Behavioral and neurochemical effects of continuous infusion of cocaine in rats

The ability of continuous intravenous infusion of cocaine (60 mg/kg per day for 11 or 12 days; by osmotic minipump) to alter responses to acute injection of cocaine (20 mg/kg, i.p.; given 24 hr after termination of the infusion by minipump) was tested in conscious, tethered Sprague-Dawley rats. Extracellular levels of cocaine, dopamine and metabolites of dopamine in the striatum were determined by in vivo microdialysis. Locomotor activity and stereotyped behavior were evaluated simultaneously during dialysis sampling. Prior infusion of cocaine blunted the ability of acute challenge with cocaine to increase the efflux of dopamine in the striatum, locomotor activity and stereotypy. Increases in extracellular levels of homovanillic acid in the striatum were significantly greater in cocaine-infused rats than vehicle-infused controls, both prior to and after acute injections of cocaine. However, no differences between these two groups were observed in levels of cocaine in the striatum after acute challenge. Extracellular levels of dopamine in the striatum correlated significantly (P less than 0.05) with stereotypy in both groups but with locomotor activity only in cocaine-infused rats. The results indicate that behavioral tolerance occurred after continuous intravenous infusions of cocaine, that this was correlated with neurochemical tolerance to acute cocaine challenge and that alterations in the metabolism of cocaine did not account for the observed behavioral responses.