Enhanced cocaine self-administration in adult rats with adolescent isolation experience

It is widely accepted that early environmental influences may affect the behavior of adult animals and their responses to psychotropic drugs. Rearing animals in isolation is a relevant paradigm for studying early life stress and for understanding the development of certain neurological and psychiatric diseases. The present study evaluated the effect of adolescent isolation on intravenous cocaine self-administration in adult rats. Male Sprague-Dawley rats were raised from postnatal day 22 to 55 either alone (isolated) or in groups of four per cage (grouped). Then, rats were trained for cocaine self-administration. Our results showed that both isolated and grouped rats acquired stable cocaine self-administration during 5 days of self-administration training. Numbers of both lever presses and cocaine infusions in isolated rats were significantly more than those in grouped rats. Especially, numbers of incorrect lever presses in isolated rats were significantly more than those in grouped rats. In addition, the intervals of inter-reinforcement for cocaine in isolated rats were significantly shorter as compared with grouped rats. These results indicate that rats with adolescent isolation experience have enhanced cocaine self-administration behavior.     

Repeated neonatal maternal separation alters intravenous cocaine self-administration in adult rats

 Behavioural responses to psychostimulant drugs can be profoundly affected by early environmental influences. The aim of this study was to describe the effects of repeated brief separations of rat pups from their dams during the early neonatal period on cocaine self-administration behaviour as adults. Lister hooded rats exposed to a repeated maternal separation procedure (REMS) showed altered acquisition and maintenance of cocaine self-administration as adults, the effects being dose and gender-dependent. Overall, the patterns of acquisition of self-administration across three doses of cocaine (0.05, 0.08 and 0.5 mg/injection) suggested a rightward shift in the acquisition dose-effect functions for the REMS animals relative to control animals. At 0.05 mg/injection, there was a retarded acquisition of cocaine self-administration in male and female neonatally separated rats. At 0.08 mg/ injection there was a facilitated acquisition in female neonatally separated subjects. After establishment of stable self-administration of the training dose, in the same cohort of subjects, rightward and downward shifts in the cocaine self-administration dose-effect functions were determined for female and male REMS subjects, respectively, relative to their controls. The dose-effect function for both female groups was shifted to the left of that of the respective male groups, although the lighter body weights of the females meant that they administered a higher unit dose per unit body weight than the males. Whereas male REMS subjects tended to self-administer less cocaine than the controls at the dose eliciting maximal responding (0.03 mg/injection) and to make fewer lever responses overall at each dose tested, female REMS subjects self-administered significantly more cocaine than their respective controls at a dose of 0.03 mg/injection. There was no differential sensitivity to the rate-altering effects of the selective dopamine D₂ receptor antagonist, eticlopride, or to the selective dopamine D₁ receptor antagonist, SCH 23390. These data provide further evidence that altered early environment affects drug-taking behaviour in a developmentally specific and gender-specific manner, with the effects of neonatal separation contrasting with previously published data on the effects of post-weaning isolation rearing. Received: 4 December 1997 / Final version: 2 July 1998     

Wheel running as a predictor of cocaine self-administration and reinstatement in female rats

Avidity for behaviors mediated by nondrug rewards, such as novelty seeking or intake of sweets or fats, is predictive of enhanced vulnerability to the locomotor-activating and rewarding effects of drugs of abuse. The purpose of the present study was to determine whether avidity for wheel running was predictive of subsequent cocaine-induced locomotor activity, cocaine self-administration, and cocaine-seeking behavior in rats. Rats with high (HiR) and low (LoR) levels of wheel running were selected from an outbred sample of Wistar rats. These rats were first tested for their locomotor response to an acute injection of cocaine (10 mg/kg, i.p.). Subsequently, a multi-phase self-administration procedure was used to examine the effect of wheel running on the maintenance, extinction, and cocaine-induced reinstatement of cocaine-seeking behavior in HiR and LoR rats. The results indicate no significant differences between HiR and LoR rats in the cocaine-induced stimulation of locomotor activity. During maintenance, HiR rats self-administered more cocaine than LoR rats. While there were no group differences in saline self-administration behavior during extinction, HiR rats showed higher cocaine-induced reinstatement than LoR rats. Rats that were previously high responders to novelty (day 1 in locomotor track) also showed significantly higher reinstatement than low novelty responders. These results suggest that a propensity for wheel running is associated with increased vulnerability for cocaine self-administration and reinstatement and that HiR rats are more motivated than LoR rats to seek cocaine.     

