Subsequent Cocaine Research Articles

Co-sensitivity to the incentive properties of palatable food and cocaine in rats; implications for co-morbid addictions

Several lines of evidence suggest that there may be a shared vulnerability to acquire behaviors motivated by strong incentive stimuli. Non-food restricted male Sprague-Dawley rats (n = 78) underwent place conditioning with Oreos, and were subsequently tested on cocaine self-administration (SA) on fixed and progressive ratios, as well as extinction and reinstatement by cocaine primes and by consumption of Oreos. Although there was a group preference for the Oreo-paired compartment, at the individual level some rats (69%) displayed a preference and others did not. In cocaine SA, 'preference' rats achieved higher break points on a progressive ratio, and displayed greater responding during extinction and cocaine-induced reinstatement. Within the context of this study, Oreo-cocaine cross-reinstatement was not observed. In a control study, rats (n = 29) conditioned with a less palatable food (rice cakes) also displayed individual differences in place preference, but not on subsequent cocaine tests. These findings indicate that there is a relationship between incentive learning promoted by palatable foods and by cocaine. This supports the hypothesis that co-morbid food-drug addictions may result from a shared vulnerability to acquire behaviors motivated by strong incentives.

Reinforcement-Related Regulation of AMPA Glutamate Receptor Subunits in the Ventral Tegmental Area Enhances Motivation for Cocaine

Chronic cocaine use produces numerous biological changes in brain, but relatively few are functionally associated with cocaine reinforcement. Here we show that daily intravenous cocaine self-administration, but not passive cocaine administration, induces dynamic upregulation of the AMPA glutamate receptor subunits GluR1 and GluR2 in the ventral tegmental area (VTA) of rats. Increases in GluR1 protein and GluR1(S845) phosphorylation are associated with increased GluR1 mRNA in self-administering animals, whereas increased GluR2 protein levels occurred despite substantial decreases in GluR2 mRNA. We investigated the functional significance of GluR1 upregulation in the VTA on cocaine self-administration using localized viral-mediated gene transfer. Overexpression of GluR1(WT) in rat VTA primarily infected dopamine neurons (75%) and increased AMPA receptor-mediated membrane rectification in these neurons with AMPA application. Similar GluR1(WT) overexpression potentiated locomotor responses to intra-VTA AMPA, but not NMDA, infusions. In cocaine self-administering animals, overexpression of GluR1(WT) in the VTA markedly increased the motivation for cocaine injections on a progressive ratio schedule of cocaine reinforcement. In contrast, overexpression of protein kinase A-resistant GluR1(S845A) in the VTA reduced peak rates of cocaine self-administration on a fixed ratio reinforcement schedule. Neither viral vector altered sucrose self-administration, and overexpression of GluR1(WT) or GluR1(S845A) in the adjacent substantia nigra had no effect on cocaine self-administration. Together, these results suggest that dynamic regulation of AMPA receptors in the VTA during cocaine self-administration contributes to cocaine addiction by acting to facilitate subsequent cocaine use.

The impact of cocaine use on outcomes in HIV-infected patients receiving buprenorphine/naloxone.

Cocaine use is common in opioid-dependent HIV-infected patients, but its impact on treatment outcomes in these patients receiving buprenorphine/naloxone is not known. We conducted a prospective study in 299 patients receiving buprenorphine/naloxone who provided baseline cocaine data and a subset of 266 patients who remained in treatment for greater than or equal to one quarter. Assessments were conducted at baseline and quarterly for 1 year. We evaluated the association between baseline and in-treatment cocaine use on buprenorphine/naloxone retention, illicit opioid use, antiretroviral adherence, CD4 counts, HIV RNA, and risk behaviors. Sixty-six percent (197 of 299) of patients reported baseline cocaine use and 65% (173 of 266) of patients with follow-up data reported in-treatment cocaine use. Baseline and in-treatment cocaine use did not impact buprenorphine/naloxone retention, antiretroviral adherence, CD4 lymphocytes, or HIV risk behaviors. However, baseline cocaine use was associated with a 14.8 (95% confidence interval [CI], 9.0-24.2) times greater likelihood of subsequent cocaine use (95% CI, 9.0-24.2), a 1.4 (95% CI, 1.02-2.00) times greater likelihood of subsequent opioid use, and higher log10 HIV RNA (P < 0.016) over time. In-treatment cocaine use was associated with a 1.4 (95% CI, 1.01-2.00) times greater likelihood of concurrent opioid use. Given cocaine use negatively impacts opioid and HIV treatment outcomes, interventions to address cocaine use in HIV-infected patients receiving buprenorphine/naloxone treatment are warranted.

