinstatement of cocaine seeking, a model of relapse, in male rats. The current experiments were designed to evaluate the effect of electrical DBS on cocaine reinstatement in female rats across the estrous cycle. Rats were allowed to self-administer cocaine and lever responding was subsequently extinguished. Cocaine seeking was reinstated by an acute injection of experimenter-delivered cocaine. The effect of nucleus accumbens shell DBS vs. sham stimulation on cocaine-primed reinstatement was evaluated in female and male rats using a within-subjects counterbalanced design. Consistent with previous work, accumbens shell DBS suppressed cocaine seeking in male rats. In sharp contrast, accumbens shell DBS had no effect on cocaine reinstatement in female rats evaluated in either the estrus or non-estrus phases. These results suggest that changes across the estrous cycle are not responsible for the differences in the effect of DBS on cocaine reinstatement between female and male rats.

Polysubstance-Induced Hepatotoxicity and the Role of Supportive Management.

With the continued rise of polysubstance use throughout the country, it has been shown to affect a multitude of organ systems. Drug-induced liver injury (DILI) has been widely documented in its association with salicylates or acetaminophen and the utility of using N-acetylcysteine (NAC) for its hepatoprotective effects. However, DILI caused by illicit drug use and guideline-directed management has had little research. We present the case of a 29-year-old female who presented with altered mental status. She was found to have a concomitant liver injury and was treated supportively without the use of NAC, with gradual improvement.

Cocaine versus xylometazoline to prevent epistaxis after nasotracheal intubation: A randomized trial.

BACKGROUND: Nasotracheal intubation is associated with a risk of epistaxis. Several drugs, including cocaine and xylometazoline may be used as decongestants prior to nasotracheal intubation to prevent this. We hypothesized that xylometazoline would prevent epistaxis more effectively than cocaine, demonstrated by a lower proportion of patients with bleeding after nasotracheal intubation. METHODS: We conducted a single-center, outcome assessor and analyst-blinded, clinical randomized controlled trial following approval from the local research ethics committee and the national medicine agency. Written informed consent was obtained from all patients. Patients scheduled for surgery under general anesthesia with nasotracheal intubation were randomized to receive either 2 mL 4% cocaine or 2 mL 0.05% xylometazoline prior to nasotracheal intubation. Immediately following intubation, epistaxis was evaluated by the blinded intubating anesthetist on a four-point scale. We measured heart rate and blood pressure the first 5 min after drug administration. Adverse events were followed up after 24 h. RESULTS: A total of 53 patients received cocaine and 49 patients received xylometazoline. Bleeding occurred in 32 patients receiving cocaine (60.4%) and in 34 patients receiving xylometazoline (69.4%) (p = .41, Fisher's exact test) with a difference of 9.0% (95% CI: -9.4% to 27%). There was no statistically significant difference between groups regarding the heart rate or blood pressure. No adverse cardiac events were recorded in either group. CONCLUSION: We found no statistically significant difference between cocaine and xylometazoline in preventing epistaxis after nasotracheal intubation, and the choice of vasoconstrictor should be based on other considerations, such as pricing, availability and medicolegal issues.

Detection of cocaine 24 h after administration before nasotracheal intubation.

BACKGROUND: Cocaine may be applied to decongest the nasal mucosa before nasotracheal intubation, but patients risk a criminal offence if cocaine is detected when patients drive a car shortly after surgery. We aimed to evaluate whether benzoylecgonine levels in saliva exceeded the cut-off point 24 h after administration in patients undergoing nasotracheal intubation and whether cocaine would be detectable above the Danish legal fixed limit in blood samples 1 and 24 h after surgery. METHODS: We conducted a prospective study following approval from the local research ethics committee and the national medicine agency. Written informed consent was obtained from all patients. We included patients scheduled for surgery under general anaesthesia with nasotracheal intubation. They received 80 mg cocaine as a nasal spray 5 min before induction and nasotracheal intubation. The primary outcome was a dichotomous assessment of benzoylecgonine levels in saliva samples measured 24 h after administration of nasal cocaine with a cut-off limit of 200 ng/mL. Secondary outcomes were dichotomous assessments of cocaine in whole blood samples measured 1 and 24 h after administration of nasal cocaine with a cut-off limit of 0.01 mg/kg. RESULTS: Overall, 70 patients had valid saliva samples and 75 had valid blood samples 24 h after cocaine administration. Benzoylecgonine in saliva was traceable above the cut-off in 9/70 patients (13%; CI95%: 6% to 23%), and cocaine in blood was detected above the cut-off in 2/75 patients (3%; CI95%: 0.3% to 9%). CONCLUSION: We found benzoylecgonine traceable in saliva in 13% of patients and cocaine traceable in blood in 3% of patients 24 h after administration of 80 mg nasal cocaine. Patients should be informed when receiving cocaine and advised not to drive for at least 24 h.