Effect of cocaine self-administration on striatal PKA-regulated signaling in male and female rats

Rationale

Chronic cocaine produces changes in the dopamine (DA)/D1/cAMP/protein kinase A (PKA)-regulated signaling pathway that may underlie the development of addiction.

Objective

Given sex differences in the progression to cocaine addiction, we examined the possibility that the PKA pathway is differentially activated by cocaine in male and female rats.

Materials and methods

Rats were given 24-h access to cocaine (1.5 mg/kg) or saline for 7 days under a discrete trial procedure (four trials per hour). Rats were then retested on responding for cocaine under a progressive-ratio schedule after either 0 (no-delay retest) or 10 (10-day-delay retest) days of abstinence. Markers of PKA-regulated signaling in the striatum and nucleus accumbens were evaluated by Western blotting, including phosphorylation of DA and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr 34 and glutamate receptor 1 (GluR1) at Ser 845.

Results

Compared to males, females had higher levels of DARPP-32 phosphorylated at the PKA site in the striatum. Increased phosphorylation of DARPP-32 at the PKA site was also seen in the nucleus accumbens of females compared to males, particularly among controls and rats tested after a 10-day abstinence period. DARPP-32 phosphorylation was also increased as a consequence of cocaine when tested after a 0-day abstinence period in male rats but not female rats.

Conclusion

These findings indicate sex differences in PKA-regulated signaling in drug-naïve controls. Furthermore, these data suggest that regulation of PKA signaling by cocaine is differentially influenced in male and female rats as a consequence of cocaine exposure and cocaine abstinence period.

     

Effect of gonadectomy and gonadal hormone replacement on cocaine self-administration in female and male rats.

Both sex and gonadal steroid hormones may influence the abuse-related behavioral effects of cocaine under some conditions, but there is considerable inconsistency in the literature. In the present study, rats were trained under a fixed ratio (FR) 5 schedule of food presentation and were then allowed to self-administer cocaine (1.0 mg/kg/injection) until behavior stabilized. Subsequently, complete dose-effect functions for cocaine self-administration (0.032-3.2 mg/kg/injection) were determined in female and male rats before and after gonadectomy, and in gonadectomized female and male rats before and during chronic treatment with estradiol or testosterone, respectively. Sex, gonadectomy, and gonadal hormones did not alter the shape or position of dose-effect functions for cocaine self-administration. These results suggest that sex, estrogen, and testosterone levels are not critical determinants of cocaine's reinforcing effects in rats under these conditions. This study differed from earlier studies in that complete dose-effect functions for cocaine were determined. These findings suggest that the behavioral training history, the unit dose of cocaine, and the schedule of reinforcement are important variables in studies of sex and gonadal hormone effects on cocaine self-administration.     

The effects of aerobic exercise on cocaine self-administration in male and female rats

Rationale  

In drug self-administration procedures, extended-access test sessions allow researchers to model maladaptive patterns of excessive and escalating drug intake that are characteristic of human substance-abusing populations.     

Effects of estradiol on cocaine self-administration and cocaine discrimination by female rhesus monkeys.

