Maintenance Of Cocaine Self-administration Research Articles

Toll-like receptor 4 antagonists reduce cocaine-primed reinstatement of drug seeking.

Cocaine can increase inflammatory neuroimmune markers, including chemokines and cytokines characteristic of innate inflammatory responding. Prior work indicates that the Toll-like receptor 4 (TLR4) initiates this response, and administration of TLR4 antagonists provides mixed evidence that TLR4 contributes to cocaine reward and reinforcement. These studies utilize (+)-naltrexone, the TLR4 antagonist, and mu-opioid inactive enantiomer to examine the role of TLR4 on cocaine self-administration and cocaine seeking in rats. (+)-Naltrexone was continuously administered via an osmotic mini-pump during the acquisition or maintenance of cocaine self-administration. The motivation to acquire cocaine was assessed using a progressive ratio schedule following either continuous and acute (+)-naltrexone administration. The effects of (+)-naltrexone on cocaine seeking were assessed using both a cue craving model and a drug-primed reinstatement model. The highly selective TLR4 antagonist, lipopolysaccharide from Rhodobacter sphaeroides (LPS-Rs), was administered into the nucleus accumbens to determine the effectiveness of TLR4 blockade on cocaine-primed reinstatement. (+)-Naltrexone administration did not alter the acquisition or maintenance of cocaine self-administration. Similarly, (+)-naltrexone was ineffective at altering the progressive ratio responding. Continuous administration of (+)-naltrexone during forced abstinence did not impact cued cocaine seeking. Acute systemic administration of (+)-naltrexone dose-dependently decreased cocaine-primed reinstatement of previously extinguished cocaine seeking, and administration of LPS-Rs into the nucleus accumbens shell also reduced cocaine-primed reinstatement of cocaine seeking. These results complement previous studies suggesting that the TLR4 plays a role in cocaine-primed reinstatement of cocaine seeking, but may have a more limited role in cocaine reinforcement.

Motor impulsivity but not risk-related impulsive choice is associated to drug intake and drug-primed relapse.

Motor impulsivity and risk-related impulsive choice have been proposed as vulnerability factors for drug abuse, due to their high prevalence in drug abusers. However, how these two facets of impulsivity are associated to drug abuse remains unclear. Here, we investigated the predictive value of both motor impulsivity and risk-related impulsive choice on characteristics of drug abuse including initiation and maintenance of drug use, motivation for the drug, extinction of drug-seeking behavior following drug discontinuation and, finally, propensity to relapse. We used the Roman High- (RHA) and Low- Avoidance (RLA) rat lines, which display innate phenotypical differences in motor impulsivity, risk-related impulsive choice, and propensity to self-administer drugs. Individual levels of motor impulsivity and risk-related impulsive choice were measured using the rat Gambling task. Then, rats were allowed to self-administer cocaine (0.3 mg/kg/infusion; 14 days) to evaluate acquisition and maintenance of cocaine self-administration, after which motivation for cocaine was assessed using a progressive ratio schedule of reinforcement. Subsequently, rats were tested for their resistance to extinction, followed by cue-induced and drug-primed reinstatement sessions to evaluate relapse. Finally, we evaluated the effect of the dopamine stabilizer aripiprazole on reinstatement of drug-seeking behaviors. We found that motor impulsivity and risk-related impulsive choice were positively correlated at baseline. Furthermore, innate high levels of motor impulsivity were associated with higher drug use and increased vulnerability to cocaine-primed reinstatement of drug-seeking. However, no relationships were observed between motor impulsivity and the motivation for the drug, extinction or cue-induced reinstatement of drug-seeking. High levels of risk-related impulsive choice were not associated to any aspects of drug abuse measured in our study. Additionally, aripiprazole similarly blocked cocaine-primed reinstatement of drug-seeking in both high- and low-impulsive animals, suggesting that aripiprazole acts as a D2/3R antagonist to prevent relapse independently of the levels of impulsivity and propensity to self-administer drugs. Altogether, our study highlights motor impulsivity as an important predictive factor for drug abuse and drug-primed relapse. On the other hand, the involvement of risk-related impulsive choice as a risk factor for drug abuse appears to be limited.

