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PubMed1998

Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self-administration and relapse of cocaine-seeking behavior.

cAMP-dependent protein kinase (PKA) in the nucleus accumbens (NAc) has been implicated in cocaine addiction because (1) cocaine reinforcement is mediated by dopamine receptors that modulate cAMP formation, and (2) repeated exposure to cocaine upregulates the cAMP system in NAc neurons. This study tested PKA involvement in cocaine self-administration and relapse of cocaine-seeking behavior by infusing cAMP analogs that activate or inhibit PKA into the NAc of rats. Bilateral intra-NAc infusions of the PKA inhibitor Rp-cAMPS reduced baseline cocaine self-administration, shifted the dose-response curve for cocaine self-administration to the left, and induced relapse of cocaine-seeking behavior after extinction from cocaine self-administration, consistent with an enhancement of cocaine effects in each paradigm. In contrast, pretreatment with intra-NAc infusions of a PKA activator, Sp-cAMPS or dibutyryl cAMP, increased baseline cocaine self-administration during the second hour of testing and shifted the dose-response curve to the right, consistent with an antagonist-like action. After extinction from cocaine self-administration, similar infusions of Sp-cAMPS induced generalized responding at both drug-paired and inactive levers. As an index of PKA activity in vivo, NAc infusions of Rp-cAMPS reduced basal levels of dopamine-regulated phosphoprotein-32 phosphorylation and blocked amphetamine-induced increases in cAMP response element-binding protein (CREB) phosphorylation. Conversely, NAc infusions of Sp-cAMPS increased phosphorylation of CREB. Together, these results suggest that sustained upregulation of the cAMP system in the NAc after repeated cocaine exposure could underlie tolerance to cocaine reinforcement, whereas acute inhibition of this system may contribute to drug craving and relapse in addicted subjects.

Animals↗
PubMed2002

Cocaine-seeking behavior after extended cocaine-free periods in rats: role of conditioned stimuli.

RATIONALE: Cocaine abstinence symptoms and conditioned stimuli (CSs) previously associated with cocaine administration are postulated to contribute to relapse to drug taking in humans. OBJECTIVE: The present study assessed the role of both non-contingent CS presentation and experimenter-imposed extended cocaine-free periods on cocaine-seeking behavior in rats. METHODS: A fixed interval (FI) second-order schedule of intravenous cocaine (0.5 mg/infusion) reinforcement of the type FI 15 min (fixed ratio 8:S) was used. RESULTS: Non-contingent CS presentation before exposure to a cocaine binge had no effect on responding under the second-order schedule of reinforcement for cocaine after 23 h of no access to cocaine. By contrast, six non-contingent presentations of the CS during a 1-min period before the test session increased the number of responses in both no-binge (daily 2-h sessions, five infusions) and binge (two 12-h overnight sessions; maximum 48 infusions) exposed rats on day 7 of the cocaine-free period compared to no-binge- and binge-exposed rats that were not presented with the CSs. On day 30 of the cocaine-free period, only binge-exposed rats presented with the CSs exhibited a tendency for increased level of responding. CONCLUSIONS: The results indicated that non-contingent CS presentation had no effect after 23 h of no access to cocaine, increased drug-seeking behavior on day 7 of the cocaine-free period independent of binge exposure, and a strong tendency to increase drug-seeking behavior only in binge-exposed rats, on day 30 of the cocaine-free period, illustrating the interactive effects of conditioned stimuli with the extended cocaine-free period.

Animals↗
PubMed2000

Evaluation of anti-cocaine antibodies and a cocaine vaccine in a rat self-administration model.

RATIONALE: Previous pre-clinical studies with an anti-cocaine monoclonal antibody left open several issues critical to assessing the effectiveness of a vaccine for altering cocaine self-administration behavior. OBJECTIVES: The objectives of this study were to determine, first, whether changes in self-administration behavior would be systematically related to antibody level and, second, how the antibody affected the self-administration of different doses of cocaine. METHODS: Two experiments were conducted using a second-order schedule of drug delivery in rats. The first was a passive-administration study using the anti-cocaine monoclonal antibody MO240 to examine the relationship between antibody level and cocaine self-administration behavior, and the second was an active-immunization study to examine the efficacy of the cocaine vaccine IPC-1010 for blocking various doses of self-administered cocaine. RESULTS: The passive-administration experiment with control and 4-mg or 12-mg MO240 treatments showed that antagonism of the 1 mg/kg cocaine training dose was dependent on antibody level. In animals whose serum antibody levels were sustained above 0.05 mg/ml, there was a sufficient amount of antibody to reduce drug-seeking behavior and drug intake. In the active-immunization experiment, the cocaine vaccine IPC-1010 induced average serum antibody levels of 0.08 mg/ml and reduced the reacquisition of behavior by 1 mg/kg cocaine. Antagonism of cocaine self-administration after immunization was evident across a range of doses of cocaine and was only apparent in animals whose serum antibody levels exceeded 0.05 mg/ml. Furthermore, there was no evidence that the antagonism was surmountable within the dose range examined (up to 5.6 mg/kg). CONCLUSIONS: Antagonism of cocaine self-administration across a range of doses is feasible after immunization with a cocaine vaccine as long as antibody levels are of a sufficient concentration.