The ovarian steroid hormone, estradiol, enhances the reinforcing and locomotor activating effects of cocaine in rodents under some conditions. The present study evaluated the acute effects of estradiol benzoate (E(2)beta) on cocaine self-administration and cocaine discrimination in female rhesus monkeys. Cocaine self-administration (0.10 mg/kg/inj., i.v.) was maintained on a fixed-ratio (FR) 30 schedule of reinforcement, and monkeys had access to cocaine during one 2-h session each day. E(2)beta in a cyclodextrin vehicle (0.00001-0.01 mg/kg, i.m.) was administered 30 min before test sessions conducted twice each week. Cocaine doses were administered in an irregular order during each dose-effect curve determination (0.001-0.3 mg/kg/inj.). Blood samples were collected after test sessions to determine 17beta-estradiol levels. Banana-flavored food pellets were available on an FR 30 schedule in three 1-h sessions each day. Five monkeys were trained to discriminate cocaine (0.18 mg/kg, i.m.) from saline in a two-key food-reinforced procedure, and the effects of pretreatment with E(2)beta in cyclodextrin and in sesame oil were studied. Acute administration of E(2)beta did not consistently alter the cocaine self-administration or drug discrimination dose-effect curves in comparison to saline control treatment. Females also did not self-administer E(2)beta (0.00001-0.10 mg/kg, i.v.) above saline levels. Finally, E(2)beta (0.0001-0.01 mg/kg, i.m.) did not substitute for cocaine in monkeys trained to discriminate cocaine from saline. Taken together, these data suggest that over the dose range studied, estradiol administration does not consistently alter the abuse-related effects of cocaine in female rhesus monkeys.     

Neonatal isolation stress potentiates cocaine seeking behavior in adult male and female rats.

Little is known with regard to how sex and stress might interact as vulnerability factors in cocaine abuse. In this study, we compared the effects of neonatal isolation stress on cocaine self-administration under extended access conditions and on subsequent responding in a cue-induced reinstatement paradigm in adult male and female rats. Pups from each litter were subjected to either neonatal isolation (1 h/day) or brief daily handling from postnatal day 2 through 12. Adults rats were then trained to self-administer cocaine, and once they acquired lever responding for cocaine under a fixed ratio 1 schedule, they were given 24-h access to intravenous cocaine infusions (1.5 mg/kg) that were available in discrete trials (4, 10 min trials/h) for 7 consecutive days. At 10 days after the last discrete trial session, responding was assessed during six to eight 1-h extinction sessions that were followed by a 1-h cue-induced reinstatement session. Results revealed that females took more cocaine than did males over the 7-day discrete trial self-administration period and tended to respond at higher levels during the initial extinction sessions. Although intake did not differ between handled control rats and isolated rats under extended access conditions, stress effects were observed under subsequent extinction and cue-induced reinstatement testing conditions with isolated rats responding at higher levels during both phases. Notably, stress seemed to obscure sex differences in extinction responding such both isolated males and females responded at high levels. These findings demonstrate robust and enduring effects of neonatal isolation stress on cocaine seeking behavior in adult male and female rats.     

Nicotine reinforcement in rats with histories of cocaine self-administration

Few reports have described conditions under which nicotine self-administration occurs in rats. In this study, rats which initially lever pressed for cocaine infusion (0.05 mg/kg) during 1 h experimental sessions continued to obtain similar infusion numbers when nicotine (0.03 mg/kg) was available. When saline was substituted for nicotine, infusions decreased from 11.8±4.5/h to 5.4±1.1/h but returned to pre-saline levels when it was reintroduced (12.0±5.5/h). These results indicate that nicotine can serve as a positive reinforcer for rats under the historical and schedule conditions described.     

Dose-related effects of the acetylcholinesterase inhibitor tacrine on cocaine and food self-administration in rats

Rationale Acetylcholine (ACh) is involved in brain reward and learning functions and contributes to opiate- and psychostimulant-motivated behaviors. Tacrine is a centrally acting, reversible cholinesterase inhibitor that also inhibits monoamine oxidase (MAO) and blocks reuptake of dopamine (DA) and serotonin. Objectives To determine the effects of pretreatment with tacrine on self-administration of cocaine and nondrug reinforcers. Materials and methods Male Wistar rats were trained to self-administer cocaine under a fixed-ratio-5 (FR-5) schedule during 2-h multiple-component sessions in which 0.1, 0.2, and 0.4 mg/kg per injection of cocaine were each available for 40 min. Other animals self-administered 45 mg food pellets under FR-30 or 20% Ensure (liquid food) under FR-5 in amounts of 30, 60, or 120 μl. Vehicle or tacrine was administered as single intravenous doses 20 min before self-administration of cocaine, food pellets, or liquid food. Results Although pretreatment with 0.032 mg/kg of tacrine increased self-administration of food pellets, pretreatment with higher doses of tacrine attenuated self-administration of cocaine, food pellets, or liquid food. Tacrine’s ED₅₀ value for attenuating self-administration of 0.1 mg/kg per injection of cocaine was more than sixfold lower than values for attenuating liquid food- or food pellet-reinforced behavior. However, ED₅₀ values for attenuating self-administration of higher doses of cocaine were similar to those observed for 30 or 60 μl of liquid food. Conclusions Tacrine can selectively attenuate self-administration of low-dose cocaine, but its effects on higher doses of cocaine are similar to its ability to decrease self-administration of nondrug reinforcers.     

