Regulation of cocaine self-administration in humans: Lack of evidence for loading and maintenance phases

Background

In rodents, cocaine self-administration under a fixed-ratio schedule and with timeout intervals limited to the duration of the infusions is characterized by an initial burst of drug intake (loading) followed by more stable infusion rates (maintenance). We sought to examine whether similar phases might characterize self-regulated cocaine use in humans.

Methods

31 Non-treatment seeking, cocaine dependent subjects participated in three (8, 16, and 32 mg/70 kg/infusion), self-regulated, 2-h cocaine self-administration sessions under a fixed-ratio 1, 5-min timeout schedule. Data were assessed for visual (e.g., by graphs of cumulative numbers of infusions) and statistical evidence of change in phase (by step-function analyses of individual infusion rates).

Results

Graphs of cumulative infusions over time suggested a single, linear rate of self-administration over 2 h at each cocaine dose. Statistical analyses of infusion data by generalized estimating equation (GEE) models also failed to support a loading/maintenance pattern (suggesting, if anything, the possibility of increasing infusion rates over time).

Conclusions

Our findings fail to support the existence of distinct loading and maintenance phases of self-regulated cocaine administration in humans at behaviorally relevant doses. Several factors may account for these observations including differences between humans and rodents in self-regulated drug intake.     

Differential effects of acute and chronic treatment with the α2-adrenergic agonist,lofexidine, on cocaine self-administration in rhesus monkeys

Background

Lofexidine, an α₂-adrenergic agonist, is being investigated as a treatment for reducing opioid withdrawal symptoms and blocking stress-induced relapse to cocaine taking. Opioid abusers are often polydrug abusers and cocaine is one frequent drug of choice. However, relatively little is known about lofexidine interactions with cocaine. The present study investigated the effects of acute and chronic treatment with lofexidine in a pre-clinical model of cocaine self-administration.

Methods

Male rhesus monkeys were trained to respond for food (1 g) and cocaine (0.01 mg/kg/injection) under a fixed ratio 30 (FR30) or a second order FR2 (VR16:S) schedule of reinforcement. Systematic observations of behavior were conducted during and after chronic treatment with lofexidine.

Results

Acute treatment with lofexidine (0.1 or 0.32 mg/kg, IM) significantly reduced cocaine self-administration but responding for food was less effected. In contrast, chronic treatment (7–10 days) with lofexidine (0.1–0.32 mg/kg/h, IV) produced a leftward shift in the cocaine self-administration dose–effect curve, but had no effect on food-maintained responding. Lofexidine did not produce any observable side effects during or after treatment.

Conclusions

Lofexidine potentiated cocaine's reinforcing effects during chronic treatment. These data suggest that it is unlikely to be effective as a cocaine abuse medication and could enhance risk for cocaine abuse in polydrug abusers.     

5-HT induces temporomandibular joint nociception in rats through the local release of inflammatory mediators and activation of local β adrenoceptors

Objectives

The present studies assessed the effects of adolescent and adult ethanol exposure on the rewarding effects of cocaine as measured with the conditioned place preference procedure.

Methods

Male rats were exposed to intraperitoneal (IP) injections of ethanol or vehicle for 10 days [postnatal days (PNDs) 30-39 or PNDs 70-79; 2 mg/kg]. Place preference conditioning began on PND 65 or PND 105, respectively, and consisted of a baseline test followed by four conditioning cycles with either 0, 5, 10 or 20 mg/kg cocaine. Following the fourth conditioning cycle a final preference test was performed. Changes in time on the drug-paired side between the baseline and final test were analyzed.

Results

Animals exposed to vehicle (during adolescence or adulthood) showed a significant place preference at 20 mg/kg cocaine. Animals exposed to ethanol (during adolescence or adulthood) showed a significant place preference at 10 mg/kg cocaine.

Conclusions

Exposure to ethanol (adolescents or adults) sensitized the rewarding effects of cocaine. This may indicate an increase in the abuse liability of cocaine following a history of ethanol exposure.     