Animals↗
PubMed1992

Pharmacogenetic assessment of the effects of carbamazepine on cocaine-kindled and cocaine-induced seizures.

The effects of chronic carbamazepine (CBZ) on the development and expression of cocaine-kindled seizures and seizures produced by an acute injection of cocaine were evaluated in BALB/cByJ, C57Bl/6J and SJL/J mice. The repeated administration of a subconvulsant dose of cocaine initially resulted in the development of an increased sensitivity to the convulsant effects of cocaine in the three strains. Chronic, dietary carbamazepine attenuated this initial sensitization to cocaine-induced seizures. While the continued administration of cocaine resulted in a relatively permanent sensitization to cocaine-induced seizures among SJL mice, tolerance to cocaine-induced seizures ultimately developed among C57 mice and to a lesser degree among BALB mice. Genetic factors were found to mediate the effects of chronic CBZ on the development of sensitization and/or tolerance to the convulsant effects of cocaine. Among BALB mice, chronic CBZ appears to have eliminated the development of tolerance to cocaine-induced seizures and allowed an underlying sensitization to be manifest. Among SJL mice, however, the sensitization observed following repeated cocaine injections was reduced, but not eliminated. Genetic factors were also found to be associated with the effects of CBZ on seizures induced by the acute administration of cocaine. BALB and C57 mice, but not SJL mice, chronically treated with dietary CBZ were less susceptible to a consulvant dose of cocaine than their corresponding dietary controls for at least 72 h after stopping CBZ administration. In addition, there were genotype-specific lethal effects associated with the concurrent administration of CBZ and cocaine.

Animals↗
PubMed1996

Effect of cocaine on dopamine transporter receptors depends on routes of chronic cocaine administration.

Investigation of residual behavioral states produced by withdrawal from different routes of cocaine administration indicates that depending on the mode of intake, chronic cocaine produces either tolerance or sensitization to subsequent challenge doses of cocaine. We studied the effect of routes of cocaine administration on the dopamine transporter receptors (DATR), the presumed neuronal mediator of cocaine reward, using the diphenyl substituted piperazine derivative, [3H]GBR 12935 and the cocaine analogue [3H]WIN 35,428. Alzet osmotic mini-pumps filled with either cocaine (100 mg/ml) or saline were surgically implanted on rats into a subcutaneous pocket at the dorsal midline, continuously infusing cocaine at the rate of 40 mg/kg/day. The pumps were removed 14 days later, and the rats were killed 7 days after the removal of pumps. For the intermittent administration, two groups of rats were injected daily either with 40 mg/kg of cocaine or saline for 14 days. Rats were killed 7 days following the last injection. Continuous infusion of cocaine did not alter the [3H]GBR 12935 dopamine transporter (DAT) binding either in the caudate nucleus or in the prefrontal cortex, but it enhanced the density of [3H]WIN 35,428-labeled DAT receptor sites in the caudate putamen. In contrast, intermittent administration of cocaine resulted in a selective alteration of [3H]GBR 12935 binding in the prefrontal cortex but not in the caudate; the cocaine-injected rats had a 48% decrease in [3H]GBR 12935, Bmax (p < .05), without changing the KD. The contrast between the lack of effect of cocaine on [3H]GBR 12935-DATR and the increased binding of [3H]WIN 35,428-DATR highlights the differential sensitivities of the two binding sites to the continuous presence of cocaine.

Animals↗
PubMed2004

Cocaine-induced relaxation of isolated rat aortic rings and mechanisms of action: possible relation to cocaine-induced aortic dissection and hypotension.