5-HT1B receptor agonist enhances breakpoint for cocaine on a progressive ratio (PR) schedule during maintenance of self-administration in female rats but reduces breakpoint for sucrose.

Background: Previous research showed that the 5-HT1B receptor agonist CP94253 enhanced cocaine reinforcement rate during maintenance of daily self-administration (SA), but inhibited reinforcement rate after 21 days of abstinence in male rats. Here we examined whether female rats show similar effects of CP94253 during maintenance as males across estrous cycle phases. Methods: Female rats trained on a fixed ratio 5 (FR5) cocaine reinforcement schedule were tested for the effects of CP94253 (5.6 mg/kg, s.c.) on cocaine reinforcement rate during each phase of the estrous cycle, with access to either low (0.075 and 0.1875) or high (0.375 and 0.75) cocaine doses available for 1 h sequentially in descending dose order. Other female and male rats trained on a progressive ratio (PR) schedule of cocaine or sucrose reinforcement were tested for CP94253 (0, 3.2, 5.6, and 10 mg/kg, s.c.) effects on reinforcement rate in 3-h sessions. CP94253 effects on responding during sucrose cue-reactivity were also examined post-abstinence. Results: Regardless of sex, CP94253 enhanced breakpoints on the PR schedule during maintenance of cocaine SA but attenuated breakpoints for sucrose reinforcement and decreased responding during sucrose cue-reactivity. FR results showed that CP94253 attenuated cocaine reinforcement rate during all estrous cycle phases except metestrus. Conclusions: Overall, we suggest that CP94253 increased incentive motivation for cocaine during maintenance of SA in female and male rats, yet decreased motivation for sucrose. We also suggest that 5-HT1BRs modulate motivation similarly across sexes except when females are in metestrus.

Persistence of Operant Responding for Food After Prior Cocaine Exposure in Fischer 344 But Not Lewis Rats.

Chronic cocaine exposure has differential neural effects in Fischer 344 (F344) vs Lewis inbred rats that may explain strain-dependent differences during acquisition vs maintenance of cocaine self-administration. We assessed whether prior cocaine exposure alters operant responding for food across various phases (acquisition, maintenance, extinction, spontaneous recovery, reinitiation) in these strains. Lewis and F344 rats (N = 12) were administered three cocaine (15 mg/kg) or saline injections at hourly intervals for 3 consecutive days. Beginning the next day for 24 days, rats had access to operant chambers in which one lever depression resulted in the delivery of a food pellet. Then, four extinction sessions were conducted in which food was no longer available, but other stimulus conditions remained the same. After a 2-day break, spontaneous recovery was assessed over four sessions. Food delivery was then restored for 3 days to test reinitiation followed by a progressive ratio session. Lewis rats acquired the operant faster than F344 rats. F344 rats showed lower maintenance rates than Lewis rats but higher spontaneous recovery responding. Cocaine exposure caused persistence of responding during extinction in F344 but not Lewis rats. All groups reinitiated responding when food was available again and did not differ in final ratios completed under the progressive ratio schedule. That prior cocaine exposure led to persistence of responding in F344 rats during extinction may reflect heightened contextual conditioning that interferes with the ability to extinguish responding. Results have implications for the genetic contribution to relapse-like behaviors. (Am J Addict 2021;00:00-00).