Interactions between the mGluR2/3 agonist, LY379268, and cocaine on in vivo neurochemistry and behavior in squirrel monkeys

Recent evidence indicates that group II metabotropic glutamate receptors (mGluR2 and mGluR3) may play a role in the pathology of cocaine addiction. The purpose of the current study was to determine the effects of the mGluR2/3 agonist, LY379268, on cocaine-induced changes in DA neurochemistry in nonhuman primates. Furthermore, the current study aimed to determine if changes in DA neurochemistry would correlate with LY379268-induced changes in the behavioral effects of cocaine. In vivo microdialysis was conducted in conscious squirrel monkeys (n = 4) in order to monitor cocaine-induced changes in extracellular DA in the caudate nucleus. Separate groups of subjects were trained on a fixed-interval schedule of stimulus termination (n = 4) or a second-order schedule of cocaine self-administration (n = 5) to characterize the behavioral-stimulant and reinforcing effects, respectively. LY379268 significantly attenuated cocaine-induced increases in DA. LY379268 also significantly attenuated cocaine-induced behavioral-stimulant effects following a short pretreatment time, but not following a longer pretreatment time. Cocaine self-administration was significantly attenuated but only at an intermediate pretreatment dose of LY379268. Moreover, reinstatement of previously extinguished cocaine self-administration was not significantly attenuated by LY379268. Hence, drug interactions on neurochemistry did not correlate well with behavioral measures.     

Psychosocial treatments for cocaine dependence: the role of depressive symptoms

Background

The association between cocaine use and depression has been frequently observed. However, less is known about the significance of depression in the treatment of cocaine use disorders. This study examined possible interrelations between drug use and depression severity among cocaine-dependent patients in psychosocial treatments for cocaine dependence.

Methods

Monthly assessed drug use and depression severity scores of N = 487 patients during 6-month psychosocial treatments for cocaine dependence were analyzed using hybrid latent growth models.

Results

Results indicated a moderate but statistically significant (z = 3.13, p < .01) influence of depression severity on increased drug use in the upcoming month, whereas drug use did not affect future depression severity.

Conclusions

Findings suggest that depression symptoms are an important predictor of drug use outcomes during psychosocial treatments for cocaine dependence and, hence, underline the importance of adequately addressing depression symptoms to improve treatment outcomes.     

Executive dysfunction in chronic cocaine users: an exploratory study

Introduction

Chronic cocaine use is associated with some executive deficits. We assessed executive functions using ecologically valid tests in chronic cocaine users.

Objectives

To investigate the relationship between executive deficits and three measures of severity of cocaine use: years of use, quantity used, and frequency of use.

Methods

Twenty-four cocaine users were compared with twenty-seven community controls. We used Student's t-test and Chi-squared to compare means and categorical variables, respectively. Linear regression analyses for the adjusted comparative analysis between cases and controls, and severity of cocaine use among cocaine users were performed.

Results

Chronic cocaine users performed worse on measures of attention and working memory (Forward and Backward Digit Span, p < .001), set-shifting abilities (difference score between the Trail Making B and A, TMB-A, p = .006), cognitive test of mental flexibility and response inhibition (Rule Shift Cards) (p < .001), and prefrontal functioning (Wisconsin Card Sorting Test, WCST, p = .023) than controls. Years of cocaine use were associated with deficits in the Backward Digit Span (p = .041; CI 95%: −.760 to −.002), the TMB-A (p = .026; CI 95%: .687 to 9.761), the Zoo Map (p = .034; CI 95%: −.480 to −.021), and the Rule Shift Cards (p = .006; CI 95%: −.836 to −.164), among others. Quantity of cocaine use was associated with executive deficits measured by the Forward Digit Span (p = .007; CI 95%: −.727 to −.133), the TMB-A (p = .021; CI 95%: 5.304-57.945), and the number of perseverative errors in the WSCT (p = .002; CI 95%: −10.654 to −2.800). Frequency of cocaine was associated with deficits in the Backward Digit Span (p = .042; CI 95%: −1.548 to −.030).

Conclusions

Chronic use of cocaine is associated with executive deficits, which may influence patients’ functionality, prognosis, and therapeutic failure.     

Exposure to alcohol during adolescence alters the aversive and locomotor-activating effects of cocaine in adult rats

Objectives

The present study assessed the effect of adolescent alcohol exposure on the later aversive and locomotor-activating effects of cocaine.