Cocaine-Induced Toxic Leukoencephalopathy: A Case Report.

Cocaine is a widely abused controlled substance. Cocaine use is associated with a myriad of side effects and a sequelae of consequences secondary to its harmful nature and potential adulterants, the most recently described and less known sequelae being leukoencephalopathy. In our case, we describe a 58-year-old male who presented to the ED with agitation and acute stroke-like symptoms with reported rapid onset. Cocaine induced toxic leukoencephalopathy is a diagnosis of exclusion, thus other etiologies of disease were ruled out in a full neurological and infectious workup; most importantly consisting of extensive brain imaging, alluding to the diagnosis of acute cocaine induced toxic leukoencephalopathy in an individual with a confirmed history of cocaine and cannabinoid abuse. Although there is no targeted therapy for the condition to our knowledge, we utilized a supportive approach to treatment in contrast to other reported treatment modalities which included the use of steroids, plasma exchange, and intravenous immunoglobulin. Furthermore, we describe the clinical evaluation and treatment throughout the patient's hospital course with his eventual marked improvement from initial presentation.

Behavioral and neuronal extracellular vesicle biomarkers associated with nicotine's enhancement of the reinforcing strength of cocaine in female and male monkeys.

While the majority of people with cocaine use disorders (CUD) also co-use tobacco/nicotine, most preclinical cocaine research does not include nicotine. The present study examined nicotine and cocaine co-use under several conditions of intravenous drug self-administration in monkeys, as well as potential peripheral biomarkers associated with co-use. In Experiment 1, male rhesus monkeys (N = 3) self-administered cocaine (0.001-0.1 mg/kg/injection) alone and with nicotine (0.01-0.03 mg/kg/injection) under a progressive-ratio schedule of reinforcement. When nicotine was added to cocaine, there was a significant leftward/upward shift in the number of injections received. In Experiment 2, socially housed female and male cynomolgus monkeys (N = 14) self-administered cocaine under a concurrent drug-vs-food choice schedule of reinforcement. Adding nicotine to the cocaine solution shifted the cocaine dose-response curves to the left, with more robust shifts noted in the female animals. There was no evidence of social rank differences. To assess reinforcing strength, delays were added to the presentation of drug; the co-use of nicotine and cocaine required significantly longer delays to decrease drug choice, compared with cocaine alone. Blood samples obtained post-session were used to analyze concentrations of neuronally derived small extracellular vesicles (NDE); significant differences in NDE profile were observed for kappa-opioid receptors when nicotine and cocaine were co-used compared with each drug alone and controls. These results suggest that drug interactions involving the co-use of nicotine and cocaine are not simply changing potency, but rather resulting in changes in reinforcing strength that should be utilized to better understand the neuropharmacology of CUD and the evaluation of potential treatments.

The Structural Basis of the Activity Cliff in Modafinil-Based Dopamine Transporter Inhibitors.

Modafinil analogs with either a sulfoxide or sulfide moiety have improved binding affinities at the human dopamine transporter (hDAT) compared to modafinil, with lead sulfoxide-substituted analogs showing characteristics of atypical inhibition (e.g., JJC8-091). Interestingly, the only distinction between sulfoxide and sulfide substitution is the presence of one additional oxygen atom. To elucidate why such a subtle difference in ligand structure can result in different typical or atypical profiles, we investigated two pairs of analogs. Our quantum mechanical calculations revealed a more negatively charged distribution of the electrostatic potential surface of the sulfoxide substitution. Using molecular dynamics simulations, we demonstrated that sulfoxide-substituted modafinil analogs have a propensity to attract more water into the binding pocket. They also exhibited a tendency to dissociate from Asp79 and form a new interaction with Asp421, consequently promoting an inward-facing conformation of hDAT. In contrast, sulfide-substituted analogs did not display these effects. These findings elucidate the structural basis of the activity cliff observed with modafinil analogs and also enhance our understanding of the functionally relevant conformational spectrum of hDAT.

Comprehensive glycomic and proteomic analysis of mouse striatum and lateral hypothalamus following repeated exposures to cocaine or methamphetamine.

