Nipping cue reactivity in the bud: baclofen prevents limbic activation elicited by subliminal drug cues.

Relapse is a widely recognized and difficult to treat feature of the addictions. Substantial evidence implicates cue-triggered activation of the mesolimbic dopamine system as an important contributing factor. Even drug cues presented outside of conscious awareness (i.e., subliminally) produce robust activation within this circuitry, indicating the sensitivity and vulnerability of the brain to potentially problematic reward signals. Because pharmacological agents that prevent these early cue-induced responses could play an important role in relapse prevention, we examined whether baclofen-a GABAB receptor agonist that reduces mesolimbic dopamine release and conditioned drug responses in laboratory animals-could inhibit mesolimbic activation elicited by subliminal cocaine cues in cocaine-dependent individuals. Twenty cocaine-dependent participants were randomized to receive baclofen (60 mg/d; 20 mg t.i.d.) or placebo. Event-related BOLD fMRI and a backward-masking paradigm were used to examine the effects of baclofen on subliminal cocaine (vs neutral) cues. Sexual and aversive cues were included to examine specificity. We observed that baclofen-treated participants displayed significantly less activation in response to subliminal cocaine (vs neutral) cues, but not sexual or aversive (vs neutral) cues, than placebo-treated participants in a large interconnected bilateral cluster spanning the ventral striatum, ventral pallidum, amygdala, midbrain, and orbitofrontal cortex (voxel threshold p < 0.005; cluster corrected at p < 0.05). These results suggest that baclofen may inhibit the earliest type of drug cue-induced motivational processing-that which occurs outside of awareness-before it evolves into a less manageable state.

Methylphenidate and cocaine self-administration produce distinct dopamine terminal alterations.

Methylphenidate (MPH) is a commonly abused psychostimulant prescribed for the treatment of attention deficit hyperactivity disorder. MPH has a mechanism of action similar to cocaine (COC) and is commonly characterized as a dopamine transporter (DAT) blocker. While there has been extensive work aimed at understanding dopamine (DA) nerve terminal changes following COC self-administration, very little is known about the effects of MPH self-administration on the DA system. We used fast scan cyclic voltammetry in nucleus accumbens core slices from animals with a 5-day self-administration history of 40 injections/day of either MPH (0.56 mg/kg) or COC (1.5 mg/kg) to explore alterations in baseline DA release and uptake kinetics as well as alterations in the interaction of each compound with the DAT. Although MPH and COC have similar behavioral effects, the consequences of self-administration on DA system parameters were found to be divergent. We show that COC self-administration reduced DAT levels and maximal rates of DA uptake, as well as reducing electrically stimulated release, suggesting decreased DA terminal function. In contrast, MPH self-administration increased DAT levels, DA uptake rates and DA release, suggesting enhanced terminal function, which was supported by findings of increased metabolite/DA tissue content ratios. Tyrosine hydroxylase messenger RNA, protein and phosphorylation levels were also assessed in both groups. Additionally, COC self-administration reduced COC-induced DAT inhibition, while MPH self-administration increased MPH-induced DAT inhibition, suggesting opposite pharmacodynamic effects of these two drugs. These findings suggest that the factors governing DA system adaptations are more complicated than simple DA uptake blockade.

Striatal CB1 and D2 receptors regulate expression of each other, CRIP1A and δ opioid systems.

Although biochemical and physiological evidence suggests a strong interaction between striatal CB1 cannabinoid (CB1 R) and D2 dopamine (D2 R) receptors, the mechanisms are poorly understood. We targeted medium spiny neurons of the indirect pathway using shRNA to knockdown either CB1 R or D2 R. Chronic reduction in either receptor resulted in deficits in gene and protein expression for the alternative receptor and concomitantly increased expression of the cannabinoid receptor interacting protein 1a (CRIP1a), suggesting a novel role for CRIP1a in dopaminergic systems. Both CB1 R and D2 R knockdown reduced striatal dopaminergic-stimulated [(35) S]GTPγS binding, and D2 R knockdown reduced pallidal WIN55212-2-stimulated [(35) S]GTPγS binding. Decreased D2 R and CB1 R activity was associated with decreased striatal phosphoERK. A decrease in mRNA for opioid peptide precursors pDYN and pENK accompanied knockdown of CB1 Rs or D2 Rs, and over-expression of CRIP1a. Down-regulation in opioid peptide mRNAs was followed in time by increased DOR1 but not MOR1 expression, leading to increased [D-Pen2, D-Pen5]-enkephalin-stimulated [(35) S]GTPγS binding in the striatum. We conclude that mechanisms intrinsic to striatal medium spiny neurons or extrinsic via the indirect pathway adjust for changes in CB1 R or D2 R levels by modifying the expression and signaling capabilities of the alternative receptor as well as CRIP1a and the DELTA opioid system.