Sensitivity to food and cocaine cues are independent traits in a large sample of heterogeneous stock rats

Sensitivity to cocaine and its associated stimuli (“cues”) are important factors in the development and maintenance of addiction. Rodent studies suggest that this sensitivity is related, in part, to the propensity to attribute incentive salience to food cues, which, in turn, contributes to the maintenance of cocaine self-administration, and cue-induced relapse of drug-seeking. Whereas each of these traits has established links to drug use, the relatedness between the individual traits themselves has not been well characterized in preclinical models. To this end, the propensity to attribute incentive salience to a food cue was first assessed in two distinct cohorts of 2716 outbred heterogeneous stock rats (HS; formerly N:NIH). We then determined whether each cohort was associated with performance in one of two paradigms (cocaine conditioned cue preference and cocaine contextual conditioning). These measure the unconditioned locomotor effects of cocaine, as well as conditioned approach and the locomotor response to a cocaine-paired floor or context. There was large individual variability and sex differences among all traits, but they were largely independent of one another in both males and females. These findings suggest that these traits may contribute to drug-use via independent underlying neuropsychological processes.

OSU-6162, a Sigma1R Ligand in Low Doses, Can Further Increase the Effects of Cocaine Self-Administration on Accumbal D2R Heteroreceptor Complexes

Cocaine was previously shown to act at the Sigma1R which is a target for counteracting cocaine actions. It therefore becomes of interest to test if the monoamine stabilizer (–) OSU-6162 (OSU-6162) with a nanomolar affinity for the Sigma1R can acutely modulate in low doses the effects of cocaine self-administration. In behavioral studies, OSU-6162 (5 mg/kg, s.c.) did not significantly change the number of active lever pressing and cocaine infusions. However, a trend to reduce cocaine readouts was found after 3 days of treatment. In contrast, in maintenance of cocaine self-administration, the proximity ligation assay performed on brains from rats pretreated with OSU-6162 showed highly significant increases in the density of the D2R-Sigma1R heteroreceptor complexes in the shell of the nucleus accumbens versus OSU-6162 induced increases in this region of yoked saline rats. In cocaine self-administration, highly significant increases were also induced by OSU-6162 in the A2AR-D2R heteroreceptor complexes in the nucleus accumbens shell versus vehicle-treated rats. Furthermore, ex vivo, the A2AR agonist CGS21680 (100 nM) produced a marked and significant increase of the D2R Ki high values in the OSU-6162-treated versus vehicle-treated rats under maintenance of cocaine self-administration. These results indicate a substantial increase in the inhibitory allosteric A2AR-D2R interactions following cocaine self-administration upon activation by the A2AR agonist ex vivo. The current results indicate that OSU-6162 via its high affinity for the Sigma1R may increase the number of accumbal shell D2R-Sigma1R and A2AR-D2R heteroreceptor complexes associated with further increases in the antagonistic A2AR-D2R interactions in cocaine self-administration.

Modified single prolonged stress reduces cocaine self-administration during acquisition regardless of rearing environment

Until recently, there were few rodent models available to study the interaction of post-traumatic stress disorder (PTSD) and drug taking. Like PTSD, single prolonged stress (SPS) produces hypothalamic-pituitary-adrenal (HPA) axis dysfunction and alters psychostimulant self-administration. Other stressors, such as isolation stress, also alter psychostimulant self-administration. However, it is currently unknown if isolation housing combined with SPS can alter the acquisition or maintenance of cocaine self-administration. The current study applied modified SPS (modSPS; two hours restraint immediately followed by cold swim stress) to rats raised in an isolation condition (Iso), enrichment condition (Enr), or standard condition (Std) to measure changes in cocaine self-administration and HPA markers. Regardless of rearing condition, rats exposed to modSPS had greater corticosterone (CORT) release and reduced cocaine self-administration during initial acquisition compared to non-stressed controls. In addition, during initial acquisition, rats that received both Iso rearing and modSPS showed a more rapid increase in cocaine self-administration across sessions compared to Enr and Std rats exposed to modSPS. Following initial acquisition, a dose response analysis showed that Iso rats were overall most sensitive to changes in cocaine unit dose; however, modSPS had no effect on the cocaine dose response curve. Further, there was no effect of either modSPS or differential rearing on expression of glucocorticoid receptor (GR) in hypothalamus, medial prefrontal cortex, amygdala, or nucleus accumbens. By using modSPS in combination with Iso housing, this study identified unique contributions of each stressor to acquisition of cocaine self-administration.

Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation.

Altered mesolimbic dopamine signaling has been widely implicated in addictive behavior. For the most part, this work has focused on dopamine within the striatum, but there is emerging evidence for a role of the auto-inhibitory, somatodendritic dopamine D2 receptor (D2R) in the ventral tegmental area (VTA) in addiction. Thus, decreased midbrain D2R expression has been implicated in addiction in humans. Moreover, knockout of the gene encoding the D2R receptor (Drd2) in dopamine neurons has been shown to enhance the locomotor response to cocaine in mice. Therefore, we here tested the hypothesis that decreasing D2R expression in the VTA of adult rats, using shRNA knockdown, promotes addiction-like behavior in rats responding for cocaine or palatable food. Rats with decreased VTA D2R expression showed markedly increased motivation for both sucrose and cocaine under a progressive ratio schedule of reinforcement, but the acquisition or maintenance of cocaine self-administration were not affected. They also displayed enhanced cocaine-induced locomotor activity, but no change in basal locomotion. This robust increase in incentive motivation was behaviorally specific, as we did not observe any differences in fixed ratio responding, extinction responding, reinstatement or conditioned suppression of cocaine, and sucrose seeking. We conclude that VTA D2R knockdown results in increased incentive motivation, but does not directly promote other aspects of addiction-like behavior.

Dopamine decreases NMDA currents in the oval bed nucleus of the stria terminalis of cocaine self-administering rats

Dopamine (DA) and N-methyl-D-aspartate receptors (NMDARs) contribute in the neural processes underlying drug-driven behaviors. DA is a potent modulator of NMDAR, but few studies have investigated the functional interaction between DA and NMDAR in the context of substance abuse. We combined the rat model of cocaine self-administration with brain slice electrophysiology to study DA modulation of NMDA currents in the oval bed nucleus of the stria terminalis (ovBNST), a dense DA terminal field involved in maintenance of cocaine self-administration amongst other drug related behaviors. Long-Evans rats self-administered intravenous cocaine (0.75 mg/kg/injection) on a progressive ratio (PR) schedule of reinforcement for 15 days and whole-cell patch-clamp recordings were done on the 16th day. DA reduced NMDA currents in brain-slices from cocaine self-administering rats, but not in those of drug-naïve and sucrose self-administering, or when cocaine exposure was passive (yoked), revealing a mechanism unique to voluntary cocaine intake. DA reduced NMDA currents by activating G-protein-coupled D1- and D2-like receptors that converged on phospholipase C and protein phosphatases. Accordingly, our study reveals a mechanism that may contribute to dysfunctional synaptic plasticity associated with drug-driven behaviors during acute withdrawal.

Oxidative Stress Biomarkers in Some Rat Brain Structures and Peripheral Organs Underwent Cocaine

Oxidative stress (OS) generates or intensifies cocaine-evoked toxicity in the brain and peripheral organs. The aim of this study was to examine superoxide dismutase (SOD) activity and lipid peroxidation [measured by malondialdehyde (MDA) levels] in rats during maintenance of cocaine self-administration and after withdrawal by a yoked-triad procedure. Our results indicate that repeated cocaine self-administration provoked an elevation of SOD activity in the hippocampus, frontal cortex, dorsal striatum, and liver. MDA levels were reduced in the brain, increased in the liver, kidney, and heart during maintenance of self-administration, and increased in the kidney in cocaine-yoked rats. In addition, following extinction training, we found enhanced MDA levels and SOD activity in the rat hippocampus, while changes in the activity of OS biomarkers in other brain structures and peripheral tissues were reminiscent of the changes seen during cocaine self-administration. These findings highlight the association between OS biomarkers in motivational processes related to voluntary cocaine intake in rats. OS participates in memory and learning impairments that could be involved in drug toxicity and addiction mechanisms. Therefore, further studies are necessary to address protective mechanisms against cocaine-induced brain and peripheral tissue damage.