Methods

Male rats were exposed to alcohol or vehicle for 10 days [postnatal day (PND) 30-39; 2 g/kg IP]. Taste aversion conditioning began on PND 65. During aversion conditioning, subjects were presented with saccharin followed by cocaine (32 mg/kg; 15, 180 or 300 min post saccharin) or saline. Following each injection, animals were placed in locomotor chambers for 1 h. To determine if any effects seen were specific to the adolescent developmental period, the procedure was replicated in adult animals.

Results

Animals exposed to vehicle during adolescence showed significant aversions at all time delays. Animals exposed to ethanol during adolescence showed a decrease in consumption only at the 15 and 180 min delays. Groups exposed to alcohol during adolescence showed a decrease in gross, and an increase in fine, motor activity in response to cocaine. Animals exposed to alcohol during adulthood also showed attenuated taste aversions.

Conclusions

Exposure to ethanol during adolescence attenuated the aversive effects of cocaine and altered its locomotor-activating effects. Although this effect is not specific to adolescence, this is the time when alcohol use is typically initiated so that such exposure may enhance later abuse liability of cocaine.     

Violence among men and women in substance use disorder treatment: A multi-level event-based analysis

Background

This study examined associations between acute alcohol and drug use and violence towards others in conflict incidents (overall, partner, and non-partner conflict incidents) by men and women recruited from substance use disorder (SUD) treatment.

Methods

Semi-structured interviews were used to obtain details about interpersonal conflict incidents (substance use, whether specific conflicts were with intimate partners or non-partners) in the 180 days pre-treatment. Participants for this study were selected for screening positive for past-year violence (N = 160; 77% men, 23% women).

Results

Multi-level multinomial regression models showed that after adjusting for clustering within individual participants, the most consistent predictors of violence across models were acute cocaine use (significant for overall, intimate partner and non-partner models), acute heavy alcohol use (significant for overall and non-partner models), and male gender (significant in all models).

Conclusions

This study was the first to explicitly examine the role of acute alcohol and drug use across overall, partner and non-partner conflict incidents. Consistent with prior studies using a variety of methodologies, alcohol, cocaine use and male gender was most consistently and positively related to violence severity (e.g., resulting in injury). The results provide important and novel event-level information regarding the relationship between acute alcohol and specific drug use and the severity of violence in interpersonal conflict incidents.     

The preferential dopamine D3 receptor antagonist S33138 inhibits cocaine reward and cocaine-triggered relapse to drug-seeking behavior in rats

We have previously reported that selective dopamine (DA) D₃ receptor antagonists are effective in a number of animal models of drug addiction, but not in intravenous drug self-administration, suggesting a limited ability to modify drug reward. In the present study, we evaluated the actions of S33138, a novel partially selective D₃ receptor antagonist, in animal models relevant to drug addiction. S33138, at doses of 0.156 or 0.625 mg/kg (i.p.), attenuated cocaine-enhanced brain-stimulation reward (BSR), and the highest dose tested (2.5 mg/kg) produced a significant aversive-like rightward shift in BSR rate-frequency reward functions. Further, S33138 produced biphasic effects on cocaine self-administration, i.e., a moderate dose (2.5 mg/kg, p.o.) increased, while a higher dose (5 mg/kg, p.o.) inhibited, cocaine self-administration. The increase in cocaine self-administration likely reflects a compensatory response to a partial reduction in drug reward after S33138. In addition, S33138 (0.156-2.5 mg/kg, p.o.) also dose-dependently inhibited cocaine-induced reinstatement of drug-seeking behavior. The reduction in cocaine-enhanced BSR and cocaine-triggered reinstatement produced by lower effective doses (e.g., 0.156 or 0.625 mg/kg) of S33138 is unlikely due to impaired locomotion, as lower effective doses of S33138 decreased neither Y_max levels in the BSR paradigm, rotarod performance, nor locomotion. However, the higher doses (2.5 or 5 mg/kg) of S33138 also significantly inhibited sucrose self-administration and rotarod performance, suggesting non-D₃ receptor-mediated effects on non-drug reward and locomotion. These data suggest that lower doses of S33138 interacting essentially with D₃ receptors have pharmacotherapeutic potential in treatment of cocaine addiction, while higher doses occupying D₂ receptors may influence locomotion and non-drug reward.     