Paradoxical tolerance to cocaine after initial supersensitivity in drug-use-prone animals.

There is great interest in outlining biological factors and behavioral characteristics that either predispose or predict vulnerability to substance use disorders. Response to an inescapable novel environment has been shown to predict a "drug-use-prone" phenotype that is defined by rapid acquisition of cocaine self-administration. Here, we showed that response to novelty can also predict the neurochemical and behavioral effects of acute and repeated cocaine in rats. We used cocaine self-administration under a fixed-ratio 1 schedule followed by fast-scan cyclic voltammetry in brain slices to measure subsecond dopamine (DA) release and uptake parameters in drug-use-prone and -resistant phenotypes. Despite no significant differences in stimulated release and uptake, animals with high responses to a novel environment had DA transporters that were more sensitive to cocaine-induced uptake inhibition, which corresponded to greater locomotor activating effects of cocaine. These animals also acquired cocaine self-administration more rapidly and, after 5 days of extended access cocaine self-administration, high-responding animals showed robust tolerance to DA uptake inhibition by cocaine. The effects of cocaine remained unchanged in animals with low novelty responses. Similarly, the rate of acquisition was negatively correlated with DA uptake inhibition by cocaine after self-administration. Thus, we showed that tolerance to the cocaine-induced inhibition of DA uptake coexists with a behavioral phenotype that is defined by increased preoccupation with cocaine as measured by rapid acquisition and early high intake.

The hypocretin-orexin system regulates cocaine self-administration via actions on the mesolimbic dopamine system.

Recent evidence suggests that the hypocretin-orexin system participates in the regulation of reinforcement processes. The current studies examined the extent to which hypocretin neurotransmission regulates behavioral and neurochemical responses to cocaine, and behavioral responses to food reinforcement. These studies used a combination of fixed ratio, discrete trials, progressive ratio and threshold self-administration procedures to assess whether the hypocretin 1 receptor antagonist, SB-334867, reduces cocaine self-administration in rats. Progressive ratio sucrose self-administration procedures were also used to assess the extent to which SB-334867 reduces responding to a natural reinforcer in food-restricted and food-sated rats. Additionally, these studies used microdialysis and in vivo voltammetry in rats to examine whether SB-334867 attenuates the effects of cocaine on dopamine signaling within the nucleus accumbens core. Furthermore, in vitro voltammetry was used to examine whether hypocretin knockout mice display attenuated dopamine responses to cocaine. Results indicate that when SB-334867 was administered peripherally or within the ventral tegmental area, it reduced the motivation to self-administer cocaine and attenuated cocaine-induced enhancement of dopamine signaling. SB-334867 also reduced the motivation to self-administer sucrose in food-sated but not food-restricted rats. Finally, hypocretin knockout mice displayed altered baseline dopamine signaling and reduced dopamine responses to cocaine. Combined, these studies suggest that hypocretin neurotransmission participates in reinforcement processes, likely through modulation of the mesolimbic dopamine system. Additionally, the current observations suggest that the hypocretin system may provide a target for pharmacotherapies to treat cocaine addiction.

Gene expression changes in the medial prefrontal cortex and nucleus accumbens following abstinence from cocaine self-administration.