Protracted Withdrawal from Cocaine Self-Administration Flips the Switch on 5-HT1B Receptor Modulation of Cocaine Abuse-Related Behaviors

The role of serotonin-1B receptors (5-HT(1B)Rs) in modulating cocaine abuse-related behaviors has been controversial due to discrepancies between pharmacological and gene knockout approaches and opposite influences on cocaine self-administration versus cocaine-seeking behavior. We hypothesized that modulation of these behaviors via 5-HT(1B)Rs in the mesolimbic pathway may vary depending on the stage of the addiction cycle. To test this hypothesis, we examined the effects of increasing 5-HT(1B)R production by microinfusing a viral vector expressing either green fluorescent protein and 5-HT(1B)R or green fluorescent protein alone into the medial nucleus accumbens shell of rats either during maintenance of cocaine self-administration (i.e., active drug use) or during protracted withdrawal. 5-HT(1B)R receptor gene transfer during maintenance shifted the dose-response curve for cocaine self-administration upward and to the left and increased breakpoints and cocaine intake on a progressive ratio schedule, consistent with enhanced reinforcing effects of cocaine. In contrast, following 21 days of forced abstinence, 5-HT(1B)R gene transfer attenuated breakpoints and cocaine intake on a progressive ratio schedule of reinforcement, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. This unique pattern of effects suggests that mesolimbic 5-HT(1B)Rs differentially modulate cocaine abuse-related behaviors, with a facilitative influence during periods of active drug use, in striking contrast to an inhibitory influence during protracted withdrawal. These findings suggest that targeting 5-HT(1B)Rs may lead to a novel treatment for cocaine dependence and that the therapeutic efficacy of these treatments may vary depending on the stage of the addiction cycle.

Cocaine self-administration is not dependent upon mesocortical α1 noradrenergic signaling

The rewarding properties of psychomotor stimulants are traditionally thought to be independent of norepinephrine. Recent findings, however, suggest that local noradrenergic signaling through α1 receptors in the medial prefrontal cortex and the ventral tegmental area - brain regions critically important in natural and drug rewards - is in a position to influence stimulant reward. Despite this controversy, the contribution of this targeted signaling to stimulant self-administration has not been directly assessed. We have thus examined whether pharmacological blockade of α1 receptors in the medial prefrontal cortex and ventral tegmental area alters cocaine self-administration. Rats were trained to lever-press for cocaine (1.0 mg/kg/infusion) under a fixed ratio 1 schedule of reinforcement for 10 days. After training, the rats received a bilateral microinjection of an α1 noradrenergic antagonist (terazosin: 1.0, 5.0, or 10 mM/side), a D1 dopaminergic antagonist (SCH23390: 12.3 mM/side), or saline into either the medial prefrontal cortex or ventral tegmental area immediately before a cocaine self-administration session. Although SCH23390 significantly increased cocaine self-administration when injected into either brain region, terazosin, at all doses and sites tested, failed to alter this behavior. Thus, the maintenance of cocaine self-administration appears to be under the influence of D1 dopaminergic, rather than α1 noradrenergic, signaling at these mesocortical sites.

