Tolerance-like attenuation to contingent and noncontingent cocaine-induced elevation of extracellular dopamine in the ventral striatum following 7 days of withdrawal from chronic treatment

Time-dependent changes in mesolimbic dopamine (DA) function are believed to play a role in behavioral sensitization and drug craving experienced during withdrawal from chronic cocaine administration. The present study utilized intravenous (IV) cocaine self-administration coupled with intracranial microdialysis in rats to investigate time dependent changes during withdrawal from chronic cocaine exposure. Following 2 weeks of IV cocaine self-administration, rats were allowed contingent access to cocaine at 1 and 7 days of withdrawal while extracellular levels of DA were measured from the ventral striatum. A second group of animals received yoked, noncontingent cocaine for 2 weeks and were then administered noncontingent cocaine on days 1 and 7 of withdrawal. In addition, a third group of animals received 2 weeks of yoked saline followed by noncontingent cocaine 1 day after withdrawal. There were no significant differences between groups for the overall cocaine dosage or temporal pattern of infusions on days 1 and 7 of withdrawal. Basal extracellular DA concentrations did not differ between any treatment groups at either withdrawal time. Extracellular DA levels were increased throughout the session on both days; however, the increases at day 7 were significantly less than day 1 for both contingent and noncontingent conditions. DA overflow on day 1 did not differ between animals receiving chronic yoked cocaine or saline. These results suggest that tolerance-like attenuation to the DA-elevating effects of cocaine is not apparent early in withdrawal, but does develop by later time points. DA release in the ventral striatum may not be directly related to cocaine self-administration following withdrawal, since DA levels were attenuated after 7 days of withdrawal while responding for cocaine was unaltered.     

Influence of cocaine self-administration on learning related to prefrontal cortex or hippocampus functioning in rats

Rationale Individuals who abuse cocaine have cognitive deficits, particularly in functions associated with the orbitofrontal cortex. It is not clear to what extent the impact of cocaine on cognitive functioning is related to its role as a behavioral reinforcer. A preclinical means to investigate this issue is to use a yoked-triad procedure in which sets of three animals either contingently self-administer cocaine or receive passive administration of cocaine or saline in a noncontingent manner. Objective Using this procedure, we assessed cocaine’s effect on learning that requires a functionally intact prefrontal cortex (prelimbic or insular/orbital subregions) or hippocampus. Methods Rats self-administering 1-mg/kg unit doses of cocaine responded under a fixed-ratio 5, time-out 20-s schedule of drug delivery. Testing took place in a radial-arm maze within the first 30 min after 2-hr drug sessions ended, beginning after 2.5 months of cocaine or saline exposure. Results Rats self-administering cocaine earned 14–18 infusions on average throughout different phases of the study. In groupwise comparisons, learning in the visually guided delayed win-shift (prelimbic prefrontal cortex-related) and win-shift (hippocampus-related) tasks was not influenced by contingent or noncontingent cocaine exposure. Session latency, though, was shorter in both cocaine-exposed groups during the win-shift task. During the odor-guided delayed win-shift task (insular/orbital prefrontal cortex-related), learning was disrupted in rats self-administering cocaine, with no influence of noncontingent cocaine exposure. Conclusions Based on these and previous findings, learning related to functioning of the insular/orbital prefrontal cortex and amygdala is the most consistently disrupted in cocaine-intoxicated rats after long-term drug exposure.     

Contingent and noncontingent cocaine administration in rhesus monkeys: a comparison of the effects on the acquisition and performance of response sequences

Previous studies have suggested that the effects of contingent (response dependent) and noncontingent (response independent) cocaine administration may differ, which could limit the generality and validity of laboratory studies that use only noncontingent administration. Therefore, two separate three-component multiple schedules of operant responding were used to examine the effects of both types of cocaine administration on the acquisition and performance of response sequences, in four rhesus monkeys. In one multiple schedule, responding under a fixed-ratio (FR) 60 schedule was followed by intravenous (i.v.) saline or cocaine (0.0032-0.32 mg/kg per infusion), whereas responding in the other two components (i.e. acquisition and performance) was followed by food presentation. In the second multiple schedule, the cocaine administration component consisted of a variable-time (VT) schedule that mimicked each subject's pattern of self-administration. When compared to saline administration, increasing infusion doses of cocaine decreased overall response rates comparably in both food-maintained components, irrespective of the cocaine contingency. The 0.1-0.32 mg/kg infusion doses also increased the percentage of errors in 2 of 4 subjects; however, these disruptions in accuracy were not differentially associated with the type of cocaine administration and generally occurred at doses that produced large rate-decreasing effects. Taken together, these data suggest that the effects of cocaine on complex operant behavior in monkeys may not differ substantially as a function of contingent or noncontingent administration.     