BACKGROUND: Many studies of cocaine-responsive gene expression have focused on changes occurring during cocaine exposure, but few studies have examined the persistence of these changes with cocaine abstinence. Persistent changes in gene expression, as well as alterations induced during abstinence may underlie long-lasting drug craving and relapse liability. RESULTS: Whole-genome expression analysis was conducted on a rat cocaine binge-abstinence model that has previously been demonstrated to engender increased drug seeking and taking with abstinence. Gene expression changes in two mesolimbic terminal fields (mPFC and NAc) were identified in a comparison of cocaine-naïve rats with rats after 10 days of cocaine self-administration followed by 1, 10, or 100 days of enforced abstinence (n = 6-11 per group). A total of 1,461 genes in the mPFC and 414 genes in the NAc were altered between at least two time points (ANOVA, p < 0.05; +/- 1.4 fold-change). These genes can be subdivided into: 1) changes with cocaine self-administration that do not persist into periods of abstinence, 2) changes with cocaine self-administration that persist with abstinence, 3) and those not changed with cocaine self-administration, but changed during enforced abstinence. qPCR analysis was conducted to confirm gene expression changes observed in the microarray analysis. CONCLUSIONS: Together, these changes help to illuminate processes and networks involved in abstinence-induced behaviors, including synaptic plasticity, MAPK signaling, and TNF signaling.

Hold-down as an alternative to unit dose in cocaine self-administration experiments: Characterization using a progressive ratio schedule.

RATIONALE: Virtually all cocaine self-administration studies have used a "unit dose" as a reinforcing stimulus; the subject is a passive recipient of an experimenter-selected dose. OBJECTIVES: The present experiments examined the consequence of requiring the subject to actively determine the dose and speed of each injection. METHODS: A two-lever procedure was used in which responding on a progressive ratio (PR) schedule provided access to cocaine on a hold down (HD) schedule. With HD, the pump is turned on for the duration that the lever is held down, thus the dose and speed of injection is determined by the behavior of the subject. The procedure allows for the evaluation of both drug taking and drug seeking responses. RESULTS: The results were qualitatively different from PR self-administration studies using unit dose. The self-administered HD dose varied across the session; the self-administered dose was found to inversely correlate with drug levels at the time of access. Importantly, the 2 L-PR-HD procedure identified a subpopulation of subjects that showed extremes in both drug seeking and drug taking. Subjects at the top end of the distribution displayed unprecedented final ratios (> 900) and rapidly self-administered very large doses (> 1.4 mg; ~ 4.2 mg/kg). Manipulation of drug-taking variables (HD access duration and concentration of drug in the pump) showed that the immediacy of a cocaine bolus, not the duration of access, is the major determinant of drug seeking. CONCLUSIONS: Incorporating a consummatory response into a PR procedure provides a unique perspective on the interactions of drug-seeking and drug-taking.

Cocaine self-administration on a hold-down schedule of reinforcement in rats.

RATIONALE AND OBJECTIVE: Although many contingencies operating in the natural environment include continuous dimensions of responses and reinforcers, previous studies of drug self-administration have almost exclusively used discrete dimensions of responses (e.g., a lever press) and reinforcers (e.g., 1.0 mg/kg/injection cocaine). Therefore, the present study provides an initial examination under experimental conditions with both responses and reinforcers measured along continuous dimensions. MATERIALS AND METHODS: Cocaine-maintained responding was studied in rats under a novel, hold-down schedule of reinforcement wherein the duration of the response was directly related to the magnitude of the reinforcer. These conditions were established by activating the syringe pump when the lever was pressed down and turning the pump off when the lever was released. The concentration of cocaine available in the syringe was varied across sessions. RESULTS: Cocaine self-administration was readily maintained under these conditions and remained stable across sessions. Responding was concentration dependent, with the number of responses and total duration of the response inversely related to concentration, and overall session intake of cocaine was stable across concentrations. In general, the duration of the responses were less than 0.5 s and did not vary as a function of concentration. CONCLUSIONS: Stability of responding under these schedule conditions was acquired quickly. This schedule of reinforcement may be useful for comparing across drug classes, can be extended for use with other types of responses and reinforcers, and may be more representative of the natural world where response-reinforcer contingencies are more likely to be experienced along continuous, rather than discrete, dimensions.

Persistent alterations in mesolimbic gene expression with abstinence from cocaine self-administration.