The effects of cannabinoid CB1, CB2 and vanilloid TRPV1 receptor antagonists on cocaine addictive behavior in rats

There is evidence that indicates that tonic activation of cannabinoid CB1 receptors plays a role in extinction/reinstatement of cocaine seeking-behavior but is not involved in the maintenance of cocaine self-administration. To further explore the importance of other endocannabinoid-related receptors in an animal model of cocaine addiction, the present paper examines cannabinoid CB2 receptor antagonist N-((1S)-endo-1,3,3-trimethylbicyclo(2.2.1)heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) and the transient receptor potential vanilloid type-1 (TRPV1) receptor antagonist N-(3-methoxyphenyl)-4-chlorocinnamide (SB366791) on intravenous (i.v.) cocaine self-administration and extinction/reinstatement of cocaine-seeking behavior in rats. For comparison and reference purposes, the effect of the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) was also examined. Moreover, for comparison effects of those drugs on operant lever responding for artificial (cocaine) vs. natural (food) reward, food self-administration was also evaluated. Our findings show that AM251 (1–3mg/kg), SR144528 (0.1–1mg/kg) and SB366791 (0.3–1mg/kg) did not affect cocaine self-administration. However, AM251 (0.1–1mg/kg), SR144528 (0.1–1mg/kg) and SB366791 (0.1–1mg/kg) decreased cocaine-induced reinstatement of cocaine-seeking behavior, and AM251 (0.3–1mg/kg) decreased cue-induced reinstatement. Moreover, AM251 (3mg/kg), SR144528 (0.1–1mg/kg) and SB366791 (0.1–1mg/kg) slightly decreased food self-administration behavior, but only AM251 (3mg/kg) reduced food reward. In conclusion, our results indicate for the first time, that tonic activation of CB2 or TRPV1 receptors is involved in cocaine-induced reinstatement of cocaine-seeking behavior, but their activity is not necessary for the rewarding effect of this psychostimulant. In contrast to CB1 receptors, neither CB2 nor TRPV1 receptors play a role in cue-induced reinstatement of cocaine-seeking behavior.

Impact of early life stress on the reinforcing and behavioral-stimulant effects of psychostimulants in rhesus monkeys

Early life stress has effects on behavior and stress reactivity, which are linked to enhanced sensitivity to stimulants in rodents. This study investigated whether rhesus monkeys that experienced early life stress would show altered sensitivity to the reinforcing effects of stimulants as compared with controls. Control (n=5) and maternally separated (n=4) monkeys were trained to self-administer cocaine (0.1 mg/kg/injection) under a second-order schedule of intravenous drug delivery. The rate of acquisition and subsequent dose-effect determinations for cocaine (0.01-1.0 mg/kg/injection) and amphetamine (0.003-0.3 mg/kg/injection) provided complementary measures of reinforcing effectiveness. In addition, stimulant-induced increases in home cage activity and dopamine D2 receptor binding potential were quantified with positron emission tomography neuroimaging. Compared with controls, maternally separated monkeys showed lower responding during the acquisition of self-administration and in the dose-response curves for both stimulants, and significantly lower response rates during maintenance of cocaine self-administration. Maternally separated monkeys also failed to exhibit stimulant-induced increases in motor activity. Groups did not differ in dopamine D2 receptor binding potential in the caudate nucleus or the putamen. Taken together, the results of this study do not provide support for early life stress leading to enhanced vulnerability to stimulant use in the nonhuman primate model employed.

Sex Differences in Non-Reinforced Responding for Cocaine

Prior studies report no sex differences in cocaine consumption during maintenance of self-administration. We find female rats show poorer lever discrimination during acquisition of self-administration. Now, we test whether female rats show greater non-reinforced or ineffective responding (presses during infusion and time-out periods as well as inactive lever presses) than male rats during maintenance of cocaine self-administration (.0625–1.0 mg/kg/infusion) in Experiment 1. Persistence of responding during extinction when saline-replaced cocaine was also examined. Whether response differences reflect sex differences in movements under a non-drug condition was tested in Experiment 2. Because cocaine may affect lever press rates differentially between sexes, we examined the effects of cocaine (.3–30 mg/kg; IP) on responding for food in Experiment 3. Cocaine consumption does not differ between female and male rats. However, females respond more during infusion and time-out periods and during extinction than males. There is no sex difference in movements and high cocaine doses decrease responding for food more in female vs. male rats. That females engage in more ineffective responding may represent heightened “craving” and cannot be explained by increased movements or cocaine-stimulated increases in lever pressing. In contrast, responding for cocaine in males appears driven by drug delivery.