Effects of contingent and non-contingent cocaine on drug-seeking behavior measured using a second-order schedule of cocaine reinforcement in rats.

Rats were trained to respond with intravenous cocaine as the reinforcer under a fixed interval 15-min schedule, during which conditioned stimuli paired with cocaine were presented contingent on completion of a fixed ratio of 10 responses (i.e., second-order schedule of reinforcement). The effects of contingent and noncontingent cocaine were investigated. The results show that pretreatment with noncontingent (i.e., experimenter-administered) cocaine led to a satiation-like effect that was reflected in decreased numbers of responses and a tendency for an increased latency to initiate responding when the doses of cocaine administered were similar to or higher than the training/maintenance dose of cocaine. By contrast, noncontingent administration of cocaine doses lower than the training/maintenance dose, and response-contingent cocaine administration, led to increased drug-seeking behavior, as reflected in increased numbers of responses. The present data indicate that at least two factors determine whether administration of cocaine would lead to drug-seeking behavior: whether the cocaine administration is contingent or noncontingent, and the relative magnitude of the cocaine dose administered in relation to the training/maintenance dose of cocaine.     

Calcium antagonists isradipine and nimodipine suppress cocaine and morphine intravenous self-administration in drug-naive mice.

The effect of isradipine and nimodipine, two dihydropyridine calcium antagonists, on intravenous self-administration of cocaine and morphine in naive mice has been investigated. When morphine or cocaine injections were made contingent upon nose-poke response by naive mice, they increased their rate of nose-poking with respect to animals receiving contingent saline injections or yoked control animals, receiving noncontingent cocaine or morphine injections. Pretreatment of mice with isradipine (1.0-3.0 mg/kg, SC) or nimodipine (5-20 mg/kg, SC) inhibited in a dose-related manner self-administration both of cocaine and morphine contingent upon a nose-poke response. The ED50 of isradipine against cocaine and morphine self-administration was 1.7 and 2.1 mg/kg, respectively. The relative values for nimodipine were 14.5 and 11.4 mg/kg, respectively. These data suggest that nimodipine and, especially, isradipine suppress the reinforcing properties of morphine and cocaine and may be an effective pharmacotherapy for treatment of cocaine and heroin abuse.     

Riboflavin reduces hyperalgesia and inflammation but not tactile allodynia in the rat

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

Non-contingent electric footshock facilitates the acquisition of intravenous cocaine self-administration in rats

The experiments described below were designed to investigate whether contingent versus non-contingent electric footshock would affect the acquisition of intravenous cocaine self-administration in rats. During the first component of a multiple schedule, triads of rats were trained to respond under a discrete-trial, fixed-ratio 10 schedule of food reinforcement. Random footshock presentation (0.6 mA) for the first and second rats from each triad was yoked to food lever responding by the rats in the first group only, while the third group of rats was never shocked. When stable baselines of food-reinforced responding were obtained, all three rats from each triad were allowed to self-administer increasing doses of cocaine (0.031–0.5 mg/kg per infusion) during the second component. Rats from the second group, receiving noncontingent footshock presentation, self-administered cocaine (0.125 mg/kg per infusion) at higher rates and at one-half the dose which maintained responding in rats from the other two treatment groups. Plasma corticosterone, measured before the acquisition of cocaine self-administration, was highly correlated with drug intake at this concentration for all three groups of rats. These data demonstrate that non-contingent experimental stress facilitates the acquisition of intravenous cocaine self-administration in rats.     