Basolateral Amygdala Cdk5 Activity Mediates Consolidation and Reconsolidation of Memories for Cocaine Cues

Cocaine use and relapse involves learned associations between cocaine-associated environmental contexts and discrete stimuli and cocaine effects. Initially, these contextual and discrete cues undergo memory consolidation after being paired with cocaine exposure. During abstinence, cocaine cue memories can undergo memory reconsolidation after cue exposure without the drug. We used a conditioned place preference (CPP) procedure in rats to study the role of neuronal protein kinase cyclin-dependent kinase 5 (Cdk5) in consolidation and reconsolidation of cocaine cue memories. We found that the expression of cocaine CPP in drug-free tests 1 d after CPP training (four pairings of 10 mg/kg cocaine with one context and four pairings of saline with a different context) increased Cdk5 activity, and levels of the Cdk5 activator p35 in basolateral but not central amygdala. We also found that basolateral (but not central) amygdala injections of the Cdk5 inhibitor beta-butyrolactone (100 ng/side) immediately (but not 6 h) after cocaine-context pairings during training prevented subsequent cocaine CPP expression. After training, acute basolateral (but not central) amygdala beta-butyrolactone injections immediately before testing prevented the expression of cocaine CPP; this effect was also observed on a second test performed 1 d later, suggesting an effect on reconsolidation of cocaine cue memories. In support, basolateral beta-butyrolactone injections, given immediately (but not 6 h) after a single exposure to the cocaine-paired context, prevented cocaine CPP expression 1 and 14 d after the injections. Results indicate that basolateral amygdala Cdk5 activity is critical for consolidation and reconsolidation of the memories of cocaine-associated environmental cues.

Sensitization of rapid dopamine signaling in the nucleus accumbens core and shell after repeated cocaine in rats.

Repeated cocaine exposure and withdrawal leads to long-term changes, including behavioral and dopamine sensitization to an acute cocaine challenge, that are most pronounced after long withdrawal periods. However, the changes in dopamine neurotransmission after short withdrawal periods are less well defined. To study dopamine neurotransmission after 1-day withdrawal, we used fast-scan cyclic voltammetry (FSCV) to determine whether repeated cocaine alters rapid dopamine release and uptake in the nucleus accumbens (NAc) core and shell. FSCV was performed in urethane anesthetized male Sprague-Dawley rats that had previously received one or seven daily injections of saline or cocaine (15 mg/kg, ip). In response to acute cocaine, subjects showed increased dopamine overflow that resulted from both increased dopamine release and slowed dopamine uptake. One-day cocaine pre-exposure, however, did not alter dopaminergic responses to a subsequent cocaine challenge. In contrast, 7-day cocaine-treated subjects showed a potentiated rapid dopamine response in both the core and shell after an acute cocaine challenge. In addition, kinetic analysis during the cocaine challenge showed a greater increase in apparent K(m) of 7-day cocaine exposed subjects. Together, the data provide the first in vivo demonstration of rapid dopamine sensitization in the NAc core and shell after a short withdrawal period. In addition, the data clearly delineate cocaine's release and uptake effects and suggest that the observed sensitization results from greater uptake inhibition in cocaine pre-exposed subjects.