Cocaine-responsive gene expression changes have been described after either no drug abstinence or short periods of abstinence. Little data exist on the persistence of these changes after long-term abstinence. Previously, we reported that after discrete-trial cocaine self-administration and 10 days of forced abstinence, incubation of cocaine reinforcement was observable by a progressive ratio schedule. The present study used rat discrete-trial cocaine self-administration and long-term forced abstinence to examine extinction responding, mRNA abundance of known cocaine-responsive genes, and chromatin remodeling. At 30 and 100 days of abstinence, extinction responding increased compared to 3-day abstinent rats. Decreases in both medial prefrontal cortex (mPFC) and nucleus accumbens c-fos, Nr4a1, Arc, and EGR1 mRNA were observed, and in most cases persisted, for 100 days of abstinence. The signaling peptides CART and neuropeptide Y (NPY) transiently increased in the mPFC, but returned to baseline levels following 10 days of abstinence. To investigate a potential regulatory mechanism for these persistent mRNA changes, levels of histone H3 acetylation at promoters for genes with altered mRNA expression were examined. In the mPFC, histone H3 acetylation decreased after 1 and 10 days of abstinence at the promoter for EGR1. H3 acetylation increased for NPY after 1 day of abstinence and returned to control levels by 10 days of abstinence. Behaviorally, these results demonstrate incubation after discrete-trial cocaine self-administration and prolonged forced abstinence. This incubation is accompanied by changes in gene expression that persist long after cessation of drug administration and may be regulated by chromatin remodeling.

Increased breakpoints on a progressive ratio schedule reinforced by IV cocaine are associated with reduced locomotor activation and reduced dopamine efflux in nucleus accumbens shell in rats.

RATIONALE: It has been hypothesized that sensitization of the neurochemical effects within the mesolimbic dopamine (DA) system might account for specific aspects of the addiction process. We have recently developed a self-administration procedure which produces increases in responding reinforced by cocaine on a progressive ratio (PR) schedule. This may reflect an increased motivation to self-administer cocaine, one hallmark of addiction. OBJECTIVES: The goal of this experiment was to investigate behavioral and neurochemical changes associated with increased cocaine self-administration on a PR schedule. MATERIALS AND METHODS: Rats self-administered cocaine over 14 days under a PR schedule. Cocaine-stimulated locomotor activity was evaluated before as well as 1 or 14 days after self-administration training. Cocaine-induced DA changes in the core and shell of the nucleus accumbens in the same animals were also examined. RESULTS: Subjects showed increased responding over time, to about 200% of baseline. Cocaine-induced locomotor activation was decreased at both withdrawal times compared to naïve animals. Microdialysis showed no differences after self-administration in the nucleus accumbens core dopamine response at either time point. There was, however, a significant decrease in the dopamine response to cocaine in the shell of the nucleus accumbens. CONCLUSION: The present results demonstrate that a progressive increase in breakpoints on a PR schedule can be established in rats at a time when the ability of cocaine to increase extracellular DA levels and stimulate locomotor activity is reduced. Therefore, sensitization of the mesolimbic DA system does not account for the observed change in drug-taking behavior.

Cocaine self-administration reinforced on a progressive ratio schedule decreases with continuous D-amphetamine treatment in rats.

RATIONALE: To date, there is no medication specifically approved for cocaine addiction. Agonist medications are used clinically in the treatment of other addictions, which suggests that this method of drug therapy could potentially be successful in treating cocaine addiction as well. OBJECTIVE: The objective of this study was to determine the effect of extended D-amphetamine treatment on responding on a progressive ratio (PR) schedule reinforced by cocaine. MATERIALS AND METHODS: Rats were trained to self-administer cocaine (0.19, 0.38, 0.75, or 1.5 mg/kg/injection) or food on a PR schedule. After stable baseline breakpoints (the number of reinforcers earned in one session) were established over 3 days, animals were implanted with osmotic mini-pumps that continuously delivered D-amphetamine (5 mg/kg/day) for a duration of either 7 or 14 days. Breakpoints were then determined during and/or after this treatment period. RESULTS: Rats demonstrated dose-dependent decreases in cocaine-reinforced responding over the D-amphetamine treatment period. Breakpoints for doses of 0.75 mg/kg/injection and below decreased significantly when compared to baseline and remained decreased for up to 14 days after mini-pump removal, whereas those for the highest dose of cocaine remained unchanged. Additionally, D-amphetamine treatment during a 14-day abstinence period from cocaine self-administration had no effect on breakpoints when tested the day after mini-pump removal. CONCLUSIONS: These data suggest that the reduction in cocaine-reinforced responding after continuous D-amphetamine treatment cannot be accounted for by tolerance alone. Instead, the roles of learning and the interaction between cocaine and D-amphetamine must be considered and examined in future studies.

