Neurochemical predisposition to self-administer cocaine in rats: individual differences in dopamine and its metabolites

Abstract

Using in vivo microdialysis, this study attempted to determine whether a neurochemical predisposition to self-administer cocaine could be identified. Estimated extracellular levels of dopamine and its metabolites were measured bilaterally in the mesocorticolimbic and nigrostriatal systems of naive rats that were subsequently trained to self-administer cocaine intravenously. There were several significant relationships between dopamine and dopamine metabolite (3,4-dihydroxyphenylacetic acid and homovanillic acid) levels and rates of cocaine self-administration during both acquisition and asymptotic phases of testing. Dopamine levels in the nucleus accumbens were non-monotonically related to rates of self-administration during both phases: low to moderate dopamine levels were positively correlated with self-administration rates whereas moderate to high dopamine levels were negative correlated with self-administration rates. Dopamine, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid) levels in the striatum were inversely correlated with self-administration rates during the acquisition phase. DOPAC and HVA levels in the left and right sides of the medial prefrontal cortex were positively and negatively correlated, respectively, with self-administration rates during the asymptotic phase; left/right asymmetries in cortical metabolite levels were also correlated with asymptotic rates. There were no significant relationships between any neurochemical indices and rates of bar-pressing for water. These results suggest that the normal variability in drug seeking behavior is at least in part attributable to individual differences in the activity of brain dopamine systems. Furthermore, different mechanisms appear to be responsible for the acquisition and maintenance phases of cocaine self-administration: dopamine release in the nucleus accumbens appears to be a critical component of both mechanisms, with an optimal level of dopamine appearing to be a major predisposing factor; dopamine release in the striatum appears to modulate acquisition; and there appears to be a left-right lateralized influence of the medial prefrontal cortex on maintenance. Although previous data have indicated that dopaminergic activity in the same brain regions also predisposes rats to self-administer morphine, the precise determinants of morphine and cocaine self-administration appear to be substantially different in terms of how these dopaminergic brain regions act and interact.