A placebo-controlled trial of memantine for cocaine dependence with high-value voucher incentives during a pre-randomization lead-in period

Preclinical findings suggest that the inhibition of NMDA glutamatergic neurotransmission may have beneficial effects in the treatment of cocaine dependence. We hypothesized that memantine, a low potency, uncompetitive NMDA receptor antagonist, would be safe and effective in the treatment of cocaine dependence, particularly in preventing relapse to cocaine use in abstinent individuals. Cocaine dependent patients ( N = 112) were enrolled. The trial began with a 2-week placebo lead-in period during which patients received high-value voucher contingency management to induce abstinence. Participants were then randomized to receive either memantine 20 mg bid ( N = 39) or placebo ( N = 42) for 12-weeks in combination with individual relapse-prevention therapy. The randomization was stratified by abstinence status during the lead-in period. The primary outcome was the weekly proportion of days of cocaine use. There were no significant differences in cocaine use outcome between the groups treated with memantine versus placebo. Thus, the efficacy of memantine 40 mg/d for the treatment of cocaine dependence was not supported. Urine-confirmed abstinence during the lead-in period was achieved by 44% of participants, and was a strong predictor of subsequent cocaine abstinence during the trial. This suggests that this clinical trial design, an intensive behavioral intervention during a lead-in period, resolves cocaine dependent patients into two subgroups, one that rapidly achieves sustained abstinence and may not need a medication, and another that displays persistent cocaine use and would most likely benefit from a medication to help induce abstinence. Targeting the latter subgroup may advance medication development efforts.

Cocaine‐induced stereotypy is linked to an imbalance between the medial prefrontal and sensorimotor circuits of the basal ganglia

The dysfunction of basal ganglia circuits related to stereotyped motor activity was analysed using the well-established model of cocaine-induced stereotypy in the rat. We examined and compared the neurochemical and electrophysiological effects occurring in medial prefrontal and sensorimotor basal ganglia circuits of the dorsal striatum after cocaine injection in sensitized and non-sensitized rats. Acute injections of cocaine (25 mg/kg), not inducing stereotyped behaviour, affected both medial prefrontal and sensorimotor circuits in a similar way: (i) a mild and delayed increase and decrease of N-methyl-D-aspartate-evoked dopamine and acetylcholine release, respectively and (ii) a marked decrease of cortically evoked inhibition of substantia nigra pars reticulata neurons revealing an imbalance of information transmission between the direct and indirect trans-striatal pathways. In contrast, following sensitization to cocaine, a challenge injection of the same dose of cocaine, generating strong stereotyped behaviour, provoked neurochemical and electrophysiological effects only in the medial prefrontal but not in the sensorimotor circuits: (i) a strong increase of dopamine and decrease of acetylcholine release in the medial prefrontal territory of the dorsal striatum and (ii) a reduction of all inhibitory and excitatory components of the responses evoked in substantia nigra pars reticulata by medial prefrontal stimulation. Therefore, these data disclose distinct reactivity of the medial prefrontal and sensorimotor circuits of the basal ganglia to repeated cocaine administration leading to stereotyped behaviour induced by subsequent cocaine challenge. Thus, we suggest that stereotyped behaviour is correlated to an imbalance between the medial prefrontal and sensorimotor circuits of the basal ganglia resulting in a loss of control of motor behaviour.

Reactivity to laboratory stress provocation predicts relapse to cocaine

Background Cocaine dependence is a chronic relapsing disorder characterized by periods of abstinence and high rates of return to drug using behavior. Elevated levels of stress have been associated with relapse to cocaine; however, the nature of this association is not well understood. Methods The relationship between reactivity to three human laboratory provocations and relapse to cocaine was investigated. Participants were 53 cocaine-dependent individuals who were admitted for a 2-day inpatient stay during which a psychosocial provocation (i.e., the Trier Social Stress Task), a pharmacological provocation (i.e., administration of 1 μg/kg corticotrophin releasing hormone; CRH), and a drug cue exposure paradigm were completed. Adrenocortico-trophic hormone (ACTH), cortisol, heart rate, and subjective cocaine craving and stress were assessed at baseline and at multiple time points post-task. Participants’ cocaine use was monitored for approximately 1 month following testing. Results The majority (72.3%) of participants relapsed to cocaine during the follow-up period. In response to the CRH and drug cue exposure, elevated subjective craving and stress were significant predictors of cocaine use during follow-up. In response to the Trier, attenuated neuroendocrine responses were significant predictors of cocaine use. Conclusions The findings provide further evidence of the ability of laboratory paradigms to predict relapse. The observed associations between stress reactivity and subsequent cocaine use highlight the clinical importance of the findings. Predictors of relapse may vary based on the type of provocation utilized. Interventions aimed at normalizing stress response, as measured using laboratory paradigms, may prove useful in relapse prevention.