Lesions of the dorsomedial frontal cortex block sensitization to the positive-reinforcing effects of cocaine.

Previous studies have reported that rats exposed to a binge-abstinence history of cocaine self-administration exhibit sensitization to the positive-reinforcing effects of cocaine on a progressive ratio (PR) schedule of reinforcement. The purpose of the present study was to determine whether lesions of the dorsomedial frontal cortex block sensitization to the reinforcing effects of cocaine in rats with a history of binge-abstinence self-administration. Separate groups of male rats received bilateral infusions of either ibotenic acid (lesion) or sterile saline (sham) into the dorsomedial frontal cortex, or were left undisturbed (intact). All rats were then implanted with jugular catheters and trained to self-administer cocaine. Following acquisition, cocaine was made available on a PR schedule of reinforcement and breakpoints were determined in each group. Rats were then exposed to a discrete-trials (DT) procedure in which cocaine was made available during 10-min discrete-trials that occurred every 15 min (i.e., 4 times per hr) during daily, 24-hr sessions. This procedure elicited a "binge" in all groups, during which high rates of responding were maintained over a period of 1-2 days. After 10 days, the DT procedure was terminated, and no cocaine was available for the next 7 days. Following 7 days of forced "abstinence", cocaine-reinforced breakpoints were redetermined on the PR schedule. Prior to the DT procedure, no differences were observed in breakpoints across the three groups. Following the 7-day abstinence period, breakpoints on the PR schedule increased significantly in intact and sham rats, indicating an increase in the reinforcing efficacy of cocaine. In contrast, breakpoints did not increase in lesion rats, and were similar to those obtained prior to the binge-abstinence history. These data suggest that lesions of the dorsomedial frontal cortex block sensitization to the positive-reinforcing effects of cocaine in rats with a history of binge-abstinence self-administration.

Parsing the Addiction Phenomenon: Self-Administration Procedures Modeling Enhanced Motivation for Drug and Escalation of Drug Intake.

Investigators who study drug addiction are fortunate to have access to excellent animal models. Such models will be invaluable in the assessment of factors involved in the progression of drug addiction. The relevance of these findings, however, will depend on the general understanding of how each model is related to drug addiction. The present review focuses on several procedures that were designed to model the addiction process and questions whether these models are tapping into the same underlying process or whether each is addressing a unique feature. Furthermore, various factors (e.g., rate of drug onset, dose magnitude, early drug history, periods of abstinence) influencing the progression of these addiction-like changes in behavior are discussed.

Cross-sensitization of the reinforcing effects of cocaine and amphetamine in rats.

RATIONALE: Cross-sensitization between cocaine and amphetamine has been demonstrated in different behavioral paradigms. There is a relative paucity of studies examining whether cross-sensitization occurs between amphetamine and cocaine when both are self-administered. OBJECTIVE: The current study was designed to test whether animals sensitized to the reinforcing effects of cocaine would show cross-sensitization of the reinforcing effects of amphetamine, using a self-administration paradigm. MATERIALS AND METHODS: Male, Sprague-Dawley rats were trained to self-administer cocaine and given limited or high exposure to cocaine under a fixed ratio (FR) 1 procedure. After the initial exposure to cocaine, animals self-administered cocaine (1.5 mg/kg per injection) under a progressive ratio (PR) procedure. Subsequently, breakpoints on a PR schedule and rates of intake on an FR schedule maintained by different doses of amphetamine were assessed. RESULTS: Animals with high initial exposure to cocaine (40 injections of 1.5 mg/kg per injection per day for 5 days) showed stable breakpoints throughout testing. Animals given limited initial cocaine exposure (20 injections of 0.75 mg/kg per injection for 1 day) produced a gradual increase in breakpoints maintained by cocaine over time (i.e., sensitization of the reinforcing effects of cocaine). When subsequently tested with amphetamine, the dose-effect curve was shifted upward in the limited-exposure group relative to the high-exposure group, suggesting cross-sensitization of the reinforcing effects of amphetamine. CONCLUSIONS: Sensitization of the reinforcing effects of cocaine resulted in cross-sensitization of the reinforcing effects of amphetamine. This phenomenon occurs even when both drugs are self-administered.