Cocaine HCl is well known for its toxic effects on the cardiovascular system, but little is known about its effects on different regional blood vessels. We designed experiments to determine if cocaine HCl could influence the tension of isolated aortic rings, i.e., induce contraction or relaxation. Surprisingly, cocaine HCl (1 x 10(-5) to 6 x 10(-3) M) relaxed isolated aortic rings precontracted by phenylephrine in a concentration-dependent manner. No significant differences were found between intact or denuded isolated aortic rings (P>0.05). The maximal % relaxations of intact vs. denuded isolated aortic rings were 108.9+/-24.3% vs. 99.5+/-8.3% (P>0.05). Cocaine HCl, 2 x 10(-3) M, was found to inhibit contractions by phenylephrine; EC50s were increased (P<0.01) and Emax's were decreased (51.3+/-16.4% vs. 89.8+/-10.6%, P<0.01). A variety of amine antagonists could not inhibit the relaxant effects of cocaine HCl (P>0.05). The cyclooxygenase-1 inhibitor, indomethacin, also failed to inhibit relaxations induced by cocaine HCl (P>0.05). Neither L-arginine, NG-monomethyl-L-arginine (L-NMMA), nor methylene blue could inhibit the relaxations induced by cocaine HCl (P>0.05), suggesting cocaine HCl does not relax isolated aortic rings by inducing the synthesis or release of nitric oxide (NO) or prostanoids from either endothelial or vascular muscle cells. Inhibitors of cAMP, cGMP and protein kinase G (PKG) also failed to inhibit cocaine-induced relaxations. Cocaine HCl (1 x 10(-5) to 6 x 10(-3) M) could also relax isolated aortic rings precontracted by phenylephrine in high K+ depolarizing buffer. Surprisingly, calyculin A, an inhibitor of myosin light chain (MLC) phosphatase, inhibited cocaine-induced relaxations in a concentration-dependent manner, suggesting the probable importance of cocaine-induced MLC phosphatase activation in rat aortic smooth muscle cells. It was also found that cocaine HCl could dose-dependently inhibit Ca2+-induced contractions of isolated aortic rings in high K+-Ca2+-free buffer, suggesting that cocaine HCl may inhibit Ca2+ influx and/or intracellular release.

Aortic Dissection↗
PubMed2003

Individual differences in cocaine-induced locomotor activity in rats: behavioral characteristics, cocaine pharmacokinetics, and the dopamine transporter.

Outbred male Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor response to acute cocaine. Concomitant measurement of dopamine clearance in these rats revealed that the differential behavioral responses are associated with the magnitude of dopamine transporter (DAT) inhibition by cocaine. Here, we investigated several factors that might contribute to cocaine-induced behavioral variability and its association with differential inhibition of DAT function. In rats classified as LCRs or HCRs after 10 mg/kg cocaine injection, we found no differences in (1) novelty-induced locomotion, (2) cocaine levels in dorsal striatum or nucleus accumbens (NAc), (3) DAT number or affinity in NAc, or (4) DAT affinity for cocaine in NAc. In rats given 20 mg/kg cocaine, behavior was more uniform across individuals, but still warranted separation into LCR/HCR categories. Additionally, we analyzed the stability of the LCR/HCR classification made during the first test with 10 or 20 mg/kg cocaine by retesting rats 7 days later with saline or cocaine (10 or 20 mg/kg). Before injection, HCRs were more active relative to LCRs and to their own behavior on the first test day. Following cocaine, LCRs and HCRs exhibited similar drug-induced changes in locomotion, but there were unique effects that depended on the cocaine dose given on the first and second test days. Our results argue against several likely explanations for individual differences in cocaine-induced behavior and highlight the influence of a single cocaine exposure on subsequent behavioral responses to the drug.

Animals↗
PubMed2005

Mu-opioid receptors are not involved in acute cocaine-induced locomotor activity nor in development of cocaine-induced behavioral sensitization in mice.