Progesterone inhibits behavioral responses and estrogen increases corticosterone levels after acute cocaine administration

Accumulating evidence suggests that estrogen and progesterone contribute to the sexually dimorphic behavioral response to cocaine. In this study, we tested the hypothesis that varying the level of estrogen or progesterone affects cocaine-induced locomotive behavior in female rats. Ovariectomized (OVX) rats received estrogen (0, 5, 10, 20, or 50 μg) 48 h or progesterone (0, 50, 100, 250, or 500 μg) 24 h before acute saline or cocaine (15 mg/kg) administration. Although estrogen did not affect cocaine-induced ambulatory and rearing behaviors, it affected stereotypic behaviors regardless of cocaine administration (animals receiving 50 μg had higher stereotypic counts than did the OVX group). In contrast, progesterone affected rearing activity dose-dependently: 50 and 500 μg of progesterone inhibited, whereas 100 μg and 250 μg stimulated, rearing in response to cocaine. That estrogen and progesterone did not affect overall baseline behavioral activity suggests their effects are mediated in part through interactions with cocaine. Progesterone administration did not affect corticosterone levels in saline- or cocaine-treated rats. Estrogen administration, however, affected levels of corticosterone both at baseline and after cocaine treatment. After accounting for baseline differences, we found that rats receiving 5 or 10 μg of estrogen and cocaine had higher percentage increases in serum corticosterone levels than did the control group that did not receive estrogen. On the basis of these observations, we suggest that progesterone fluctuations during the estrous cycle impact cocaine-induced behavioral responses, whereas estrogen may affect activity in the hypothalamic–pituitary–adrenal axis. Thus, dose-dependent effects of gonadal hormones may underlie some of the reported sex differences and reproductive cycle effects of cocaine.     

Extinction of cocaine self-administration produces a differential time-related regulation of proenkephalin gene expression in rat brain.

The purpose of this study was to examine the time course effects of extinction of cocaine self-administration behavior on proenkephalin (PENK) gene expression in caudate-putamen nucleus (ST), nucleus accumbens (Acc), olfactory tubercle (Tu), piriform cortex (Pir), ventromedial hypothalamic nucleus (VMN), and central amygdala (Ce) as measured by in situ hybridization histochemistry. Seventy-two littermate male Lewis rats were randomly assigned in triads to one of three conditions: (1) contingent intravenous self-administration of 1 mg/kg/injection of cocaine (CONT); (2) noncontingent injections of either 1 mg/kg/injection of cocaine (NONCONT); or (3) saline yoked (SALINE) to the intake of the self-administering subject. The self-administering rats were trained to self-administer cocaine under a FR5 schedule of reinforcement for a minimum of 3 weeks. After stable baseline levels of drug intake had been reached, saline was substituted for drug. Following this first extinction period, cocaine self-administration was reinstated for an additional period of 2 weeks. Immediately after cessation of the last session of cocaine self-administration (day 0) and 1-, 5-, and 10-day after the second extinction period, animal brains in each triad were removed to be processed for in situ hybridization. PENK mRNA levels were significantly higher in the cocaine groups when compared with SALINE group in the ST, Acc, Pir, and Tu regions on days 0, 1, 5, and 10 of the extinction and lower in the Ce region of CONT group when compared to NONCONT and SALINE groups on days 1, 5, and 10 of the extinction period. In the VMN nucleus, PENK mRNA content in CONT group versus NONCONT and SALINE groups was also lower, but there were statistically significant differences only on day 5. These results suggest that changes in PENK gene expression after contingent cocaine administration might be involved in cocaine withdrawal states.     

Self-administered and passive cocaine infusions produce different effects on corticosterone concentrations in the medial prefrontal cortex (MPC) of rats

Although our lab, as well as several others, has demonstrated a role for corticosterone in cocaine self-administration, there are no studies of the central dynamics of this hormone over the course of a behavioral session when rats are self-administering cocaine or receiving passive injections. The assay of corticosterone in microdialysates collected during such sessions allows for determinations of changes in brain corticosterone during drug-taking behavior. By using the combination of microdialysis in terminal fields for the mesocorticolimbic dopaminergic system and the yoked-triad model, one can distinguish between the direct cocaine-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis from the activation of the HPA axis related to drug-taking. In these experiments, we measured corticosterone in microdialysis samples collected from probes aimed at the medial prefrontal cortex, nucleus accumbens and basolateral amygdala in rats self-administering cocaine and receiving identical, passive infusions of cocaine or saline. While corticosterone was increased in all three brain regions in rats receiving cocaine, medial prefrontal cortex corticosterone was increased significantly more in rats receiving non-contingent infusions of the drug compared to rats self-administering cocaine. The results of these experiments demonstrate that control over drug delivery can affect the influence of a hormonal input on the functional characteristics of specific anatomical projections of the central nervous system. These results also provide evidence of the role steroid hormones play in shaping the functional activity of the brain.     