Anticonvulsant drugs in cocaine dependence: A systematic review and meta-analysis

A systematic review and meta-analysis according to the methodology developed by the Cochrane Collaboration and the Quality of Reporting of Meta-Analyses statement based on randomized controlled trials to evaluate the efficacy of anticonvulsants in subjects with cocaine dependence were performed. Fifteen randomized, double-blind, placebo-controlled clinical trials involving 1,236 patients were included. Two outcome measures were evaluated: retention in the anticonvulsant treatment (compared to the placebo treatment) and the subsequent cocaine use, measured by urinalysis results. The efficacy of the seven anticonvulsant drugs analyzed was not homogenous. On average, 50% of the enrolled participants were lost to follow-up. Treatments did not show an improvement in subject retention compared to placebo. Overall, the number of cocaine-positive urine samples was close to statistical significance (95% confidence interval = 0.85–1.06) compared to placebo. Available clinical trials indicate that there is insufficient evidence to justify the use of anticonvulsant drugs in treating cocaine dependence.

Age‐Related Neural Changes After Brief Exposure to Nicotine

Adolescence is a critical period for the onset of tobacco smoking, with more than 90% of smokers beginning at this age. Clinical studies have shown that children who tried a single cigarette by the age of 11 continue to be susceptible to smoking throughout the rest of their lives. In animal models, it has been shown that adolescents exhibit unique responses to nicotine exposure, as compared to adults. Furthermore, subchronic treatment with a low dose of nicotine in early adolescence increases subsequent cocaine self‐administration. The purpose of this study was to examine the behavioral effects and age‐related neurochemical changes that occur after exposure to nicotine. Male Sprague‐Dawley rats aged P28 or P86, were given one or four daily i.v. injections of saline or nicotine (2 x 0.03 mg/kg/0.1 ml spaced 1 min apart). Immediately after the last injection, locomotor behavior was monitored for 30 minutes and brains were collected for anatomical analysis. Acute nicotine treatment produced increased locomotor activation in adolescents, which persists through the subchronic treatment. Adults show a decrease in activity after one injection of nicotine, whereas repeat nicotine treatment has no effect. Preliminary analysis of nicotine‐induced IEG expression has shown selective nicotine activation of limbic forebrain in adolescents. In vivo microdialysis studies are currently being conducted to further elucidate changes after nicotine exposure. These findings provide evidence that nicotine administration during adolescence causes unique neural adaptations not seen following treatment of adults.

Altered Dendritic Spine Plasticity in Cocaine-Withdrawn Rats

Chronic cocaine treatment is associated with changes in dendritic spines in the nucleus accumbens, but it is unknown whether this neuroplasticity alters the effect of a subsequent cocaine injection on spine morphology and protein content. Three weeks after daily cocaine or saline administration, neurons in the accumbens were filled with the lipophilic dye, DiI. Although daily cocaine pretreatment did not alter spine density compared with daily saline, there was a shift from smaller to larger diameter spines. During the first 2 h after an acute cocaine challenge, a bidirectional change in spine head diameter and increase in spine density was measured in daily cocaine-pretreated animals. In contrast, no change in spine diameter or density was elicited by a cocaine challenge in daily saline animals during the first 2 h after injection. However, spine density was elevated at 6 h after a cocaine challenge in daily saline-pretreated animals. The time-dependent profile of proteins in the postsynaptic density subfraction elicited by a cocaine challenge in daily cocaine-pretreated subjects indicated that the changes in spine diameter and density were associated with a deteriorating actin cytoskeleton and a reduction in glutamate signaling-related proteins. Correspondingly, the amplitude of field potentials in accumbens evoked by stimulating prefrontal cortex was reduced for up to 6 h after acute cocaine in daily cocaine-withdrawn animals. These data indicate that daily cocaine pretreatment dysregulates dendritic spine plasticity elicited by a subsequent cocaine injection.