Although mu-opioid receptors have been extensively investigated for their role in drug reinforcement, little is known about the contribution of these receptors to the acute and sensitized locomotor response to cocaine. In this study mu-opioid receptor involvement in acute cocaine-induced locomotor activity and in the development of cocaine-induced behavioral sensitization was evaluated using mu-opioid receptor knockout mice and chronic naltrexone (NTX) pretreatment as models. In addition, co-administration of the specific mu-opioid receptor antagonist CTOP with repeated saline or cocaine injections was used to establish the involvement of mu-opioid receptors in sensitization to the locomotor stimulant effects of cocaine. The acute locomotor response to cocaine (3, 10, 20, or 30 mg/kg i.p.) of mu-opioid receptor knockout or chronic NTX pretreated mice was not different from the cocaine response of their respective controls. With respect to cocaine-induced behavioral sensitization, induced by daily injections of 20 mg/kg cocaine for 11 subsequent days, mu-opioid receptor knockout mice developed behavioral sensitization to the locomotor stimulant effects of cocaine (challenge 10 mg/kg i.p.) comparable to wild-type littermates and the mu-opioid receptor antagonist CTOP did not affect cocaine-induced sensitization either. However, mice that were pretreated with NTX exhibited augmented cocaine-induced behavioral sensitization relative to placebo pretreated controls, which may be ascribed to increased delta-opioid receptor levels as has been described for chronic NTX pretreated mice. The present findings suggest that mu-opioid receptors are not required for the acute locomotor response to cocaine nor are they essential for the development of cocaine-induced behavioral sensitization.

Animals↗
PubMed2005

Effects of high-dose methadone maintenance on cocaine place conditioning, cocaine self-administration, and mu-opioid receptor mRNA expression in the rat brain.

Methadone maintenance at appropriate doses can effectively reduce cocaine abuse in heroin-dependent individuals. In the present studies, we investigated the effect of high-dose methadone maintenance cocaine conditioned place preference (CPP) and cocaine intravenous self-administration. Rats implanted with methadone-filled osmotic mini-pumps (20 and 55 mg/kg/day, SC) and conditioned with cocaine (1, 5, and 20 mg/kg, i.p.) did not express cocaine CPP. Similarly, rats implanted with methadone pumps (55 mg/kg/day) after cocaine conditioning (20 mg/kg) displayed neither spontaneous nor cocaine-precipitated (20 mg/kg, i.p.) CPP. In contrast, methadone maintenance (30 and 55 mg/kg/day, SC) did not alter the intravenous self-administration (continuous schedule of reinforcement) of various doses of cocaine (0.1, 0.5, and 2.0 mg/kg/inf). To explore neuropharmacological interactions between methadone maintenance and cocaine conditioning, we quantitatively measured mRNA levels of mu-opioid receptor (MOR) and proopiomelanocortin genes 10 days after methadone maintenance. MOR mRNA levels in both the nucleus accumbens core and frontal cortex were significantly elevated in rats exposed to cocaine during CPP conditioning. However, upregulation of MOR mRNA levels in the nucleus accumbens core were reduced by methadone maintenance in a dose-dependent manner. In conclusion, our results suggest that high-dose methadone maintenance does not alter the direct reinforcing effect of cocaine, but blocks spontaneous and cocaine-precipitated cocaine-seeking, possibly by preventing MOR alterations in the nucleus accumbens core induced by cocaine conditioning.

Analysis of Variance↗
PubMed2003

Individual differences in cocaine-induced locomotor sensitization in low and high cocaine locomotor-responding rats are associated with differential inhibition of dopamine clearance in nucleus accumbens.

Behavioral sensitization to cocaine reflects neuroadaptive changes that intensify drug effects. However, repeated cocaine administration does not induce behavioral sensitization in all male Sprague-Dawley rats. Because cocaine inhibits the dopamine (DA) transporter (DAT), we investigated whether altered DAT function contributes to these individual differences. Freely moving rats had electrochemical microelectrode/microcannulae assemblies chronically implanted in the nucleus accumbens so that exogenous DA clearance signals were recorded simultaneous with behavior. The peak DA signal amplitude (A(max)) and efficiency of clearance (k) were used as indices of in vivo DAT function. Low and high cocaine responders (LCRs and HCRs, respectively) were identified based on their locomotor responsiveness to an initial injection of cocaine (10 mg/kg i.p.). Consistent with DAT inhibition, cocaine elevated A(max) and reduced k in HCRs, but not in LCRs. The same dose of cocaine was administered for six additional days and after a 7-day withdrawal. Baseline behavioral and dopamine clearance indices were unaltered by repeated cocaine or after withdrawal. Only LCRs expressed cocaine-induced sensitized locomotor activation, and this was accompanied by cocaine-induced elevations in A(max) and reductions in k. These sensitized responses to cocaine persisted in LCRs after withdrawal. In contrast, neither locomotor nor electrochemical responses were altered by repeated saline administration or a saline challenge after repeated cocaine administration, suggesting that conditioning did not significantly contribute. Our results suggest that increased DAT inhibition by cocaine is associated with locomotor sensitization and that DAT serves as a common substrate for mediating both the initial and sensitized locomotor responsiveness to cocaine.

