In the rat, continuous access to d -amphetamine (d-AMPH) leads to lengthy bouts of self-administration, voluntary abstinence, and relapse to self-administration. Previous studies have revealed that the progression from psychostimulant self-administration to abstinence to relapse is mediated in part by the ventral hippocampus. Stimulation of the ventral subiculum (vSub) during voluntary abstinence from d-AMPH self-administration reinstates self-administration and increases nucleus accumbens (NAc) dopamine efflux. Quantitative proteomic examination of the hippocampus from rats naïve to amphetamine, during a self-administration session ‘Binge’, during voluntarily abstinence ‘Abstinent’, and after reinstatement of self-administration ‘Relapse’, revealed a differential proteomic state during abstinence. Actin- and cytoskeletal-related proteins were over-represented in the changes occurring during abstinence and suggest a decrease in actin filament polymerization. These changes may underlie alterations in neuronal tone during abstinence that could affect both neurotransmission and behavior. These data provide the first classification of addiction-related behaviors based on clustering of quantitative proteomic measurements.

Drug-dependent neural plasticity related to drug addiction and schizophrenia can be modeled in animals as behavioral sensitization, which is induced by repeated noncontingent or self-administration of many drugs of abuse. Molecular mechanisms that are critical for behavioral sensitization have yet to be specified. Long-term depression (LTD) of α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptor (AMPAR)–mediated synaptic transmission in the brain has been proposed as a cellular substrate for learning and memory. The expression of LTD in the nucleus accumbens (NAc) required clathrin-dependent endocytosis of postsynaptic AMPARs. NAc LTD was blocked by a dynamin-derived peptide that inhibited clathrin-mediated endocytosis or by a GluR2-derived peptide that blocked regulated AMPAR endocytosis. Systemic or intra-NAc infusion of the membrane-permeable GluR2 peptide prevented the expression of amphetamine-induced behavioral sensitization in the rat.

AIMS Here we briefly review the preclinical and clinical evidence that gamma-aminobutyric acid (GABA(B)) agonists may be useful in the treatment of cocaine addiction. An extensive series of studies in rats has demonstrated that baclofen and other GABA(B) agonists reduce cocaine self-administration in an apparently specific manner. METHODS A number of schedules of reinforcement, including fixed-ratio, progressive-ratio and discrete trials procedures, have been used to model various aspects of cocaine reinforcement and addiction. RESULTS The results show that systemic pretreatment with baclofen can reduce cocaine intake at doses that do not affect responding for other positive reinforcers, such as food. Direct intracerebral injections of baclofen into the ventral tegmental area also produce a specific reduction in cocaine self-administration, suggesting that an inhibition of dopaminergic neurons may be responsible for the effect. Recent clinical evidence and case reports indicate some therapeutic value for baclofen in controlling cocaine intake and craving, although the evidence from controlled clinical trials has been less than convincing. Perhaps the most intriguing data come from human imaging studies, wherein cocaine addicts report increased cocaine craving and activation of orbital-frontal cortex, anterior cingulate and amygdala when shown videotapes of drug paraphernalia and other addicts taking cocaine. The craving is reduced and the limbic activation is eliminated in cocaine-dependent patients who had been taking baclofen (10-20 mg twice daily) for 7-10 days. CONCLUSIONS Systematic clinical studies of GABA(B) agonists are needed to determine the extent to which these drugs might serve as tools to promote abstinence in cocaine users seeking treatment for their addiction. Several areas must still be addressed, including potential side-effects that may limit compliance and whether GABA(B) agonists interfere with other, non-drug-related behaviours.