Oral self-administration of ethanol and cocaine in rats

Most laboratory animal studies on self-administration of drugs of abuse use only one drug, whereas humans frequently engage in polydrug use. For this reason, we studied oral self-administration of ethanol (E) and cocaine (C) with the free choice bottle method using a single drug alone, a combination (E and C in separate bottles) or a mixture of both drugs in a single bottle. Young female rats (45 days) consumed similar amounts of C if offered alone (12.4 +/- 7.5 mg/kg/day), in the presence of ethanol (10.6 +/- 3.5) or as E/C mixture (8.0 +/- 4.0). They also consumed similar amounts of E if offered alone (3.8 +/- 1.6 ml/kg/day), in the presence of C (2.3 +/- 0.8) or E/C mixture (2.4 +/- 1.1). Voluntary consumption of both drugs varied markedly among animals but was consistent in a given rat. No correlation occurred between consumption of E and C. Young male rats behaved similarly and consumed similar amounts of E and C alone, in combination and as mixture. While E consumption was similar, C consumption was higher in female rats. Old male rats (180 days) were similar to young male rats. The presence of a saccharin solution as a distracter had no effect on intake of E or C in young females but reduced E intake only in young male rats. In young animals, prior voluntary consumption of either E or C had no effect on subsequent voluntary consumption of the same or other drug offered in combination. These results indicate that this model may be useful to study polydrug use in humans, that consumption of both E and C is strongly controlled by an individual animal, that prior exposure to one drug had no or little effect on a subsequent consumption of the same or other drug in combination and that intake of E or C seems to be independent of each other suggesting two independent reward centers.     

Chlordiazepoxide alters intravenous cocaine self-administration in rats

This investigation was designed to examine the effects of benzodiazepines on intravenous cocaine self-administration in rats. Pretreatment with low doses of the benzodiazepine receptor agonist, chlordiazepoxide (0.3 to 1.0 mg/kg, IP), resulted in small but nonsignificant increases in drug intake with 0.5 mg/kg cocaine, while higher doses (10 mg/kg, IP) significantly decreased drug intake in all rats tested. The effects of chlordiazepoxide on self-administration were attenuated when the concentration of cocaine was increased to 1.0 mg/kg, suggesting that chlordiazepoxide was opposing rather than augmenting the pharmacological actions of cocaine. Pretreatment with the benzodiazepine receptor antagonist, Ro 15-1788 (1.0 to 10 mg/kg, IP), had no effect on self-administration, suggesting that the reinforcing properties of cocaine do not result from direct interactions with benzodiazepine receptors. The result of this investigation demonstrate that chlordiazepoxide alters intravenous cocaine self-administration in rats. Although additional research will be necessary to confirm these data, the results of this investigation suggest that chlordiazepoxide may decrease the reinforcing efficacy of cocaine through indirect actions on dopaminergic neuronal activity potentially mediated through GABAergic mechanisms via benzodiazepine receptor activation.     

Neonatal isolation enhances maintenance but not reinstatement of cocaine self-administration in adult male rats