Animals↗
PubMed1999

The relationship of alcohol use to cocaine relapse in cocaine dependent patients in an aftercare study.

OBJECTIVE: To examine the relationship between alcohol use and cocaine relapse. METHOD: Ninety-eight cocaine-dependent male patients in aftercare were followed for 6 months following completion of an intensive outpatient rehabilitation program (IOP). Past and current alcohol dependence was assessed at entrance into aftercare, and drinking behavior prior to cocaine relapse and "near miss" episodes was assessed at 3- and 6-month follow-ups. Data on cocaine and alcohol use throughout the follow-up were also obtained. RESULTS: Patients who had never met criteria for alcohol dependence and those with current alcohol dependence had worse cocaine outcomes (cocaine use on 10% and 7% of the days in the follow-up, respectively) than those with past alcohol dependence (cocaine use on 3% of the days in the follow-up), although alcohol dependence status no longer predicted cocaine use outcomes when cocaine use in IOP was controlled. Alcohol use in 4 of the first 5 follow-up months significantly predicted cocaine relapse status in the next month after cocaine use in IOP and alcohol dependence diagnosis at baseline were controlled. Patients who experienced cocaine relapses were much more likely to report drinking before the onset of the episode than those who had "near misses," particularly on the day of the episode (40% vs. 6% at 3 months; 62% vs. 0% at 6 months). Alcohol did not appear to be a factor in the relapses of cocaine patients with no history of alcohol dependence, even though they did report drinking on 5% of the days in the follow-up. CONCLUSIONS: Relapse prevention efforts with cocaine abusers who have histories of alcohol dependence should include interventions designed to reduce drinking.

Adult↗
PubMed1998

The role of corticotropin-releasing factor and corticosterone in stress- and cocaine-induced relapse to cocaine seeking in rats.

We have shown previously that footshock stress and priming injections of cocaine reinstate cocaine seeking in rats after prolonged drug-free periods (Erb et al., 1996). Here we examined the role of brain corticotropin-releasing factor (CRF) and the adrenal hormone corticosterone in stress- and cocaine-induced reinstatement of cocaine seeking in rats. The ability of footshock stress and priming injections of cocaine to induce relapse to cocaine seeking was studied after intracerebroventricular infusions of the CRF receptor antagonist D-Phe CRF12-41, after adrenalectomy, and after adrenalectomy with corticosterone replacement. Rats were allowed to self-administer cocaine (1.0 mg/kg/infusion, i.v) for 3 hr daily for 10-14 d and were then placed on an extinction schedule during which saline was substituted for cocaine. Tests for reinstatement were given after intermittent footshock (10 min; 0.5 mA) and after priming injections of saline and cocaine (20 mg/kg, i.p.). Footshock reinstated cocaine seeking in both intact animals and animals with corticosterone replacement but not in adrenalectomized animals. The CRF receptor antagonist D-Phe CRF12-41 blocked footshock-induced reinstatement at all doses tested in both intact animals and animals with corticosterone replacement. Reinstatement by priming injections of cocaine was only minimally attenuated by adrenalectomy and by pretreatment with D-Phe CRF12-41. These data suggest that brain CRF plays a critical role in stress-induced, but only a modulatory role in cocaine-induced, reinstatement of cocaine seeking. Furthermore, the data show that although reinstatement of cocaine seeking by footshock stress requires minimal, basal, levels of corticosterone, stress-induced increases in corticosterone do not play a role in this effect.

Adrenal Glands↗
PubMed2000

Modulation of intravenous cocaine effects by chronic oral cocaine in humans.