Frequency of drug access greatly affects the pattern and stability of cocaine self-administration. Previous research has shown that restricted drug availability produces remarkably consistent levels of daily cocaine intake, whereas increased or unlimited access produces more variable patterns of self-administration that may change over time. In the present study we used a discrete trials (DT) procedure to document how levels of access affect the pattern of cocaine intake. Rats that had been implanted with a chronically indwelling jugular cannula and trained to self-administer cocaine on an FR1 schedule were given access to cocaine during 10-min DT that were initiated throughout the day/night cycle for 21 days. Frequency of access (2, 3, 4 or 5 trials/h; 1.5 mg/kg/inj) and dose (1.0, 1.5, 2.0 and 2.5 mg/kg/inj, 3 trials/h) were investigated in separate groups of rats. When rats were presented with two or three trials an hour (1.5 mg/kg/inj), a highly regular and circadian pattern of intake was observed across weeks. Increasing the number of trials or increasing the unit dose resulted in a significant increase in average daily cocaine intake. Access to higher dose or higher frequency conditions produced a sustained drug-taking binge during the first few days on the schedule. Rats given access to five trials per hour typically responded at every opportunity for more than 48 h, then stabilized within a range of 80–100 mg/kg/day for the remainder of the experiment. To assess whether such high levels of cocaine intake had altered the motivation to respond, cocaine reinforced break-points were assessed on a progressive ratio schedule (0.32, 1.5 and 3.0 mg/kg/inj) in separate groups of animals before and 24 h after 5 days access on the DT procedure (5 trial/h). Sustained exposure to high levels of cocaine produced a shift in the dose–response curve to the right indicating tolerance to the reinforcing effects. This DT procedure provides a method to examine the behavioral and neurochemical effects of high cocaine intake over extended periods without toxicity.

In humans, the progression to cocaine addiction presumably involves increases in the effectiveness of cocaine to function as a reinforcer. Here we use breakpoints assessed using the progressive ratio (PR) schedule as an index of the efficacy of cocaine as a reinforcer. To date, no preclinical studies have demonstrated an increase in breakpoint as a consequence of self-administration history. In the current study, baseline performances on fixed ratio (FR) and PR schedules were determined. Rats were then exposed to different self-administration histories and deprivation periods, and responding under FR and PR schedules was reassessed. Exposure to a discrete-trials procedure (access to cocaine 4 times/hour, 24 hours/day; DT4) for 7 or 10 days, coupled with a deprivation period of 7 days, resulted in increases in breakpoint on a PR schedule, with no change in FR1 schedule responding. Exposure to an FR1 schedule for 72 consecutive hours followed by 7 days of deprivation, failed to change breakpoints, but increased rates of intake assessed with an FR1 schedule. Thus, the type of self-administration history and the length of deprivation experienced contribute to changes in the reinforcing efficacy of cocaine as measured by a PR schedule.

Alterations in gene expression caused by repeated cocaine administration have been implicated in the long-term behavioral aspects of cocaine abuse. The frontal cortex mediates reinforcement, sensory, associative, and executive functions and plays an important role in the mesocortical dopamine reinforcement system. Repeated cocaine administration causes changes in frontal cortex gene expression that may lead to changes in the behaviors subserved by this brain region. Rats treated non-contingently with a binge model of cocaine (45 mg/kg/day, i.p.) for 14 days were screened for changes in relative mRNA abundance in the frontal cortex by cDNA hybridization arrays. To confirm changes, immunoreactive protein was measured (via protein-specific immunoblots) in a second group of identically-treated animals. Protein levels of protein tyrosine kinase 2 (PYK2), activity-regulated cytoskeletal protein (ARC), as well as an antigen related to nerve growth factor I-B (NGFI-B-RA) were shown to be significantly induced after cocaine administration. Levels of NGFI-B mRNA were confirmed by real-time RT-PCR to be increased with cocaine administration. These observations are similar to previously reported cocaine-responsive changes in gene expression but novel to the frontal cortex. This study also validates the use of hybridization arrays for screening of neuronal gene expression changes and the utility of relative protein quantification as a post-hoc confirmation tool.

Chronic cocaine use is known to elicit changes in the pattern of gene expression within the brain. The hippocampus plays a critical role in learning and memory and may also play a role in mediating behaviors associated with cocaine abuse. To profile the gene expression response of the hippocampus to chronic cocaine treatment, cDNA hybridization arrays were used to illuminate cocaine-regulated genes in rats treated non-contingently with a binge model of cocaine (45 mg/kg/day, i.p.) for 14 days. Validation of mRNA changes illuminated by hybridization array analysis was accomplished by measuring immunoreactive protein (via specific immunoblots). The induction of protein kinase Calpha, potassium channel 1.1, and metabotropic glutamate receptor 5 seen by hybridization arrays was confirmed at the level of protein. Immunoblot screening of previously described cocaine-responsive genes demonstrated increased levels of protein tyrosine kinase 2, beta-catenin, and protein kinase Cepsilon. While some of these changes exist in previously described cocaine-responsive models, others are novel to any model of cocaine use. The inductions of potassium channel 1.1, protein tyrosine kinase 2 and metabotropic glutamate receptor 5 are novel findings to hippocampal cocaine-responsive gene expression. These proteins have been shown to subserve learning and memory and/or long-term potentiation functions within the hippocampus. Additionally, these genes are known to interact with one another, forming a more complex pattern of gene expression changes. The findings suggest altered expression of genes with a number of different functions in the rat hippocampus after a 'binge' style of non-contingent cocaine administration. These changes in gene expression may play roles in neuronal plasticity and the behavioral phenomena associated with cocaine abuse.

