Sensitization phenomena after repeated administration of cocaine or D-amphetamine in rats: associative and non-associative mechanisms and the role of dopamine in the striatum.

In parallel studies, the contribution of non-associative and associative mechanisms to the development of sensitization to the effects of cocaine and D-amphetamine on locomotor activity and stereotyped behaviour were tested. Rats were pretreated with cocaine, 10 mg/kg s.c. twice, D-amphetamine 1.5 mg/kg s.c. once or with saline. During the pretreatment period, one group of rats was administered the drug in positive temporal association with conditional stimuli (CS) ('associative'), another group in negative temporal association with the CS ('non-associative'), a saline pretreated control group was exposed to the CS but administered the drug only during the test ('naive'). On the test day, 7 days after the last drug administration, in the cocaine-sensitized group, cocaine produced the largest locomotor stimulation and the highest scores of stereotypies (mainly sniffing) in the 'associative' group, significantly smaller effects in the 'non-associative' group, and the smallest effects in the 'naive' group. The stereoypies (mainly licking) produced by D-amphetamine in the amphetamine-sensitized group on the test day, 7 days after the last drug administration, were also most pronounced in the 'associative' group, less pronounced in the 'non-associative' group and least in the 'naive' group, whereas the opposite sequences of intensities were found with regard to locomotor activation. The observations in D-amphetamine-treated groups suggest that there is a negative correlation between locomotor activity and stereotyped licking. Estimation of the extracellular dopamine using microdialysis in the striatum showed no significant differences between the three cocaine groups in the moderate increases. In contrast, after D-amphetamine treatment, the strong increases in dopamine were most pronounced in the 'associative' group, significantly less in the 'non-associative' group and even less in the 'naive' group. The biochemical findings in the D-amphetamine-pretreated animals are apparently related to the pronounced stereotyped licking observed in these animals which is probably induced in the striatum, whereas locomotor activation and sniffing are probably mediated elsewhere and therefore are not reflected biochemically in the striatum.