Post-retrieval β-adrenergic receptor blockade: Effects on extinction and reconsolidation of cocaine-cue memories

Contexts and discrete cues associated with drug-taking are often responsible for relapse among addicts. Animal models have shown that interference with the reconsolidation of drug-cue memories can reduce seeking of drugs or drug-paired stimuli. One such model is conditioned place preference (CPP) in which an animal is trained to associate a particular environment with the rewarding effects of a drug. Previous work from this laboratory has shown that intra-nucleus accumbens core infusions of a MEK inhibitor can interfere with reconsolidation of these drug-cue memories. A question that remains is whether post-retrieval drug effects on subsequent memories represent an interference with reconsolidation processes or rather a facilitation of extinction. In this experiment, we explore the effect of post-retrieval injections of propranolol, a beta-adrenergic receptor antagonist, on reconsolidation and extinction of cocaine CPP. After acquisition of cocaine CPP, animals were given post-retrieval propranolol injections once or each day during a protocol of unreinforced preference tests, until the animals showed no preference for the previously cocaine-paired environment. Following a cocaine priming injection, the animals that received daily post-test propranolol injections did not reinstate their preference for the drug-paired side. In contrast, a single post-retrieval propranolol injection followed by multiple days of unreinforced preference tests failed to blunt subsequent cocaine reinstatement of the memory. These data suggest that daily post-retrieval systemic injections of propranolol decrease the conditioned preference by interfering with reconsolidation of the memory for the association between the drug-paired side and the reinforcing effects of the drug, rather than facilitating new extinction learning.

Cocaine conditioned behavior: A cocaine memory trace or an anti-habituation effect

Whether cocaine locomotor conditioning represents a cocaine positive effect; i.e., a Pavlovian cocaine conditioned response; or, a cocaine negative effect; i.e., interference with habituation to the test environment, is a subject of some controversy. Three separate experiments were conducted to compare the behavior (locomotion and grooming) of separate groups of rats given 1, 9 or 14 cocaine (10 mg/kg) treatments paired/unpaired with placement into an open-field arena. The behavior of the cocaine groups on subsequent saline tests were compared with the habituation rates of saline treated rats. After one cocaine pairing with the test environment, the subsequent behavior of the cocaine paired group on saline tests was similar to a non-habituated control group. In the two experiments with repeated cocaine pairings to the test environment, the subsequent behavior of the cocaine treated groups did not parallel that of the non-habituated saline control groups. These results were not explicable in terms of cocaine anti-habituation effects. It is suggested that cocaine contextual cues paired with cocaine treatment can activate cocaine memory traces which with subsequent cocaine treatments are reinforced and strengthened. In this way repeated cocaine use can forge conditioned stimulus connections to the cocaine behavioral response that are highly resistant to extinction.

Behavioral and Electrophysiological Indices of Negative Affect Predict Cocaine Self-Administration

The motivation to seek cocaine comes in part from a dysregulation of reward processing manifested in dysphoria, or affective withdrawal. Learning is a critical aspect of drug abuse; however, it remains unclear whether drug-associated cues can elicit the emotional withdrawal symptoms that promote cocaine use. Here we report that a cocaine-associated taste cue elicited a conditioned aversive state that was behaviorally and neurophysiologically quantifiable and predicted subsequent cocaine self-administration behavior. Specifically, brief intraoral infusions of a cocaine-predictive flavored saccharin solution elicited aversive orofacial responses that predicted early-session cocaine taking in rats. The expression of aversive taste reactivity also was associated with a shift in the predominant pattern of electrophysiological activity of nucleus accumbens (NAc) neurons from inhibitory to excitatory. The dynamic nature of this conditioned switch in affect and the neural code reveals a mechanism by which cues may exert control over drug self-administration.

Inhibiting activator protein-1 activity alters cocaine-induced gene expression and potentiates sensitization

