Comparison of changes in extracellular dopamine concentrations in the nucleus accumbens during intravenous self-administration of cocaine or d-amphetamine.

Changes in extracellular concentrations of dopamine (DA) were measured in vivo in the nucleus accumbens of the rat during intravenous self-administration of either cocaine (0.25, 0.5, 1.0mg/infusion) or d-amphetamine (0.05, 0.1, 0.2mg/infusion). Drug intake was limited to 12 self-administered infusions per session for each drug/dose combination. Changes in extra-cellular DA concentrations were measured by two different techniques: chronoamperometry in conjunction with chronically-implanted stearate-modified carbon paste electrodes, or intracerebral microdialysis with off-line analyses using high performance liquid chromatography with electrochemical detection (HPLC-ED). Significant increases in extracellular DA concentrations were observed with both in vivo techniques during self-administration of each dose of cocaine or d-amphetamine. For each drug, the magnitude of change during the first hour of the test session was comparable across doses. However, the change observed over the first 2h period, as measured by microdialysis and HPLC-ED, revealed a dose effect for cocaine, but no dose-response effect for d-amphetamine. The duration of the drug-induced elevation was increased significantly as a function of dose with both cocaine and d-amphetamine. Data from the microdialysis experiments indicated that the high dose of d-amphetamine (0.2mg/infusion) produced a significantly greater increase in extracellular DA concentrations in the nucleus accumbens than did the high dose of cocaine (1.0mg/infusion), but that comparable changes were induced by doses of 0.1mg/infusion of d-amphetamine and 1.0mg/infusion of cocaine, respectively. Each dose of both psychostimulant drugs also produced a significant decrease in dihydroxyphenylacetic acid (DOPAC) levels. The latter finding indicated that the electrochemical signal measured in these studies was not due to the oxidation of DOPAC. These results confirm that self-administration of cocaine or d-amphetamine by the rat is accompanied by a significant increase in extracellular DA concentrations in the nucleus accumbens. The fact that two different psychomotor stimulant drugs of abuse have qualitatively similar neurochemical correlates when self-administered, adds credence to the hypothesis that their reinforcing properties are related to dynamic changes in DA concentrations in the ventral striatal region of the brain.

Tolerance to the reinforcing effects of cocaine in a progressive ratio paradigm.

This experiment used rats to test whether a regimen of chronic cocaine would produce tolerance to cocaine i.v. self-administration under a progressive ratio (PR) schedule of reinforcement. Under this PR schedule, an increasing number of responses was required to complete the ratio for each subsequent cocaine injection, and failure to complete the required ratio for the next injection within 1 h of the previous cocaine injection terminated the session. The number of injections taken in the session was termed the breaking point and used as the dependent variable. Rats were trained under this schedule until breaking point values were stable, after which cocaine dose-effect data were obtained: the breaking point increased as the dose of cocaine increased. Subsequently, rats were assigned to one of two groups for 7 days of chronic treatment: one group was infused with cocaine (18 mg/kg, given over 20 min once every 8 h) and the other group received 0.9% saline. Following termination of chronic treatment, cocaine dose-effect data were redetermined in both groups. Chronic cocaine treatment significantly decreased breaking point values across the entire dose-effect curve, although the effect was observed in only four of seven subjects. In contrast, chronic saline treatment produced no significant effect on the breaking point measures. Following a further 5 days of recovery from chronic treatment, cocaine dose-effect data were redetermined in both groups; these curves were essentially identical to those obtained before chronic treatments. These data support the hypothesis that tolerance occurs to the reinforcing effects of cocaine, as measured by a decrease in the breaking point, at least for a subset of animals.

Parameters of self-administration of cocaine in rats under a progressive-ratio schedule.

Progressive-ratio (PR) schedules may provide a more direct measure of drug-reinforcing efficacy than the more traditionally used fixed-ratio schedules. Under a PR schedule, an increasing number of lever presses is required for the delivery of each successive reinforcer. However, there have been few studies of fundamental parameters of cocaine self-administration under a PR schedule. This study was undertaken to assess if PR responding using cocaine reinforcement in rats would: a) be acquired rapidly; b) be maintained on a stable baseline for long periods; and c) provide data on the effect of changing the dose of cocaine that are amenable to statistical analysis. In addition, the effects of pretreatments with SCH23390, a D1 receptor antagonist, or ondansetron, a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, were tested against several doses of cocaine. Stable performance of PR cocaine self-administration (0.90 mg/kg) was acquired within 10 training sessions and was maintained for over 50 training sessions. Increasing the dose of cocaine from 0.10-2.70 mg/kg resulted in a directly related increase in a) the number of reinforcers obtained, b) the highest ratio completed, and c) the interreinforcer time (ISRT: time between each cocaine infusion). In terms of statistical analysis, the number of reinforcers obtained was found to be preferable to the highest ratio completed as a measure of breakpoint. Pretreatment with SCH23390 significantly reduced the breakpoint; this reduction was not due to a motor-incapacitating effect of SCH23390 because the ISRT showed a tendency to be shortened by SCH23390. Pretreatment with ondansetron failed to significantly affect either the number of reinforcers obtained or the ISRT. These results show that rats can readily acquire the task of self-administration of cocaine under a PR schedule and maintain a stable baseline for an extended period. Further, a PR schedule appears to be suitable for the study of pharmacological treatments that might affect cocaine self-administration. Simultaneous monitoring of the breakpoint and of the ISRT determines if a decrease in the breakpoint is the result of a motor-incapacitating side effect of the pretreatment.

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.