Potential role for the hypothalamo-pituitary-adrenal axis in the conditioned reinforcer-induced reinstatement of extinguished cocaine seeking in rats

RATIONALE: We have previously reported that pretreatment with the corticosterone synthesis inhibitor ketoconazole blocks the electric foot-shock-induced reinstatement of cocaine-seeking behavior in rats, suggesting a potential role for the hypothalamo-pituitary-adrenal (HPA) axis in this animal model of relapse. OBJECTIVES: This experiment was designed to investigate whether or not ketoconazole would also inhibit the reinstatement of cocaine seeking induced by the presentation of a conditioned reinforcer. The effects of the corticotropin-releasing hormone 1 (CRH1) receptor antagonist CP-154,526 were also investigated to further determine the involvement of the HPA axis in this behavior. METHODS: Adult male rats were implanted with jugular catheters and trained to self-administer cocaine (0.25 mg/kg per infusion) during daily 2-h sessions. During training, cocaine delivery was paired with the presentation of a tone and the illumination of a house light. Once a stable baseline of cocaine self-administration was observed, lever pressing was extinguished to less than 20% of baseline rates. During reinstatement testing, responding by rats in the contingent group resulted in the presentation of the conditioned reinforcer (i.e., the house light and tone previously paired with self-administered cocaine). Rats in the non-contingent group were presented with the tone/house light compound stimulus once every 5 min, regardless of responding. Rats were pretreated with ketoconazole (25 mg/kg, i.p.) or CP-154,526 (20 mg/kg, i.p.) 30 min prior to testing for reinstatement with the contingent presentation of the conditioned reinforcer to determine the role for the HPA axis in this behavior. RESULTS: The response-contingent presentation of the conditioned reinforcer reliably reinstated extinguished cocaine-seeking behavior, while the non-contingent presentation of the same stimulus did not. Increases in plasma corticosterone were evident during cocaine self-administration as well as during extinction and reinstatement testing. However, while plasma corticosterone returned to basal levels by the end of the session during extinction, it remained elevated through the end of the session during reinstatement. Pretreatment with ketoconazole reversed the conditioned reinforcer-induced reinstatement of extinguished cocaine-seeking behavior and also attenuated the conditioned increases in plasma corticosterone observed during reinstatement. Pretreatment with CP-154,526 resulted in a similar decrease in cocaine seeking. CONCLUSIONS: These data suggest a potential role for the HPA axis in the ability of environmental cues to stimulate cocaine-seeking behavior.     

Self-administered and noncontingent nicotine enhance reinforced operant responding in rats: impact of nicotine dose and reinforcement schedule

Rationale Nicotine infusions that are self-administered (contingent) or response-independent (noncontingent) increase lever pressing for a reinforcing nonpharmacological stimulus in rats, suggesting that in addition to primary reinforcement, nicotine self-administration may result from nicotine enhancing the reinforcement derived from nonnicotine stimuli. Objectives Based on our previous research, in this study, we tested the hypothesis that contingent and noncontingent nicotine would equally elevate responding for a moderately reinforcing visual stimulus, across a range of nicotine doses on both fixed ratio and progressive ratio reinforcement schedules. Materials and methods The rats lever pressed for a visual stimulus with contingent nicotine, noncontingent nicotine, or contingent saline. Separate groups responded for saline or nicotine without the visual stimulus. Three doses of nicotine (0.01, 0.03, and 0.09 mg/kg per infusion, free base) were tested in a between-groups design. After responding on an escalating fixed ratio reinforcement schedule, the rats were tested on a progressive ratio schedule. Results Compared to responding for the visual stimulus with saline, both contingent and noncontingent nicotine equally elevated lever pressing for the stimulus at each dose on fixed and progressive ratio schedules. In the absence of the stimulus, only the highest nicotine dose sustained self-administration. Conclusions The ability of noncontingent nicotine to elevate responding for a moderately reinforcing visual stimulus occurs across a range of doses, and both self-administered and noncontingent nicotine equally increase motivation to obtain the stimulus, as reflected by performance on a progressive ratio schedule. In the absence of a contingent stimulus, primary reinforcement from nicotine only supports self-administration at high nicotine doses in rats.     