We have expressed A-FOS, an inhibitor of activator protein-1 (AP-1) DNA binding, in adult mouse striatal neurons. We observed normal behavior including locomotion and exploratory activities. Following a single injection of cocaine, locomotion increased similarly in both the A-FOS expressing and littermate controls. However, following repeated injections of cocaine, the A-FOS expressing mice showed increased locomotion relative to littermate controls, an increase that persisted following a week of withdrawal and subsequent cocaine administration. These results indicate that AP-1 suppresses this behavioral response to cocaine. We analyzed mRNA from the striatum before and 4 and 24 h after a single cocaine injection in both A-FOS and control striata using Affymetrix microarrays (430 2.0 Array) to identify genes mis-regulated by A-FOS that may mediate the increased locomotor sensitization to cocaine. A-FOS expression did not change gene expression in the basal state or 4 h following cocaine treatment relative to controls. However, 24 h after an acute cocaine treatment, 84 genes were identified that were differentially expressed between the A-FOS and control mice. Fifty-six genes are down-regulated while 28 genes are up-regulated including previously identified candidates for addiction including brain-derived neurotrophic factor and period homolog 1. Using a random sample of identified genes, quantitative PCR was used to verify the microarray studies. The chromosomal location of these 84 genes was compared with human genome scans of addiction to identify potential genes in humans that are involved in addiction.

Effects of adolescent exposure to cocaine on locomotor activity and extracellular dopamine and glutamate levels in nucleus accumbens of DBA/2J mice

Adolescents differ from adults in their acute sensitivity to several drugs of abuse, but little is known about the long-term neurobehavioral effects of adolescent drug exposure. To explore this further, we evaluated the locomotor responses to repeated cocaine administration in adolescent and adult male DBA/2J mice and alterations in extracellular levels of dopamine (DA) and glutamate (GLU) in the nucleus accumbens (NAc) in response to a subsequent cocaine challenge. Adolescent and adult mice were treated daily with saline or cocaine (10 mg/kg, i.p) for 9 consecutive days. Ten days following the last injection, animals were implanted with microdialysis probes and 24 h later microdialysis samples were collected before and after an acute cocaine challenge. Adolescents but not adults demonstrated development of behavioral sensitization to cocaine. Microdialysis procedures revealed that cocaine-treated mice displayed greater peak increases in extracellular DA in response to a subsequent cocaine challenge as compared to saline-treated mice, in contrast with lower peak increases in extracellular GLU. While adults exhibited greater peaks in extracellular DA in response to cocaine than adolescents did, adolescent mice presented a more rapid onset of peak extracellular DA levels than adults. Our results indicate differences in the behavioral and neurochemical responses to cocaine in adolescent versus adult mice, which may be relevant to the increased risk of developing addiction in humans who are exposed to drugs of abuse during adolescence.

Acquisition of cocaine self-administration in ovariectomized female rats: Effect of estradiol dose or chronic estradiol administration

This study was conducted to investigate whether the dose of estradiol (E) administered acutely, or chronic delivery of one dose of E impacts acquisition and subsequent cocaine self-administration in ovariectomized (OVX) female rats. Five groups of female rats were compared: OVX females treated with 0, 1, 2, or 5 μg 17β-E, 30 min prior to the self-administration session, and OVX rats that received a 1.5 mg E pellet (designed to chronically release 25 μg E/day X 60 days) implanted 1 week before cocaine self-administration initiation. Rats were tested in 1 h sessions on a FR1 schedule with the dose of cocaine increasing every week (testing occurred 5 day/week; doses: 0.2, 0.3, 0.4, 0.5 and 0.75 mg/(kg infusion)). We report that OVX rats treated with 2 μg E acquired self-administration more rapidly than all of the other groups, and animals that received 1 or 2 μg E self-administered significantly more cocaine compared to OVX + vehicle at 0.3 and 0.4 mg/(kg infusion). In contrast, OVX rats given 5 μg E acutely, or chronic E via slow-release pellets did not take more cocaine than the OVX + vehicle group at any time point. Physiological serum concentrations of E were seen with 1 or 2 μg E, but 5 μg E and the E pellet produced supra-physiological concentrations. These results suggest an inverted U-shaped dose–response curve for the effect of E on acquisition of cocaine self-administration.