Effects of the selective sigma receptor ligand, 1-(2-phenethyl)piperidine oxalate (AC927), on the behavioral and toxic effects of cocaine

Background

Sigma receptors represent a unique structural class of proteins and they have become increasingly studied as viable medication development targets for neurological and psychiatric disorders, including drug abuse. Earlier studies have shown that cocaine and many other abused substances interact with sigma receptors and that antagonism of these proteins can mitigate their actions.

Methods

In the present study, AC927 (1-(2-phenethyl)piperidine oxalate), a selective sigma receptor ligand, was tested against the behavioral and toxic effects of cocaine in laboratory animals.

Results

Acute administration of AC927 in male, Swiss Webster mice significantly attenuated cocaine-induced convulsions, lethality, and locomotor activity, at doses that alone had no significant effects on behavior. Subchronic administration of AC927 also attenuated cocaine-induced conditioned place preference in mice, at doses that alone had no effects on place conditioning. In drug discrimination studies in male, Sprague-Dawley rats, AC927 partially substituted for the discriminative stimulus effects of cocaine. When it was administered with cocaine, AC927 shifted the cocaine dose-response curve to the left, suggesting an enhancement of the discriminative stimulus effects of cocaine. In non-human primates, AC927 was self-administered, maintaining responding that was intermediate between contingent saline and a maintenance dose of cocaine.

Conclusion

The ability of AC927 to elicit some cocaine-like appetitive properties and to also reduce many cocaine-induced behaviors suggests that it is a promising lead for the development of a medication to treat cocaine abuse.     

Evaluation of the hydrolytic activity of a long-acting mutant bacterial cocaine in the presence of commonly co-administered drugs

Background

Cocaine toxicity is a prevalent problem in the Unites States for which there is currently no FDA-approved pharmacotherapy. We have developed a bacterial cocaine esterase (CocE) towards this indication. A thermostabilized mutant of CocE (DM-CocE) retains the hydrolytic activity of the wild-type esterase, rapidly hydrolyzing cocaine into the inactive metabolites ecgonine methyl ester and benzoic acid, and can prevent cocaine toxicities in rodent and non-human primate models. To advance DM-CocE towards clinical use, we examine here how the hydrolytic activity of DM-CocE is altered by some drugs commonly co-administered with cocaine.

Methods

We employed a spectrophotometric cocaine hydrolysis assay to evaluate whether pharmacologically relevant doses of alcohol, nicotine, morphine, phencyclidine, ketamine, methamphetamine, naltrexone, naloxone, or midazolam would alter the Michaelis-Menten kinetics of DM-CocE for cocaine. Mass spectrometry was used to evaluate interaction with diazepam as this drug interferes with the absorbance spectra of cocaine critical for the spectrophotometric assay.

Results

Alcohol, nicotine, morphine, phencyclidine, ketamine, methamphetamine, naltrexone, naloxone, and midazolam did not alter cocaine hydrolysis by DM-CocE. However, diazepam significantly slowed DM-CocE cocaine hydrolysis at very high concentrations, most likely through interaction of the phenyl ring of the benzodiazepine with the active site of DM-CocE.

Conclusions

DM-CocE does not display significant drug interactions, with the exception of diazepam, which may warrant further study as DM-CocE progresses towards a clinically used pharmacotherapy for cocaine toxicity. Alternate benzodiazepines, e.g., midazolam could be used to avoid this potential interaction.     

Effects of cocaine esterase following its repeated administration with cocaine in mice

Background

A bacterial cocaine esterase (CocE) produces robust protection and reversal of cocaine toxicity. The aim of this study was to investigate how effectiveness of CocE was changed following its repeated administration together with cocaine.

Methods

Cocaine toxicity was quantified by measuring the occurrence of convulsions and lethality in mice. Immunologic responses of CocE were determined using ELISA. In the protection experiment, i.v. CocE 0.3 mg was given 1 min before a lethal dose of i.p. cocaine 180 mg/kg. In the rescue experiment, i.v. CocE 0.3 mg was given 1 min after the occurrence of convulsions elicited by i.p. cocaine 100 mg/kg. In both treatment paradigms, four trials were conducted in the same animals with a 2-week interval.