Acquisition and maintenance of cocaine self-administration in adolescent rats: effects of sex and gonadal hormones

Previous work has shown that adult female rats are more sensitive than adult male rats to the reinforcing effects of cocaine, an effect that appears to be due, at least in part, to ovarian hormones. In this study, we examine sex differences in cocaine self-administration during adolescence, a period of marked hormonal change. Adolescent male and female Sprague-Dawley rats were trained to self-administer cocaine (0.75 mg/kg per infusion) under a fixed ratio 1 schedule (i.e., each response was reinforced by an infusion of cocaine) beginning on postnatal day 30. After acquisition, responding was assessed under a progressive-ratio schedule until postnatal day 50 with blood sampling occurring before the first five sessions to determine the relationship between gonadal hormones (i.e., estradiol, progesterone, and testosterone) and motivation for cocaine. Estrous cycle phase was monitored throughout the study. Separate groups of adolescent male and female rats were compared on the acquisition of and progressive-ratio responding for sucrose reinforcement. Females acquired cocaine self-administration more readily than did males, and a greater percentage of females acquired self-administration. Under progressive-ratio testing conditions, adolescent females responded at higher levels than adolescent males to obtain cocaine infusions, and in females, responding was positively associated with levels of estradiol and greatest during estrus. No sex differences were observed for sucrose reinforcement. These findings suggest that sex differences are relevant during adolescence with evidence implicating circulating estradiol level as a factor that contributes to the enhanced sensitivity in females to the reinforcing effects of cocaine.

Glutamate and aspartate levels in the nucleus accumbens during cocaine self-administration and extinction: a time course microdialysis study

Accumbal excitatory amino acid (EAA) transmission has been implicated in cocaine addiction. However, the time course effects of extinction of cocaine self-administration on EAAs are unknown. The objective of this study was to define the time course of cocaine self-administration and extinction effects on glutamate and aspartate levels in the nucleus accumbens. Rats were trained to self-administer cocaine for 20 days, and the levels of extracellular glutamate and aspartate were measured by in vivo microdialysis both during cocaine self-administration and after a priming cocaine injection at different time points after extinction (1, 5, or 10 days). A food-reinforced control group was also included in this study. Furthermore, the effect of acute i.v. cocaine administration (0, 1, 2, or 4 mg/kg) on glutamate and aspartate levels was also evaluated. At any of the dose tested, acute i.v. cocaine did not affect the levels of glutamate or aspartate in the Nacc. In contrast, glutamate levels were reduced in animals trained to self-administer cocaine, although they augmented substantially during a subsequent session of cocaine self-administration, and similar changes were not observed in food-reinforced controls. After 1 or 5, but not after 10 days of extinction, the glutamate levels were also reduced, and the ability of i.v. cocaine priming injections to increase glutamate levels followed a similar time course. These effects were specific, as aspartate levels were not affected by any administration protocol. These data suggest that glutamatergic transmission could be involved in the maintenance of cocaine self-administration and in the early phases of abstinence.

The neurobiology of cocaine-induced reinforcement.