Behavioral expression of cocaine sensitization in rats is accompanied by a distinct pattern of modifications in the PKA/DARPP‐32 signaling pathway

Repeated cocaine administration induces behavioral sensitization and modifications in the phosphorylation pattern of dopamine and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32), characterized by a tonic increase in the Thr75 phosphorylated form, and a decrease in the Thr34 phosphorylated form. This study further investigated the correlations between cocaine sensitization and modifications in the DARPP-32 phosphorylation pattern, cAMP-dependent protein kinase (PKA) activity, and mGluR5 tone in the medial prefrontal cortex and nucleus accumbens. Behavioral sensitization and modifications in these neurochemical markers followed a similar temporal pattern. Moreover, in sensitized rats acute cocaine administration modified phosphorylation levels of Thr75- and Thr34-DARPP-32, GluR1, and NR1 subunits in the nucleus accumbens only at a dose double the efficacious dose in control rats. These results suggest that the high levels of phospho-Thr75 DARPP-32 maintain PKA in a prevalent inhibited state. Furthermore, in sensitized rats the acute administration of 6-methyl-2-(phenylethynyl)-pyridine, a mGluR5 antagonist, reinstated the phosphorylation levels of Thr75- and Thr34-DARPP-32, GluR1, and NR1 to control values, and a subsequent cocaine challenge did not elicit a sensitized response. These data suggest that a tonic increase in mGluR5 transmission in cocaine-sensitized rats sustains both the increase in phospho-Thr75 DARPP-32 levels and the expression of behavioral sensitization.

Amphetamine-Induced Dopamine Release: Markedly Blunted in Cocaine Dependence and Predictive of the Choice to Self-Administer Cocaine

Dopamine is an important mediator of the reinforcing effects of cocaine, and alterations in dopamine function might be involved in cocaine dependence. The goals of the present study were to characterize pre- and postsynaptic dopamine function in recently detoxified cocaine-dependent subjects. Specifically, dopamine response to an acute amphetamine challenge was assessed in striatal subregions in cocaine-dependent and healthy comparison participants using positron emission tomography (PET). Furthermore, the relationship between this dopamine response and the choice to self-administer cocaine in a laboratory model of relapse was investigated. Twenty-four cocaine-dependent participants and 24 matched healthy subjects underwent [(11)C]raclopride scans under a baseline condition and following intravenous amphetamine administration (0.3 mg/kg). Cocaine-dependent participants also completed cocaine self-administration sessions in which a priming dose of cocaine was followed by the choice to either self-administer subsequent cocaine doses or receive a monetary reward. Cocaine dependence was associated with a marked reduction in amphetamine-induced dopamine release in each of the functional subregions of the striatum (limbic striatum: -1.2% in cocaine-dependent participants versus -12.4% in healthy subjects; associative striatum: -2.6% versus -6.7%, respectively; sensorimotor striatum: -4.3% versus -14.1%). Blunted dopamine transmission in the ventral striatum and anterior caudate was predictive of the choice for cocaine over money. Cocaine dependence is associated with impairment of dopamine function, and this impairment appears to play a critical role in relapse.

Amphetamine-Induced Dopamine Release: Markedly Blunted in Cocaine Dependence and Predictive of the Choice to Self-Administer Cocaine

Objective: Dopamine is an important mediator of the reinforcing effects of cocaine, and alterations in dopamine function might be involved in cocaine dependence. The goals of the present study were to characterize pre- and postsynaptic dopamine function in recently detoxified cocaine-dependent subjects. Specifically, dopamine response to an acute amphetamine challenge was assessed in striatal subregions in cocaine-dependent and healthy comparison participants using positron emission tomography (PET). Furthermore, the relationship between this dopamine response and the choice to self-administer cocaine in a laboratory model of relapse was investigated. Method: Twenty-four cocaine-dependent participants and 24 matched healthy subjects underwent [ 11 C]raclopride scans under a baseline condition and following intravenous amphetamine administration (0.3 mg/kg). Cocaine-dependent participants also completed cocaine self-administration sessions in which a priming dose of cocaine was followed by the choice to either self-administer subsequent cocaine doses or receive a monetary reward. Results: Cocaine dependence was associated with a marked reduction in amphetamine-induced dopamine release in each of the functional subregions of the striatum (limbic striatum: –1.2% in cocaine-dependent participants versus –12.4% in healthy subjects; associative striatum: –2.6% versus –6.7%, respectively; sensorimotor striatum: –4.3% versus –14.1%). Blunted dopamine transmission in the ventral striatum and anterior caudate was predictive of the choice for cocaine over money. Conclusions: Cocaine dependence is associated with impairment of dopamine function, and this impairment appears to play a critical role in relapse.