Microinjection of the delta-opioid receptor selective antagonist naltrindole 5'-isothiocyanate site specifically affects cocaine self-administration in rats responding under a progressive ratio schedule of reinforcement.

Whether the delta-opioid receptor (DOR) system can modulate behavioral effects of cocaine remains equivocal. We examined whether site- and subtype-selective blockade of DORs within the rat mesocorticolimbic system affects cocaine self-administration. The DOR antagonist naltrindole 5'-isothiocyanate (5'-NTII; 5nmol) was microinjected into the nucleus accumbens (NAcc), ventral tegmental area (VTA), or amygdala (AMYG) in rats self-administering 1.5mg/kg cocaine under a progressive ratio (PR) schedule. Intra-NAcc 5'-NTII significantly decreased cocaine self-administration, while 5'-NTII administration into the VTA significantly increased cocaine-maintained responding. 5'-NTII administration into the AMYG produced no effect. These data support a site-specific role of DORs in cocaine's behavioral effects.

Repetitive vibrissae-elicited forelimb placing before and immediately after unilateral 6-hydroxydopamine improves outcome in a model of Parkinson's disease.

In rodent models of Parkinson's disease (PD), exercise or complex living environments introduced immediately before or during early stages of degeneration can provide beneficial effects on functional and/or neurochemical outcome. The goal of this study was to determine whether or not exposure to repetitive vibrissae-elicited forelimb placing, a dopamine-dependent sensorimotor movement, improves functional outcome in rats infused unilaterally with 6-OHDA. Prior to unilateral 6-OHDA infusions into the medial forebrain bundle, male Sprague-Dawley rats were randomly divided into groups exposed to one of five placing schedules: (1) two consecutive days pre-6-OHDA (PRE), (2) PRE+day 1 post-6-OHDA, (3) PRE+days 1, 2, 3 post-6-OHDA, (4) HANDLE, and (5) Sham infusion+handle. A session consisted of 180 total trials (90 left forelimb and 90 right forelimb trials) including 60 consecutive trials where vibrissae stimulation evoked ipsilateral forelimb movement and 30 consecutive trials where the ipsilateral forelimb was restrained so that vibrissae evoked contralateral forelimb movement (cross-midline placing). All groups were exposed to forelimb placing sessions on post-infusion days 7 and 14. The ability of vibrissae stimulation to elicit an ipsilateral response of the 6-OHDA affected forelimb was assessed on all days. Animals were sacrificed on post-lesion day 15 and substantia nigra tyrosine hydroxylase immunoreactivity (TH-ir) quantified. Repetitive forelimb placing had a significant effect on behavioral performance for all groups compared to the HANDLE group, but only the PRE+123 group was not significantly different from SHAM controls. Only the PRE+123 group showed significant sparing of TH-ir compared to the HANDLE group. These data suggest that extensive repetitive exposure to a sensorimotor task may provide therapeutic effects in an animal model of PD.

Increase in A2A receptors in the nucleus accumbens after extended cocaine self-administration and its disappearance after cocaine withdrawal.

Effects of extended cocaine self-administration and its withdrawal have been studied on A(2A) and D(2) receptor binding characteristics and expression in the nucleus accumbens and the anterior and posterior dorsal striatum of the rat (Rattus norvegicus). Biochemical binding techniques have been used with the D(2)-like receptor antagonist radioligand [(3)H]-Raclopride and the A(2A) receptor antagonist radioligand [(3)H]-ZM 241385 and immunoblots to study their expression. A substantial and significant increase in functional A(2A), but not in functional D(2) receptors, was observed in the nucleus accumbens immediately following 10 days of cocaine self-administration which returned to normal levels after 7 days of drug withdrawal. In contrast, in the posterior dorsal striatum significant reductions in A(2A) expression were observed immediately after cocaine self-administration which was associated with a trend for a reduction of the A(2A) receptor antagonist binding sites. In cocaine withdrawal groups, significant increases in the density and K(d) value of D(2)-like antagonist binding sites were observed in the nucleus accumbens in the absence of changes in D(2) expression, suggesting an up-regulation of D(3) receptors in this region after cocaine withdrawal. A(2A) receptor increases in the nucleus accumbens induced by cocaine may represent a compensatory up-regulation to counteract cocaine-induced increases in D(2) signaling and D(3) signaling which is in line with its disappearance in the 7-day withdrawal group displaying increased reinforcing efficacy of cocaine. A(2A) agonists may therefore represent cocaine antagonist drugs to be used in treatment of cocaine addiction acting inter alia by antagonizing signaling in accumbens A(2A)/D(2) and A(2A)/D(3) heteromers.