Cocaine has potent pharmacological actions on a number of monoaminergic systems in the brain, including those that use noradrenaline, dopamine and serotonin as neurotransmitters. There is growing evidence that cocaine's effects on dopaminergic neurons, particularly those that make up the mesolimbic system, are closely associated with its rewarding properties. For example, low doses of dopamine receptor antagonists reliably influence cocaine self-administration, whereas noradrenaline and serotonin receptor antagonists are without consistent effects. Similarly, selective lesions of dopaminergic terminals in the nucleus accumbens, a major target of the mesolimbic dopamine projection, disrupt cocaine self-administration in a manner that is consistent with loss of cocaine-induced reward. The introduction of in vivo brain microdialysis as a tool with which to investigate the neurochemical correlates of motivated behaviour has provided new opportunities for investigating the role of dopamine in the nucleus accumbens in the acquisition and maintenance of cocaine self-administration. Although the body of literature that has been generated by this approach appears to contain some important inconsistencies, these probably reflect the use of inappropriate microdialysis conditions by some investigators. A critical review of the literature suggests that microdialysis results are generally consistent with a role for mesolimbic dopamine in cocaine-induced reward, although it does not seem to be the case that animals will work to maintain consistent increases in extracellular concentrations of dopamine in the nucleus accumbens in all experimental conditions. Elucidation of the complete neural circuitry of cocaine-induced reward remains an important priority for future research.

Diverse effects of GABA-mimetic drugs on cocaine-evoked self-administration and discriminative stimulus effects in rats

Recent data indicate that gamma-aminobutyric acid (GABA) is a modulator of behavioral responses to cocaine. The efficacy of gabapentin (a cyclic GABA analogue), tiagabine (a GABA reuptake inhibitor), or vigabatrin (an inhibitor of GABA transaminase and reuptake) to alter cocaine-seeking behavior and discriminative effects was examined in rats. Rats were trained to press a lever for cocaine (0.5 mg/kg per infusion) paired with a cue (light + tone) using a fixed ratio (FR) 5 schedule of reinforcement. After extinction, the cocaine-seeking behavior was reinstated by cocaine priming (10 mg/kg). Another group of rats was trained to discriminate cocaine (10 mg/kg) from saline in a two-lever FR 20 task. Vigabatrin (150-250 mg/kg) decreased cocaine-maintained responding, whereas tiagabine (10 mg/kg) significantly reduced responses on the "active" lever. Vigabatrin (150-250 mg/kg) significantly decreased responding to the cocaine-priming dose and a nonsignificant attenuation of cocaine-induced reinstatement was seen after tiagabine (5-10 mg/kg). Gabapentin (10-30 mg/kg) failed to alter maintenance of cocaine self-administration or drug-induced reinstatement. Pretreatment with either gabapentin, tiagabine, or vigabatrin resulted in neither reinstatement of cocaine seeking nor alterations in cocaine discrimination. Our study demonstrates that vigabatrin (only at the 150 mg/kg dose) exerted inhibitory actions on cocaine-maintained responding and attenuated the reinstatement of extinguishing responding more effectively than gabapentin or tiagabine and with less evidence of motor impairment than the latter drugs. Present findings do not support a role for gabapentin or tiagabine for the possible treatment of cocaine relapse, whereas albeit limited effects of vigabatrin may be seen.

Strain differences in maintenance of cocaine self-administration and their relationship to novelty activity responses.

The authors previously demonstrated that Fischer 344 (F344) and Lewis inbred rats differ in acquisition of cocaine self-administration. Other studies show that acquisition and maintenance of drug self-administration are predicted by locomotor activity in a novel environment among outbred Sprague-Dawley rats. The present study was designed to determine whether this relationship extended to F344 and Lewis rats. In Experiment 1, F344, Lewis, and Sprague-Dawley rats were trained to self-administer cocaine and tested with several doses under fixed- and progressive-ratio schedules of reinforcement. Self-administered infusions and ineffective active lever presses--those emitted during infusion and time-out periods--were assessed. In Experiment 2, separate sets of rats of each strain were examined for locomotor responses (distance traveled and center time) under novelty conditions. Results show that F344 rats self-administer more cocaine than Lewis or Sprague-Dawley rats under both schedules and emit more ineffective lever presses--a possible measure of craving. Strain comparisons of locomotor responses suggest that center time, not activity, relates to self-administration behavior. Maintenance studies of cocaine self-administration rather than acquisition may better reflect vulnerability to addiction.