Rationale Previously, we demonstrated that neonatal isolation increases acquisition of cocaine self-administration in adult male rats.Objective Now we examine whether neonatal isolation enhances maintenance and cocaine-induced reinstatement of extinguished self-administration behavior. To test the specificity of the effect, a separate study examined maintenance of food responding.Methods Litters were subjected to neonatal isolation (individual isolation; 1 h/day; postnatal days 2–9) or were non-handled. In experiment 1, adult male rats trained to self-administer cocaine (0.5 mg/kg per infusion; fixed-ratio 3 or FR3) were tested under fixed and progressive ratio (PR) schedules with different cocaine doses (0.125–1.0 mg/kg per infusion). After cocaine self-administration was extinguished, cocaine (0.5 or 2 mg/kg)-induced reinstatement of responding was assessed. In experiment 2, responding for food under an FR15 and two PR schedules were assessed in separate groups of neonatally isolated and non-handled male rats.Results Neonatally isolated rats responded for low cocaine doses at higher rates and infused more cocaine relative to non-handled rats under both FR and PR schedules. However, there are no group differences in cocaine-induced reinstatement or in responding for food under the PR schedules. However, neonatally isolated rats lever pressed for food at lower rates under the FR schedule.Conclusions Together with our previous studies, the results of the present study suggest that the early life stress of neonatal isolation enhances cocaine-taking (acquisition and maintenance) at lower doses but does not alter drug-induced cocaine-seeking (reinstatement) behavior.     

Cocaine self-administration in rats with histories of cocaine exposure and discrimination

Rationale Interrelationships between the discriminative stimulus and reinforcing properties of psychoactive drugs and the way in which they may interact to control drug intake are unclear. Studies have shown that drug history can influence the expression of drug-produced behavioral effects.Objective The present study examined the acquisition and maintenance of intravenous cocaine self-administration in rats with a history of drug discrimination.Methods Two groups of male hooded rats (n=12 each) were successfully trained in a single-lever food-reinforced procedure to discriminate cocaine (10 mg/kg) from saline. Control groups (n=12 each) received drug injections and/or saline injections only and lever-pressed for food reinforcers with no discrimination training. Subsequently, all subjects were implanted with chronic jugular catheters and allowed to nose-poke for infusions of cocaine (0.2 mg/kg per infusion).Results Initial rates of responding were similar for all groups. Acquisition of self-administration on a FR-10 schedule of drug delivery was significantly faster for cocaine-exposed rats in comparison to all other groups (P<0.02). There were no differences between groups in the breaking points of cocaine and saline on a progressive ratio schedule of self-administration. Dose–response functions were obtained by two methods and were similar for all groups.Conclusion These results are consistent with earlier studies demonstrating weakly sensitized primary reinforcing properties of cocaine in preexposed rats. Previous learning to discriminate cocaine impaired this sensitization.     

Levo-tetrahydropalmatine attenuates cocaine self-administration and cocaine-induced reinstatement in rats

Rationale Levo-tetrahydropalmatine (l-THP) is an alkaloid constituent of plants from the botanical genera Corydalis and Stephania and is contained in many traditional Chinese herbal preparations. In addition to its low-affinity antagonism of D2 dopamine (DA) receptors, we report that l-THP functions as a higher-affinity antagonist at D1 DA receptors and interacts with D3 DA receptors, suggesting that it may be effective for the treatment of drug addiction. Accordingly, l-THP has been reported to reduce heroin craving and relapse in recovering addicts. Objective This study investigated the effects of l-THP (3.75, 7.5, and 15.0 mg/kg, i.p.) on cocaine self-administration (SA) and cocaine-induced reinstatement. Materials and methods Rats were trained to self-administer cocaine and food by pressing separate response levers during sessions consisting of a multiple schedule of alternating 30-min FR4 cocaine and 15-min FR4 food reinforcement. During the cocaine components of each session, the available cocaine dose varied such that rats had access to low and high dose ranges in varying sequence on alternating days. After SA, cocaine-reinforced responding was extinguished, and effects of l-THP on cocaine-induced reinstatement (10 mg/kg, i.p.) were examined. Results l-THP produced a rightward and downward shift in the dose–response curve for cocaine SA and attenuated cocaine-induced reinstatement. l-THP also reduced food-reinforced responding and locomotor activity. However, reductions in cocaine SA were found at doses that failed to alter food-reinforced responding, and significant effects were not observed on food responding during reinstatement. Conclusions These findings suggest that l-THP is potentially useful for treating cocaine addiction. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Differential effects of allopregnanolone on the escalation of cocaine self-administration and sucrose intake in female rats

Rationale  

Evidence suggests that the progesterone metabolite allopregnanolone (ALLO) decreases cocaine seeking in animal models of relapse.     