RATIONALE: Agonist therapies have proven effective for the treatment of substance dependence disorders; limited data is available on their feasibility for treating cocaine dependence. OBJECTIVES: This laboratory study was designed to test the safety and utility of employing an agonist substitution therapy for the treatment of cocaine dependence in humans. METHODS: Oral cocaine served as the agonist treatment and was administered chronically over a range of doses to volunteers with cocaine abuse histories (n=8). Oral capsules were administered daily under blind conditions (q.i.d.) during this 5-week inpatient study using a dose-rising sequence (0 mg 10 days: 25 mg 3 days, 50 mg 4 days, 100 mg 10 days, 0 mg 7 days). During each of these oral dosing periods, an i.v. cocaine challenge (0, 25, and 50 mg, 1 h apart) was administered at least once. Physiological, subjective and pharmacokinetic measures were collected before and after i.v. drug administration; additional measures were collected daily. RESULTS: Oral cocaine produced no subjective effects or signs of toxicity but produced dose-related physiological effects. Significant interactions between oral and i.v. cocaine were observed; cocaine (100 mg, p.o.) significantly decreased responses to the 25-mg but not the 50-mg dose of i.v. cocaine for heart rate, mydriasis, and some subjective measures. There was no evidence of significant additive effects, although heart rate responses to i.v. cocaine were exaggerated during the final wash-out period. CONCLUSIONS: These data indicate that treatment with a cocaine "agonist" - in this case oral cocaine - can modestly attenuate the subjective and physiological responses to cocaine in humans under conditions that are safely tolerated.

Administration, Oral↗
PubMed2006

Preadolescent methylphenidate versus cocaine treatment differ in the expression of cocaine-induced locomotor sensitization during adolescence and adulthood.

BACKGROUND: Methylphenidate (MPH), the most commonly prescribed medication for childhood attention-deficit/hyperactivity disorder (ADHD), shares chemical and mechanistic similarities to cocaine which has stimulated research to address the addiction liability following treatment. METHODS: Utilizing locomotor sensitization we examined the consequences of recurrent MPH versus cocaine treatment during preadolescence in altering cocaine-induced locomotor behavior in adolescent and adult mice. Black Swiss Webster mice were treated with MPH, cocaine, or saline during preadolescence. To test whether MPH pretreatment during preadolescence contributed to an altered sensitivity to cocaine during adolescence, these mice were treated with recurrent cocaine or saline during adolescence. All mice were challenged with cocaine as adults. RESULTS: Recurrent MPH treatment, unlike cocaine treatment in preadolescent mice, had no effect on locomotor sensitization to cocaine during adolescence or adulthood, as compared with saline controls. Furthermore, unlike cocaine, administration of MPH in adolescence did not augment the response to cocaine challenge. CONCLUSIONS: MPH treatment during preadolescence does not increase subsequent sensitivity to cocaine, whereas cocaine treatment does. Thus, MPH treatment during preadolescence does not appear to persistently induce long-term adaptations, which may underlie an enhanced liability for subsequent drug abuse.

Age Factors↗
PubMed2004

Interaction of noncontingent cocaine and contingent drug-paired stimuli on cocaine reinstatement.

Both noncontingent cocaine and the presentation of cocaine-paired external stimuli will reinstate cocaine-appropriate operant responding. However, the interaction of noncontingent cocaine and cocaine-paired stimuli in producing reinstatement has not been extensively examined. In the present study, the ability of noncontingent cocaine alone, the combination of noncontingent cocaine + contingent cocaine-paired lights + tone and contingent lights + tone alone to produce reinstatement were examined. No cocaine dose (3, 10, 17 mg/kg) produced significant reinstatement in the absence of cocaine-paired lights + tone. When responding also resulted in lights + tone presentation, all doses of cocaine produced similar, significant reinstatement. Finally, when only response contingent lights + tone were presented, none of the groups showed significant reinstatement. These findings indicate that in isolation, noncontingent cocaine alone and cocaine-paired external stimuli may be insufficient to engender significant levels of reinstatement, but when presented together produce robust reinstatement. The results highlight the important interaction between drug administration and drug-paired environmental stimuli in the reinstatement model.

Acoustic Stimulation↗
PubMed2005

The novel dopamine D3 receptor antagonist NGB 2904 inhibits cocaine's rewarding effects and cocaine-induced reinstatement of drug-seeking behavior in rats.