Results

CocE retained its effectiveness to protect or rescue mice during the first two trials and these mice did not show an immune response. In contrast, CocE's effectiveness was gradually reduced in the last two trials, accompanied by 10- and 100-fold increases in anti-CocE antibody titers. Nevertheless, effectiveness of CocE could be partially recovered by increasing the dose of CocE. In addition, escalating the dose of CocE from the minimum effective dose for repeated administration could also retain CocE's effectiveness longer and slow the production of anti-CocE antibodies.

Conclusions

These results indicate that CocE is a weak antigen and it can maintain its protective and rescuing ability initially against cocaine-induced toxicity. Decreased effectiveness of CocE following repeated use can be partially improved by adjusting the dose and frequency of CocE treatment.     

Enhancing brief cognitive-behavioral therapy with motivational enhancement techniques in cocaine users

Background

We investigated the impact of enhancing brief cognitive-behavioral therapy with motivational interviewing techniques for cocaine abuse or dependence, using a focused intervention paradigm.

Methods

Participants (n = 74) who met current criteria for cocaine abuse or dependence were randomized to three-session cognitive-behavioral therapy (CBT) or three-session enhanced CBT (MET + CBT), which included an initial session of motivational enhancement therapy (MET). Outcome measures included treatment retention, process measures (e.g., commitment to abstinence, satisfaction with treatment), and cocaine use.

Results

Participants who received the MET + CBT intervention attended more drug treatment sessions following the study interventions, reported significantly greater desire for abstinence and expectation of success, and they expected greater difficulty in maintaining abstinence compared to the CBT condition. There were no differences across treatment conditions on cocaine use.

Conclusions

These findings offer mixed support for the addition of MET as an adjunctive approach to CBT for cocaine users. In addition, the study provides evidence for the feasibility of using short-term studies to test the effects of specific treatment components or refinements on measures of therapy process and outcome.     

Contingency management with community reinforcement approach or twelve-step facilitation drug counseling for cocaine dependent pregnant women or women with young children

Background

Cocaine abuse among women of child-bearing years is a significant public health problem. This study evaluated the efficacy of contingency management (CM), the community reinforcement approach (CRA), and twelve-step facilitation (TSF) for cocaine-dependent pregnant women or women with young children.

Methods

Using a 2 × 2 study design, 145 cocaine dependent women were randomized to 24 weeks of CRA or TSF and to monetary vouchers provided contingent on cocaine-negative urine tests (CM) or non-contingently but yoked in value (voucher control, VC). Primary outcome measures included the longest consecutive period of documented abstinence, proportion of cocaine-negative urine tests (obtained twice-weekly), and percent days using cocaine (PDC) during treatment. Documented cocaine abstinence at baseline and 3, 6, 9 and 12 months following randomization was a secondary outcome.

Findings

CM was associated with significantly greater duration of cocaine abstinence (p < .01), higher proportion of cocaine-negative urine tests (p < 0.01), and higher proportion of documented abstinence across the 3-, 6-, 9- and 12-month assessments (p < 0.05), compared to VC. The differences between CRA and TSF were not significant for any of these measures (all p values ≥0.75). PDC decreased significantly from baseline during treatment in all four groups (p < 0.001) but did not differ significantly between CM and VC (p = 0.10) or between TSF and CRA (p = 0.23).

Interpretation

The study findings support the efficacy of CM for cocaine dependent pregnant women and women with young children but do not support greater efficacy of CRA compared to TSF or differential efficacy of CM when paired with either CRA or TSF.     

The cystine-glutamate transporter enhancer N-acetyl-L-cysteine attenuates cocaine-induced changes in striatal dopamine but not self-administration in squirrel monkeys