Substance use disorder is a major concern, with few therapeutic options. Heparan sulfate (HS) and chondroitin sulfate (CS) interact with a plethora of growth factors and their receptors and have profound effects on cellular signaling. Thus, targeting these dynamic interactions might represent a potential novel therapeutic modality. In the present study, we performed mass spectrometry-based glycomic and proteomic analysis to understand the effects of cocaine and methamphetamine (METH) on HS, CS, and the proteome of two brain regions critically involved in drug addiction: the lateral hypothalamus (LH) and the striatum (ST). We observed that cocaine and METH significantly alter HS and CS abundances as well as sulfate contents and composition. In particular, repeated METH or cocaine treatments reduced CS 4-O-sulfation and increased CS 6-O-sulfation. Since C4S and C6S exercise differential effects on axon growth, regeneration and plasticity, these changes likely contribute to drug-induced neural plasticity in these brain regions. Notably, we observed that restoring these alterations by increasing CS 4-0 levels in the LH by adeno-associated virus (AAV) delivery of an shRNA to Arylsulfatase B (N-acetylgalactosamine-4-sulfatase, ARSB) ameliorated anxiety and prevented the expression of preference for cocaine in a novelty induced conditioned place preference test during cocaine withdrawal. Finally, proteomics analyses revealed a number of aberrant proteins in METH- and cocaine-treated vs. saline-treated mice, including MYPR, KCC2A, SYN2, TENR, CALX, ANXA7, HDGF, NCAN, and CSPG5, and oxidative phosphorylation among the top perturbed pathway. Taken together, these data support the role of HS, CS, and associated proteins in stimulants abuse and suggest that manipulation of HSPGs can represent a novel therapeutic strategy.

HIV and HCV seroincidence, associated factors and drug use in people who inject drugs, SurvUDI network, eastern central Canada, 1995-2020.

BACKGROUND: The SurvUDI network is a biobehavioural survey among people who inject drugs (PWID) in Eastern Central Canada. OBJECTIVES: The objectives were to describe HIV and HCV seroincidence trends, associated factors and changes in drug use behaviours. METHODS: The network was initiated in 1995 and targets hard-to-reach, mostly out-of- treatment PWID. Participants were recruited mostly in harm reduction programs, completed an interviewer-administered questionnaire, provided a sample of gingival exudate for HIV and HCV antibody testing and were identified using an encrypted code allowing identification of multiple participations. Time trends were examined for HIV and HCV seroincidence, selected characteristics and behaviours. Cox proportional hazard regression was used to examine factors associated to HIV and HCV seroincidence. RESULTS: Between January 1995 and March 2020, 15,907 individuals have completed 31,051 questionnaires. HIV seroincidence decreased significantly from 5.0 per 100 person-years (p-y) in 1995 to 0.4 per 100 p-y in 2018. HCV seroincidence also decreased significantly between 1998 and 2011. The use of syringes already used by someone else decreased significantly, from 43.4 % in 1995 to 12.4 % in 2019, as well as the use of equipment other than syringe already used by someone else. Cocaine/crack injection decreased significantly while "opioids other than heroin" injection increased, concomitant to daily injection. Injection with syringes already used by someone else and cocaine as the most often injected drug were significantly associated with HIV seroincidence (1995-2020). Injected opioid other than heroin, injected cocaine/crack, injected 100 or more times in the past month, injected for less than 3 years, injected with syringes or equipment already used by someone else, injected with someone else and reported client sex partners were significantly associated with HCV seroincidence (2004-2020). CONCLUSION: HIV seroincidence and syringe/equipment sharing behaviour trends are encouraging, but HCV seroincidence remains high.

Oxytocin attenuates cocaine-associated place preference via the dorsal hippocampus in male and female rats.

Cocaine addiction is the third largest cause of overdose-related deaths in the United States. Research investigating therapeutic targets for cocaine reward processes is key to combating this issue. The neuropeptide oxytocin (OXT) has been shown to reduce cocaine reward processes, though specific mechanisms are not understood. This study examines the effect of intra-dorsal hippocampal (DH) OXT on the expression of cocaine context associations using a conditioned place preference (CPP) paradigm. In this paradigm, one of two visually distinct chambers is paired with a drug. With repeated pairings, control animals display preference for the drug-associated context by spending more time in that context at test. In the present study, four conditioning days took place where male and female rats were injected with either cocaine or saline and placed into the corresponding chamber. On test day, rats received infusions of OXT or saline (VEH) into the DH and were allowed access to both chambers. The results show that while VEH-infused rats displayed cocaine CPP, OXT-infused rats did not prefer the cocaine-paired chamber. These findings implicate the DH as necessary in the mechanism by which OXT acts to block the expression of cocaine-context associations, providing insight into how OXT may exert its therapeutic effect in cocaine reward processes.