Accumulating evidence indicates that dopamine (DA) D(3) receptor antagonists appear highly promising in attenuating cocaine reward and relapse in preclinical models of addiction. In the present study, we investigated the effects of the novel D(3)-selective antagonist NGB 2904 (N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-3-fluorenylcarboxamide) on cocaine self-administration, cocaine-enhanced brain stimulation reward (BSR), and cocaine-triggered reinstatement of drug-seeking behavior in male Long-Evans rats. We found that: (1) acute intraperitoneal (i.p.) administration of NGB 2904 (0.1-10 mg/kg) failed to alter cocaine self-administration (0.5 mg/kg/infusion) under fixed-ratio 2 (FR2) reinforcement, but 1 or 5 mg/kg NGB 2904 significantly lowered the break-point for cocaine self-administration under progressive-ratio (PR) reinforcement; (2) cocaine (1, 2, and 10 mg/kg) significantly enhanced electrical BSR (decreased brain reward thresholds), while NGB 2904 significantly inhibited the enhancement of BSR elicited by 2 mg/kg, but not 10 mg/kg of cocaine; (3) NGB 2904 alone neither maintained self-administration behavior nor altered brain reward thresholds; and (4) NGB 2904 significantly inhibited cocaine-triggered reinstatement of extinguished drug-seeking behavior, but not sucrose-plus-sucrose-cue-triggered reinstatement of sucrose-seeking behavior. Overall, these data show that the novel D(3)-selective antagonist NGB 2904 attenuates cocaine's rewarding effects as assessed by PR self-administration, BSR, and cocaine-triggered reinstatement of cocaine-seeking behavior. Owing to these properties and to its lack of rewarding effects (as assessed by BSR and by substitution during drug self-administration), NGB 2904 merits further investigation as a potential agent for treatment of cocaine addiction.

Animals↗
PubMed2004

Non-fatal cocaine overdose among injecting and non-injecting cocaine users in Sydney, Australia.

AIM: To investigate the frequency of non-fatal cocaine overdose, and responses to overdoses, among injecting and non-injecting cocaine users. DESIGN: Cross-sectional study. SETTING: Sydney, Australia. PARTICIPANTS: Two hundred current cocaine users. MEASUREMENTS: Structured interview. FINDINGS: Thirteen per cent of the sample had overdosed on cocaine, 7% in the preceding 12 months. Cocaine injectors were more likely to have overdosed, both ever (17 v 6%) and in the preceding 12 months (9 v 3%). The most common symptoms of overdose were palpitations (68%), intense sweating (44%) and seizures (40%). The use of other drugs in combination with cocaine prior to the most recent overdose was prevalent (64%), most commonly opioids (40%), alcohol (24%) and cannabis (24%). Those who had overdosed were more likely to be female, had longer cocaine use careers, had used more cocaine in the preceding month and preceding 6 months, had higher levels of cocaine dependence and more extensive polydrug use. Twenty-four per cent had witnessed a cocaine overdose, 13% in the preceding 12 months. Injectors were more likely to have witnessed overdoses, both ever (35% v 8%) and in the preceding 12 months (20% v 3%). CONCLUSIONS: Experience of, and exposure to, overdose were not rare events. Cocaine users need to be aware of the possibility and nature of overdose, and that cocaine overdose can occur irrespective of method of use. There is a need to emphasise the potential danger of combining cocaine with other drugs.

Adult↗
PubMed2004

Cocaine increases medial prefrontal cortical glutamate overflow in cocaine-sensitized rats: a time course study.

Excitatory amino acid transmission within mesocorticolimbic brain pathways is thought to play an important role in behavioural sensitization to psychomotor stimulants. The current studies evaluated a time course of the effects of cocaine on extracellular glutamate levels within the medial prefrontal cortex (mPFC) following increasing periods of withdrawal from repeated cocaine exposure. Male Sprague-Dawley rats underwent stereotaxic surgeries and were pretreated daily with saline (1 mL/kg/day x 4 days, i.p.) or cocaine (15 mg/kg/day x 4 days, i.p.) and withdrawn for 1, 7 or 30 days. After withdrawal rats were challenged with the same dose of saline or cocaine and in vivo microdialysis of the mPFC was conducted with concurrent analysis of locomotor activity. Animals that were withdrawn from repeated daily cocaine for 1 day and 7 days displayed an augmentation in cocaine-induced mPFC glutamate levels compared to saline and acute control subjects, which were similarly unaffected by cocaine challenge. At the 7 day time point, a subset of animals that received repeated cocaine did not express behavioural sensitization, nor did these animals exhibit the enhancement in mPFC glutamate in response to cocaine challenge. In contrast to these early effects, 30 days of withdrawal resulted in no significant changes in cocaine-induced mPFC glutamate levels regardless of the pretreatment or behavioural response. These data suggest that repeated cocaine administration transiently increases cocaine-induced glutamate levels in the mPFC during the first week of withdrawal, which may play an important role in the development of behavioural sensitization to cocaine.

Analysis of Variance↗