Previous exposure to psychostimulants enhances the reinstatement of cocaine seeking by nucleus accumbens AMPA.

The effect of previous exposure to psychostimulants on the subsequent self-administration of cocaine as well as reinstatement of this behavior by priming infusions of AMPA into the nucleus accumbens (NAcc) was examined. Rats were exposed to five injections, one injection every third day, of either saline or amphetamine (AMPH: 1.5 mg/kg, i.p.). Starting 10 days later, they were trained to self-administer cocaine (0.3 mg/kg/infusion, i.v.) and subsequently tested under a progressive ratio (PR) schedule for 4 consecutive days. As expected, rats exposed to AMPH worked more and obtained more cocaine infusions than saline exposed controls on the PR test sessions. Following daily extinction sessions during which saline was substituted for cocaine, the effect of priming infusions of AMPA (0.0, 0.08, or 0.8 nmol/0.5 microl/side) into the NAcc was then examined on two tests: one conducted 4 days after the last cocaine PR test session (2-3 weeks after the last AMPH exposure injection) and the next 4 weeks later. Consistent with previous reports, NAcc AMPA dose-dependently reinstated cocaine seeking on both tests regardless of exposure condition. Importantly, this priming effect of NAcc AMPA was significantly enhanced in AMPH compared to saline exposed rats on the first test conducted 2-3 weeks after AMPH. On the second test, conducted 4 weeks after cocaine, reinstatement was similarly enhanced in both groups to levels observed on the first test in AMPH exposed rats. These results indicate that both noncontingent (AMPH) and contingent (cocaine) exposure to psychostimulants enhances the reinstatement of cocaine seeking by NAcc AMPA and appears to do so in a time-dependent manner.     

Influence of infused catecholamines on the pharmacokinetics of cocaine and benzoylecgonine formation after bolus dose or continuous cocaine administration in the rat.

The purpose of this study was to determine whether a catecholamine infusion administered to simulate a stress state could alter the pharmacokinetics of administered cocaine and effect the formation of benzoylecgonine, its major metabolite, in the rat. In a previous investigation we determined that catecholamine infusion enhanced the toxicity of continuous cocaine infusion by reducing the time before the onset of convulsions and respiratory arrest. We postulated that this enhanced toxicity was an effect of catecholamines on the pharmacokinetics of cocaine. To test this hypothesis we studied plasma cocaine and benzoylecgonine disposition after intravenous bolus administration of cocaine (5 mg kg(-1)) to 19 male Sprague-Dawley rats and to 10 rats which received an initial loading-dose cocaine infusion of 1 mg kg(-1) min(-1) (for 5 min) followed by continuous infusion of 100 microg kg(-1) min(-1). Rats in both studies randomly received either continuous catecholamine infusion comprising adrenaline (7.25 microg mL(-1)), noradrenaline (4.4 microg mL(-1)) and dopamine (8.0 microg mL(-1)) or saline, administered at a similar rate. Bolus dose cocaine administration, simultaneously with catecholamine infusion, resulted in significantly higher Cmax levels for cocaine (3.8 compared with 2.5 microg mL(-1)) and lower distribution half-lives (3.3 compared with 5.9 min) and central compartment volumes of distribution (1.5 compared with 2.1 L kg(-1)) compared with saline infusion. Benzoylecgonine formation was significantly reduced in rats receiving catecholamines whereas the elimination half-lives (26.3 compared with 25.0 min) and systemic clearances (146 compared with 146 mL kg(-1) min(-1)) were not different. Continuous cocaine infusion (after an initial loading infusion) resulted in the doubling of plasma cocaine levels in rats receiving catecholamines compared with the control group. These data indicate that elevated plasma catecholamines have significant effects on cocaine pharmacokinetics. This might serve to explain the enhanced toxicity from concomitant cocaine and catecholamine infusion demonstrated in previous experiments.     