Ketoconazole reduces low dose cocaine self-administration in rats

Ketoconazole is an oral antimycotic agent approved by the FDA for the treatment of fungal disease which also blocks the synthesis of adrenocorticosteroids and functions as a glucocorticoid receptor antagonist. In these experiments, adult male Wistar rats were allowed alternating 15-min periods of access to food reinforcement and cocaine self-administration (0.125, 0.25 or 0.5 mg/kg per infusion) during daily 2-h sessions. A 1-min timeout separated access to the two reinforcers. Pretreatment with ketoconazole (25 mg/kg, i.p.) significantly decreased plasma corticosterone and reduced low dose (i.e. 0.125-0.25 mg/kg per infusion) cocaine self-administration without affecting food-reinforced responding. In fact, pretreatment with ketoconazole resulted in rates and patterns of self-administration at these doses that were indistinguishable from those observed during cocaine extinction. However, cocaine self-administration at the highest dose tested in these experiments (i.e. 0.5 mg/kg per infusion) was not significantly affected by ketoconazole. These data suggest the potential utility of ketoconazole or related drugs as adjuncts in the treatment of cocaine abuse and further underscore the role for corticosterone in cocaine reinforcement.     

Effects of GABAergic modulators on food and cocaine self-administration in baboons

Drugs that indirectly alter dopaminergic systems may alter the reinforcing effects of cocaine. The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has extensive neural connections in mesolimbic regions that appear to modulate dopamine. The current study evaluated the effects of GABA_B receptor agonists baclofen and CGP44532, the benzodiazepine agonist alprazolam, and the GABA reuptake inhibitor tiagabine on lever responding maintained by low dose cocaine injections (0.032 mg/kg) or by food pellet (1 g) delivery in baboons. The benzodiazepine antagonist flumazenil was tested as a negative control. Cocaine or food was available under a fixed ratio (FR 10) schedule of reinforcement during daily 2-h sessions. During baseline conditions, cocaine and pellets maintained similar numbers of reinforcers per session. Baclofen, CGP44532 and tiagabine dose-dependently reduced the number of cocaine injections, where as the benzodiazepine antagonist flumazenil did not. Baclofen, CGP44532 and tiagabine also produced dose-related decreases in food-maintained behavior. In contrast, the benzodiazepine agonist alprazolam, which positively modulates GABA_A receptors via the benzodiazepine site, produced decreases in cocaine self-injection, but not food-maintained behavior. Thus, the effects of alprazolam were specific for cocaine-maintained behavior, where as the effects of baclofen and CGP44532 were not.     

Effects of estrogen and progesterone on the escalation of cocaine self-administration in female rats during extended access

Estrogen increases and progesterone decreases the acquisition and reinstatement of cocaine-seeking behavior in female rats. Here estrogen and progesterone were studied for their effects on the escalation of cocaine self-administration in female rats. The rats received ovariectomy (OVX) or sham (SH) surgery and were treated with estradiol benzoate (0.05 mg/kg sc) and/or progesterone (0.5 mg/kg) or vehicle (indicated by E, P, and V), resulting in 5 groups: SH+V, SH+P, OVX+V, OVX+E, OVX+E+P. Rats self-administered intravenous cocaine (0.4 mg/kg) under a fixed ratio 1 (FR 1) schedule during 2-hr sessions and were then given 6-hr sessions (long access; LgA) (FR 1) for 21 days. After LgA, self-administration was reassessed with 2-hr sessions under the FR 1 and a progressive ratio schedule with 4 cocaine doses. There were no differences among the 5 groups in cocaine self-administration during initial 2-hr sessions. During LgA, the SH+V, OVX+E, and OVX+V groups escalated their cocaine self-administration, whereas the OVX+E+P and SH+P groups did not. Estradiol increased escalation in the OVX+E group compared with the OVX+V group, and progesterone (SH+P) reduced escalation compared with the SH+V group. When estrogen and progesterone were both administered in OVX rats (OVX+E+P), escalation was significantly lower than in the OVX+E group. Cocaine infusions during the 2-hr sessions were significantly higher after escalation than before in all groups except the progesterone-treated groups (SH+P and OVX+E+P). Estrogen promoted and progesterone inhibited escalation of cocaine self-administration, illustrating the importance of female gonadal hormones in drug-seeking behavior.