Rationale: Recent reports have indicated that the γ-aminobutyric acid (GABA)B agonist baclofen attenuates the reinforcing effects of cocaine. Objectives: To further evaluate the effect of baclofen on cocaine self-administration under a fixed ratio (FR) and progressive ratio (PR) schedule of reinforcement. Methods: In the first series of experiments, three dose–response curves were generated that examined the effect of three doses of baclofen (1.8, 3.2, or 5.6 mg/kg, i.p.) against four unit-injection doses of cocaine (0.19, 0.38, 0.75, and 1.5 mg/kg per injection) reinforced under a FR1 schedule. For comparison, an additional group of rats was pretreated with haloperidol (32, 56, or 100 µg/kg, i.p.). A separate experiment examined the effect of baclofen (1.8, 3.2, or 5.6 mg/kg, i.p.) on responding for concurrently available cocaine or food reinforcement. Results: Under the FR1 schedule, baclofen suppressed intake of low but not high unit injection doses of cocaine. In contrast to haloperidol, baclofen had no effect on the distribution of inter-injection intervals and, instead, produced long pauses in cocaine self-administration. Baclofen dose dependently reduced cocaine- reinforced responding on a PR schedule; concurrent access to a food-reinforced lever demonstrated that the animals retained the capacity to respond at high rates. Conclusion: The effect of baclofen pretreatment on cocaine self-administration is dependent on the unit injection dose of cocaine and on the response requirements of the schedule.

The effect of microinjections of baclofen into the ventral tegmental area (VTA), nucleus accumbens, or striatum on cocaine self-administration reinforced on a progressive ratio schedule was investigated. Intra-VTA baclofen produced the most potent modulation of cocaine intake, causing a significant reduction in cocaine-reinforced break points at a dose (56 ng/side) that was substantially lower than doses necessary to produce comparable reductions in the nucleus accumbens or striatum. During the time that cocaine-reinforced responding was suppressed, rats demonstrated the capacity to complete several hundred responses on a concurrently available food-reinforced lever, indicating that the effect of baclofen on cocaine intake was not due to a generalized disruption in operant responding. The results indicate that GABAB receptors in the VTA may have the potential to modulate reward processes associated with cocaine use.

Abstract: Recent experiments suggest that GABA compounds produce a clinically relevant modulation of cocaine reinforcement. This review summarizes the results of a number of studies that examined the effect of the GABAB agonist baclofen on cocaine self‐administration using a variety of schedules of reinforcement. The results demonstrate that baclofen causes a dramatic reduction in cocaine self‐administration which does not appear to be accounted for by a general disruption of behavior. However, the effect is dependent on the unit injection dose of cocaine and on the response requirements of the schedule. These results predict that in a clinical setting any potential therapeutic effect of baclofen will interact with the cost and availability of cocaine.

Previous self-administration experiments have shown that baclofen, the prototypical GABAB agonist, produces an apparent attenuation in the reinforcing effects of cocaine in rats. The present experiments examined the effects of CPG 44532, a novel and highly specific GABAB agonist, on cocaine self-administration using two distinctly different procedures. CGP 44532 (0.063–0.5 mg/kg) produced a dose dependent decrease in break point on a progressive-ratio (PR) schedule. A low dose of CGP 44532 (0.125 mg/kg) produced an apparent shift of the cocaine dose–response curve to the right. In contrast there was comparatively little effect on food-reinforced responding on the same PR schedule. Using a discrete-trials procedure that engendered a circadian pattern of self-administration, CPG 44532 (0.063–0.5 mg/kg) produced a dose-dependent suppression of cocaine intake in the 4 h period following treatment. When a concurrently available food reinforced lever was added to the discrete trials paradigm CGP 44532 failed to disrupt responding for food at any of the doses tested. Data from the PR and discrete-trials procedures taken together indicate that CGP 44532 produced a specific decrease in the motivation to self-administer cocaine.