A method for single-session cocaine self-administration in the mouse

Rationale Drug self-administration is a powerful method to measure the reinforcing effects of a drug, as well as to investigate behavioral, biochemical, and physiological effects of a drug specific to contingent delivery. With the spectrum of genetically modified mice available, there is a need for well-designed drug self-administration studies tailored for rapid completion of studies in mice.Objectives We set out to develop a methodology in mice for obtaining high levels of cocaine self-administration during the first exposure to the drug.Materials and methods C57Bl/6J mice were trained to lever press for liquid reinforcer on a fixed ratio 1, then a progressive ratio (PR) schedule of reinforcement before intravenous self-administration of cocaine on a PR schedule.Results Within a single 16-h session, each mouse self-administered either saline or 0.1, 0.3, 0.6, or 1.2 mg kg⁻¹ infusion⁻¹ of cocaine during four distinct 4-h subsessions. Mice showed a strong preference for cocaine vs saline, as demonstrated by higher breakpoints and greater preference for the active lever. Likewise, there was a dose-dependent increase in breakpoints obtained and in drug intake. Finally, animals receiving noncontingent cocaine pressed significantly less than mice self-administering the same dose of cocaine, indicating that a significant amount of active lever pressing is driven by drug-seeking and not the psychomotor-activating effects of cocaine alone.Conclusions Mice will reach high breakpoints and cocaine intake during an initial exposure to cocaine. This method is well-suited to rapidly obtain progressive ratio cocaine self-administration in mice.     

Differential effects of self-administered cocaine in adolescent and adult rats on stimulus–reward learning

Rationale Adult cocaine addicts, abstinent at the time of testing, show a variety of neurocognitive impairments. Less clear is whether there are differences in the degree of impairment if cocaine use is initiated during adolescence rather than adulthood. Objectives Using a preclinical model, we evaluated if stimulus–reward learning was impacted differently in rats exposed to cocaine during adolescence (beginning on postnatal day 37) vs adulthood (beginning on postnatal days 74–79) and then tested after a drug-free period. Materials and methods A yoked-triad design of intravenous cocaine self-administration in adult (n = 8 triads) and adolescent (n = 8 triads) rats was used. Sets of three animals either contingently self-administered cocaine or received cocaine or saline in a noncontingent manner. Rats self-administering 1-mg/kg doses of cocaine responded under a fixed-ratio 5, timeout 20-s schedule of reinforcement. After 18 2-h drug or saline sessions, all rats (now adults) began the drug-free period in their home environments. Testing in a stimulus–reward learning task (conditioned cue preference) began 19 days later. Results Self-administration behavior was similar in adolescent and adult rats. Lever responses were not significantly different, and both age groups averaged approximately 20 infusions per session. Rats contingently self-administering cocaine or passively exposed to cocaine during adulthood showed stimulus–reward learning deficits in the conditioned cue preference task. Rats exposed to contingent or noncontingent cocaine during adolescence had normal learning, showing strong preferences for a Froot Loops-paired cue. Conclusions These findings suggest that adolescents are insensitive to cocaine-induced impairment of learning related to amygdala memory system functioning.     

Ketoconazole does not block cocaine discrimination or the cocaine-induced reinstatement of cocaine-seeking behavior.

Ketoconazole is an FDA-approved antifungal agent that also blocks the synthesis of adrenocorticosteroids and functions as a glucocorticoid receptor antagonist. It has been previously demonstrated that this drug blocks the stress-induced reinstatement of cocaine-seeking behavior and reduces low-dose cocaine self-administration in rats. In the present experiments, the effects of ketoconazole on the cocaine-induced reinstatement of extinguished cocaine-seeking behavior and on cocaine discrimination were investigated in male Wistar rats. In rats trained to self-administer cocaine (0.5 mg/kg/infusion) by pressing a lever under a fixed-ratio 4 schedule of reinforcement, cocaine (5-20 mg/kg, IP) dose dependently reinstated cocaine-seeking behavior following at least 10 days of extinction, during which responding on the cocaine lever resulted in no programmed consequences. Ketoconazole (50 mg/kg, IP) failed to block cocaine-induced reinstatement despite blocking cocaine-induced increases in plasma corticosterone. Ketoconazole (25 or 50 mg/kg) also failed to block cocaine discrimination in rats trained to discriminate 10 mg/kg cocaine from saline. In these rats, generalization to the training dose of cocaine was observed in the absence of increases in plasma corticosterone. The results of these experiments indicate that corticosterone may mediate the effects of stressors on cocaine-seeking behavior but not the direct effects of cocaine itself.     

