Increases in extracellular dopamine in the nucleus accumbens by cocaine are inversely related to basal levels: Effects of acute and repeated administration

Abstract

Repeated administration of cocaine enhances several of the behavioral and neurochemical responses to subsequent cocaine injections, an effect that has been attributed, in part, to decreased somatodendritic autoreceptor sensitivity of mesocorticolimbic dopamine (DA) neurons. Such changes in autoregulation may not only modify the direct effects of cocaine on extracellular DA levels but also result in tonically increased basal DA release in the terminal areas of the mesocorticolimbic DA system. The present study was therefore designed to investigate the effects of repeated cocaine administration on basal extracellular DA concentrations in the nucleus accumbens (NAC) using in vivo microdialysis procedures in halothane- anesthetized rats. We subsequently examined the relationship between basal DA levels and the increase in extracellular DA produced by an acute injection of cocaine, and determined whether this relationship was altered by prior, repeated exposure to cocaine. Rats received one daily intraperitoneal injection of cocaine (30 mg/kg) or its vehicle (saline) for 10 consecutive days. On days 1, 3, or 7 after termination of the repeated cocaine treatment, extracellular DA levels in the NAC were determined under basal conditions and following a single intraperitoneal cocaine challenge injection (10 mg/kg) in separate groups of rats. Repeated cocaine administration produced a substantial increase in basal DA release in the NAC that was most prominent on day 1 post-cocaine (mean ± SEM: 10.7 ± 2.55 nM vs 3.55 ± 0.56 nM) but was no longer apparent on day 7 post-cocaine. Higher extracellular DA levels were also observed after cocaine challenge in rats that received repeated cocaine treatments. Similar to the increase in basal release, this effect was most pronounced on day 1 post-cocaine (23.6 ± 4.36 nM vs 12.61 ± 1.76 nM) but did not persist through day 7 post-cocaine. In spite of higher absolute DA concentrations in repeated-cocaine-treated rats, the relative increase in DA over basal levels after cocaine challenge was considerably smaller in this group (252 ± 39%) than in repeated-saline-treated control animals (412 ± 49%). Further analysis of the relationship between basal and maximal DA levels after cocaine challenge revealed a dependence of cocaine effects on basal DA levels such that the efficacy of cocaine to produce increases in DA overflow was progressively reduced with increasing basal levels. This relationship was not changed by repeated cocaine pretreatments. The results demonstrate that some form of functional tolerance to the effects of cocaine can develop in spite of marked elevations in absolute extracellular DA concentrations and suggest that the extracellular dopaminergic response to cocaine in the NAC is reduced in animals with higher levels of basal DA release.