Extrasynaptic glutamate has been shown to regulate dopamine function in the mesocorticolimbic pathway, which plays an important role in the behavioral pharmacology of psychostimulants. Basal levels of glutamate are primarily regulated by the cystine-glutamate transporter and provide glutamatergic tone on extrasynaptic glutamate receptors. The present study examined the effects of a cystine-glutamate transporter enhancer on the neurochemical and behavioral effects of cocaine and amphetamine in nonhuman primates. It was hypothesized that augmenting extrasynaptic glutamate release with N-acetyl-l-cysteine (NAC), a cystine prodrug, would attenuate cocaine- or amphetamine-induced increases in extracellular dopamine and their corresponding behavioral-stimulant and reinforcing effects. In vivo microdialysis was used to evaluate cocaine-induced changes in extracellular dopamine (DA) in the caudate nucleus (n = 3). NAC significantly attenuated cocaine-induced increases in dopamine but had inconsistent effects on amphetamine-induced increases in dopamine (n = 4). Separate groups of subjects were either trained on a fixed-interval schedule of stimulus termination (n = 6) or on a second-order schedule of self-administration (n = 5) to characterize the behavioral-stimulant and reinforcing effects of psychostimulants, respectively. Systemic administration of NAC did not alter the behavioral-stimulant effects of either cocaine or amphetamine. Furthermore, cocaine self-administration and reinstatement of previously extinguished cocaine self-administration were not altered by pretreatment with NAC. Hence, drug interactions on caudate neurochemistry in vivo were not reflected in behavioral measures in squirrel monkeys. The present results in nonhuman primates do not support the use of NAC as a pharmacotherapy for cocaine abuse, although rodent and clinical studies suggest otherwise.     

Effects of pergolide on intravenous cocaine self-administration in men and women

Clinical evidence suggests that pergolide, a D₁/D₂ dopamine receptor agonist, may be useful in maintaining cocaine abstinence. We investigated pergolide’s effects in a laboratory model of IV cocaine self-administration by humans. Twelve inpatient volunteers (7M, 5F), who reported spending an average of $170/ week on cocaine, received pergolide (0.05 mg BID) for 8 days and placebo for 8 days, with drug order balanced across subjects. Self-administration sessions occurred on the last 4 days of maintenance on each medication. A modified seven-trial progressive ratio choice procedure (0, 8, 16, 32 mg/70 kg cocaine versus $5) was utilized, with sessions consisting of: (a) two sample trials, where participants responded to receive the dose and tokens available that day, and (b) five choice trials, where participants chose between the available dose and tokens. Following each trial, the response requirement for the chosen option increased by 400. Maintenance on pergolide 1) decreased cocaine-induced increases in ratings of “High,”“Stimulated,” cocaine “Potency,” estimates of street value, and heart rate, 2) increased ratings of “I want cocaine,” and 3) had no effect on cocaine self-administration. The increased desire to use cocaine during pergolide maintenance suggests that it has limited treatment utility at this dose, but given the attenuation of cocaine’s subjective and cardiovascular effects, an investigation of a wider range of pergolide doses on cocaine self-administration and subjective effects is warranted. Received: 29 April 1997/Final version: 14 October 1997     

Cocaine abuse versus cocaine dependence: Cocaine self-administration and pharmacodynamic response in the human laboratory

Cocaine has high abuse liability but only a subset of individuals who experiment with it develop dependence. The DSM-IV (APA. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-R. American Psychiatric Association, Washington, DC, 2000) provides criteria for diagnosing cocaine abuse and cocaine dependence as distinct disorders- the latter characterized by additional symptoms related to loss of control over drug use. In this study, two groups of cocaine users (n = 8/group), matched on demographic factors and length of cocaine use history and meeting criteria for either cocaine abuse (CocAb) or cocaine dependence (CocDep), were compared on (1) measures related to impulsivity and sensation seeking, (2) response to experimenter-administered cocaine (0, 12.5, 25 and 50 mg/70 kg, i.v.), and (3) cocaine self-administration using a Relapse Choice and a Progressive Ratio Procedure (0, 12.5 and 25 mg/70 kg, i.v.). Groups did not differ on impulsivity or sensation seeking scores. After experimenter-administered cocaine, the CocAb group reported feeling more suspicious and observers rated them significantly higher on unpleasant effects (e.g., irritability, difficulty concentrating). In contrast, the CocDep group reported significantly greater desire for cocaine, which was sustained over the course of the study, and gave higher street value estimates for cocaine (p < 0.05). While cocaine self-administration was dose-related and generally comparable across the two procedures, the CocDep users chose to take significantly more cocaine than the CocAb users. These data suggest that, while regular long-term users of cocaine with cocaine abuse or dependence diagnoses cannot be distinguished by trait measures related to impulsivity, they do exhibit significant differences with regard to cocaine-directed behavior and response to cocaine administration.     