The role of corticosterone in food deprivation-induced reinstatement of cocaine seeking in the rat

Rational and objectives. Acute 1-day food deprivation stress reinstates heroin seeking in rats, but the generality of this effect to other drugs, and its underlying mechanisms, are largely unknown. Here we studied whether food deprivation would reinstate cocaine seeking and whether the stress hormone, corticosterone, is involved in this effect. Methods. Rats were trained to press a lever for cocaine for 10–12 days (0.5–1.0 mg/kg per infusion, IV, 4 h/day) and were then divided into four groups that underwent different manipulations of plasma corticosterone levels: (1) bilateral adrenalectomy (ADX) surgery, (2) ADX surgery+50-mg corticosterone pellets (ADX+P), (3) ADX surgery+50-mg corticosterone pellets+4-h access (0800–1200 hours) to corticosterone (50 μg/ml) dissolved in a drinking solution (ADX+P/W), or (4) sham surgery. Next, rats were given 7–12 days of extinction training (during which lever presses were not reinforced with cocaine), and after reaching an extinction criterion they were tested for reinstatement of cocaine seeking following exposure to 21 h of food deprivation. Results. Food deprivation was found to reinstate cocaine seeking in sham-operated rats, but not in rats in which circulating corticosterone was removed (ADX group). In addition, the effect of food deprivation on reinstatement of cocaine seeking was significantly attenuated in rats maintained on basal diurnal levels of corticosterone (ADX+P group). However, food deprivation reinstated cocaine seeking in rats with limited daily access to additional corticosterone in the drinking water (ADX+P/W group). In this group, corticosterone levels were twice as high as the ADX+P group but were significantly lower than those of sham rats. Conclusions. The present data, together with previous work on footshock-induced reinstatement of drug seeking, suggest that corticosterone plays a permissive role in stress-induced reinstatement of cocaine seeking, yet its effects are not associated with the stressor-induced increases in plasma corticosterone levels.     

Alterations in the level of OFQ/N-IR in rat brain regions by cocaine

We have previously shown that administration of orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid receptor-like (ORL-1) receptor, into the lateral ventricles or VTA blocked cocaine sensitization. In the present study, we determined the effect of acute and chronic cocaine treatment on the level of endogenous OFQ/N in rat brain regions. Male Sprague Dawley rats were tested for motor activity in response to saline or cocaine (20 mg/kg) injection once daily for three consecutive days. To determine the effect of single or repeated cocaine administration on the level of OFQ/N, rats were sacrificed 1 h following saline or cocaine injection either on day 1 or 3, respectively. Additional groups of rats were treated similarly with saline or cocaine on days 1-3 and sacrificed or tested for locomotor sensitization on day 8. Consistent with previous studies, repeated cocaine administration induced locomotor sensitization to a challenge dose of cocaine (7.5 mg/kg) given on day 8. Measurements of tissue content of OFQ/N-IR using radioimmunoassay indicated that the rat hypothalamus and striatum, respectively, contained the highest and lowest levels of the peptide among the brain regions tested. Acute cocaine decreased the level of OFQ-IR in the rat midbrain and to a lesser extent in the striatum. On the other hand, the level of OFQ/N was higher in rats treated with cocaine on days 1-3 and sacrificed on day 8. These findings suggest that endogenous OFQ/N may be involved in the actions of cocaine and possibly in cocaine-induced motor stimulation and locomotor sensitization.     

Effectiveness of payment for reduced carbon monoxide levels and noncontingent payments on smoking behaviors in cocaine-abusing outpatients wearing nicotine or placebo patches

In a 2-week intervention to reduce cigarette smoking among outpatients in treatment for cocaine addiction, 20 subjects were randomly assigned to a contingent group, receiving monetary vouchers for breath samples with carbon monoxide (CO) levels of 8 ppm or less, or to a noncontingent group, receiving vouchers regardless of CO level. Subjects wore either nicotine or placebo patches in a randomized crossover design. Contingent subjects had significantly lower CO levels and met the 8 ppm target significantly more often than did noncontingent subjects; however, number of cigarettes reported smoked did not differ between groups. Use of nicotine patches resulted in CO levels significantly lower than did use of placebo patches, but levels still exceeded 8 ppm regardless of type of patch. Because contingent reward helped cocaine-dependent smokers achieve nonsmoking CO targets, behavioral antismoking interventions merit continued study in similar populations.