Effects of saline substitution on responding and plasma corticosterone in rats trained to self-administer different doses of cocaine.

Research from our laboratory has explored the role of the hypothalamo-pituitary-adrenal (HPA) axis in cocaine reinforcement. These experiments were designed to determine the involvement of the HPA axis in extinction. Male Wistar rats were trained to self-administer cocaine [0.125, 0.25, or 0.5 mg/kg/infusion (inf)] and food pellets (45 mg) under a multiple, alternating schedule of reinforcement. When self-administration was stable, saline was substituted for cocaine. Blood samples were taken at the end of the sessions following cocaine self-administration, the first exposure to saline substitution (first); and once the criteria for extinction were met (final). Plasma corticosterone was measured using radioimmunoassays. Although there was a significant increase in the number of infusions obtained during the first saline substitution test by rats trained with 0.5 mg/kg/inf of cocaine, there was a decrease in infusions received when 0.125 mg/kg/inf of cocaine was tested. Following repeated exposure to the extinction conditions, responding by rats trained to self-administer all three doses of cocaine was decreased to similar levels. In addition, there were significant differences in plasma corticosterone in rats trained with different doses of cocaine. Lever-pressing behavior and plasma corticosterone varied during extinction in relation to the training dose of cocaine and according to whether the rats had been exposed to single or repeated extinction testing. These data are discussed in terms of the potential difficulties involved in interpreting the effects of compounds intended to reduce drug reinforcement.

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.

Chronic d-amphetamine or methamphetamine produces cross-tolerance to the discriminative and reinforcing stimulus effects of cocaine.

These experiments tested the hypothesis that chronic administration of d-amphetamine (d-A) or methamphetamine (METH) would produce cross-tolerance to the discriminative and/or reinforcing effects of cocaine. One group of rats (n = 20) was trained to detect cocaine (10.0 mg/kg; i.p.) from vehicle; cocaine (1.0-17.8 mg/kg) dose dependently substituted for the training dose. Chronic administration of d-A or METH (0.32, 1.0 and 3.2 mg/kg/12 hr for 7 days) resulted in cross-tolerance to the discriminative stimulus effects of cocaine. A second group of rats (n = 12) was implanted with indwelling jugular catheters and were trained to self-administer cocaine under a fixed-ratio 2 schedule of reinforcement. This group of rats also received chronic d-A or METH (0.32, 1.0 and 3.2 mg/kg/12 hr for 7 days. In this group, chronic administration of the highest dose of d-A and of METH (3.2 mg/kg) resulted in cross-tolerance to the self-administration of cocaine. A third group of rats (n = 15) was implanted with indwelling jugular catheters and were trained to self-administer cocaine under a progressive-ratio schedule of reinforcement. Chronic administration of d-A and METH (3.2 mg/kg/12 hr for 7 days) resulted in cross-tolerance to the self-administration of cocaine under this progressive-ratio schedule. The data obtained from these experiments demonstrate that chronic treatment with central nervous system stimulants of the amphetamine type (d-A or METH) produces cross-tolerance to both the discriminative and reinforcing effects of cocaine.

Failure of ritanserin to block the discriminative or reinforcing stimulus effects of cocaine.

Ritanserin, a 5-HT2/1C antagonist, has been suggested to reduce the preference for cocaine in rats. In the present experiment, the action of ritanserin was investigated in locomotor activity, cocaine drug discrimination, and cocaine self-administration paradigms in rats. A low dose of ritanserin (1.0 mg/kg) was without effect on locomotor activity, while a higher dose (10.0 mg/kg) reduced both horizontal and vertical locomotor activity counts during the first 30 min of the test session. Ritanserin (0.32-32 mg/kg) did not significantly affect the discrimination of 10 mg/kg of cocaine, nor did a dose of 10.0 mg/kg significantly modify the dose-effect curve for cocaine discrimination. Ritanserin (1.0 and 10.0 mg/kg) had no significant effect on the dose-response curve for cocaine self-administration. Thus, ritanserin was without effect against either the discriminative or reinforcing stimulus effects of cocaine, suggesting that ritanserin has limited efficacy as a potential treatment for cocaine abuse.

Tolerance to self-administration of cocaine in rats: time course and dose-response determination using a multi-dose method.

To assess tolerance to cocaine in a self-administration paradigm, rats were trained to self-administer cocaine (0.25 mg/injection) on a fixed-ratio 2 (FR2) schedule of reinforcement. The development of tolerance was studied during chronic administration of cocaine (20 mg/kg per 8 h for 10 days), given either contingently (self-administered by the rats) or non-contingently (infused by the experimenter). Both contingent and non-contingent administration of cocaine produced comparable tolerance, as indicated by a faster rate of cocaine self-administration (the average inter-reinforcer time, ISRT, decreased significantly). Tolerance developed by day 2 of the chronic regimen and reached a floor value (60% of baseline) from day 4 through day 10. Termination of chronic cocaine then resulted in recovery from tolerance, with ISRTs returning to baseline within 6 days of termination. A second set of experiments determined whether tolerance could be studied using a multi-dose method to obtain dose-response data in a single session. A system of multiple pumps allowed testing of three doses of cocaine during a single experimental session. Cocaine dose-response curves obtained from the multi-dose method: (i) did not differ from that obtained from a single-dose method; (ii) were reproducible; and (iii) were shifted to the right by Schering 23390. Rats were then subjected to a 7-day chronic regimen of infused cocaine (20 mg/kg per 8 h) or infused saline. At the end of this chronic cocaine period, they were tested with the multi-dose method. Chronic cocaine, as compared to chronic saline, shifted the cocaine dose-response curve to the right, indicating that the multi-dose method can be successfully applied to demonstrate tolerance to the effects of cocaine in a self-administration paradigm.