How to make a rat addicted to cocaine.

Procedures have been developed which provide extremely stable patterns of cocaine self-administration in rats and these have been useful in lesion and drug pretreatment studies aimed at understanding the neurobiology of cocaine reinforcement. The issue now is whether studying the neurobiology of reinforcement is the same as studying the neurobiology of addiction. If the goal is to understand a progressive and deteriorating disorder, then the self-administration procedures should model specific aspects of the progressive stages of the addiction process. Here we review theoretical strategies for modeling the addiction process and present data from a series of experiments from our laboratory showing conditions which produce a progressive change in the motivation to self-administer cocaine in rats. This phenomenon is revealed by an escalation in breakpoints on a progressive ratio schedule. The effect, which is robust and persistent, depends on dose and speed of injection. Interestingly, high drug intake can retard the development of this effect, which we argue indicates that the addiction process has a developmental sequence. Finally, we suggest that specific parameters (dose, price and availability) can be used to examine the transition from recreational use to binge-like intake.

Intermittent intake of rapid cocaine injections promotes robust psychomotor sensitization, increased incentive motivation for the drug and mGlu2/3 receptor dysregulation.

The choice between smoking, injecting or swallowing a drug influences the risk of addiction, as this determines both how much drug gets into the brain and how fast. Most animal studies on addiction focus on how much drug it takes to produce pathological drug use. How fast drugs get to the brain is generally ignored. A few studies have examined the influence of the speed of drug onset, but speed varied along with cumulative intake. Here we held average cumulative intake constant and determined whether variation in the speed of cocaine onset alone predicts outcome. Two groups of rats self-administered intravenous cocaine (0.25 mg/kg/injection) during daily sessions. Cocaine was available intermittently during each session. This produces the spikes and troughs in brain levels of cocaine thought to model how addicts take the drug. To vary the speed of cocaine onset, each injection was delivered over 5 s to one group, and over 90 s to the other. Average cumulative cocaine intake was the same in the two groups. However, rapid injections promoted robust psychomotor sensitization and potentiated incentive motivation for cocaine (0.063-0.25 mg/kg/injection). This addiction-relevant phenotype was accompanied by enhanced functional activity of metabotropic glutamate group II receptors (mGluR2/3s) in the prelimbic cortex and nucleus accumbens. Pharmacological activation of mGluR2/3s with LY379268 also preferentially decreased the motivation to take cocaine in rats previously exposed to rapid drug injections. Thus, varying the speed of drug onset can be used to parse the neurobiology of addiction from that of mere drug taking.

Rapid and persistent sensitization to the reinforcing effects of cocaine.

The development of drug addiction involves a transition from recreational use to compulsive drug seeking and taking, and this progression can occur rapidly with cocaine use. These data highlight the importance of early drug exposure and the development of drug dependence; however, little experimental attention has been paid to this phenomenon in animal models of drug abuse. The present experiments demonstrate a progressive and rapid sensitization to the reinforcing strength of cocaine assessed using a progressive ratio (PR) schedule in rats. The first experiment found that rats show increased breakpoints over a 2-week period following acquisition. Subsequent experiments examined the role of total cocaine intake during the initial exposure period and found that low intakes (20 mg/kg/day x 5 days) resulted in sensitization, whereas relatively higher intake (60 or 100 mg/kg/day x 5 days) suppressed the development of sensitization. In contrast, this higher level of intake (60 mg/kg/day x 5 days) only transiently suppressed the expression of sensitization. Examination of breakpoints maintained by various doses of cocaine revealed an upward and leftward displacement of the cocaine dose-effect curve, relative to nonsensitized animals. These studies describe a form of sensitization that occurs rapidly to the reinforcing effects of cocaine, and provide a model to study the potential impact of initial experience on the development of drug dependence.