Differential responsiveness to cocaine in C57BL/6J and DBA/2J mice

 The present study compared cocaine-induced hyperlocomotion and cocaine IV self-administration in DBA/2J and C57BL/6J mice. In the locomotor activity experiment, these strains were tested for hyperlocomotion after IP cocaine injection (0–60.0 mg/kg), using a Digiscan Animal Activity Monitoring System. In the cocaine IV self-administration experiment, they were compared for their ability to acquire and maintain cocaine self-administration in operant chambers with levers as the manipulanda. Animals were first trained to respond for food as a reinforcer (condensed milk solution); they were then submitted to surgical IV insertion of an indwelling catheter, and required to respond for IV cocaine (0.25–4.0 mg/kg per injection) as a reinforcer. DBA/2J mice showed significantly higher maximal cocaine-induced hyperlocomotion, more rapid acquisition of cocaine self-administration, and significantly lower rates of cocaine self-administration. Cocaine concentration in the brains of DBA/2J and C57BL/6J mice failed to differ following IP injection, suggesting that distribution factors were not involved in the differential responses to cocaine. Although not conclusive, this pattern of effects may suggest that cocaine has greater reinforcing efficacy in DBA/2J mice, confirming genetic make-up as a determinant factor in cocaine taking behavior. Received: 6 October 1997 / Final version: 4 January 1998     

CB1 receptors regulate alcohol-seeking behavior and alcohol self-administration of alcohol-preferring (P) rats

Rationale

The endogenous cannabinoid (CB) system mediates a number of behaviors associated with drug-seeking and drug self-administration. In this study the effects of CB1 receptor manipulations on operant ethanol (EtOH) responding during EtOH-seeking, EtOH-relapse as well as on-going EtOH self-administration were determined.

Methods

Alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) and water on a concurrent fixed-ratio 5-fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1-h sessions. After 10 weeks, rats underwent 7 extinction sessions, followed by 2 weeks in their home cages without access to EtOH or operant chambers. Rats were then returned to the operant chambers for testing of EtOH-seeking behavior (no EtOH present) for 4 sessions. After a week in their home cages following the EtOH-seeking test, rats were returned to the operant chambers with access to EtOH and water (relapse). Rats were then maintained in the operant chambers for daily 1-h sessions with access to 15% EtOH and water for several weeks.

Results

The CB1 receptor antagonist (SR141716A), at doses of 1 and 2 mg/kg, i.p. reduced EtOH-seeking and transiently reduced EtOH self-administration during relapse and maintenance. Conversely, treatment with the CB1 receptor agonist CP 55, 940, at doses of 1 and 10 μg/kg i.p., increased EtOH-seeking and EtOH self-administration during relapse.

Conclusions

The results of this study demonstrate that activation of CB1 receptors are involved in regulating EtOH-seeking as well as the reinforcing effects of EtOH under relapse and on-going self-administration conditions.     

Differences in self-reported and behavioral measures of impulsivity in recreational and dependent cocaine users

Background

Dependent cocaine users consistently display increased trait impulsivity on self-report questionnaires and less consistently exhibit elevated motor impulsivity in some behavioral tasks. However, trait and behavioral impulsivity measures have rarely been investigated in recreational users. Therefore, we examined self-reported trait and motor impulsivities in recreational and dependent cocaine users to clarify the role of impulse control in cocaine addiction and non-dependent cocaine use.

Methods

We investigated relatively pure recreational (n = 68) and dependent (n = 30) cocaine users, as well as psychostimulant-naïve controls (n = 68), with self-report questionnaires (Barratt Impulsiveness Scale 11; Temperament and Character Inventory) and behavioral tasks (Rapid Visual Information Processing Task; Stop-Signal Task).

Results

Compared with controls, recreational and dependent cocaine users displayed higher trait impulsivity and novelty seeking scores on self-report questionnaires. Trait impulsivity scores were strongly associated with an increased number of symptoms of depression and attention deficit hyperactivity disorder and correlated significantly with long-term cocaine intake parameters. By contrast, none of the behavioral motor impulsivity measures showed significant group effects or correlated with cocaine use parameters. The correlations among the self-report measures were high, but self-reports were scarcely correlated with behavioral task measures.

Conclusions

These findings suggest that relatively pure cocaine users already display increased trait impulsivity at a recreational level of use. However, the results do not indicate any cocaine-related elevation of behavioral impulsivity in terms of motor or response inhibition. In summary, our data imply that elevated trait impulsivity is not a specific feature of dependent cocaine use.