NEUROCHEMICAL PREDISPOSITION TO SELF-ADMINISTER COCAINE IN RATS - INDIVIDUAL-DIFFERENCES IN DOPAMINE AND ITS METABOLITES

Using in vivo microdialysis, this study attempted to determine whether a neurochemical predisposition to self-administer cocaine could be id entified. Estimated extracellular levels of dopamine and its metabolit es were measured bilaterally in the mesocorticolimbic and nigrostriata l systems of naive rats that were subsequently trained to self-adminis ter cocaine intravenously. There were several significant relationship s between dopamine and dopamine metabolite (3,4-dihydroxyphenylacetic acid and homovanillic acid) levels and rates of cocaine self-administr ation during both acquisition and asymptotic phases of testing. Dopami ne levels in the nucleus accumbens were non-monotonically related to r ates of self-administration during both phases: low to moderate dopami ne levels were positively correlated with self-administration rates wh ereas moderate to high dopamine levels were negative correlated with s elf-administration rates. Dopamine, DOPAC (3,4-dihydroxyphenylacetic a cid) and HVA (homovanillic acid) levels in the striatum were inversely correlated with self-administration rates during the acquisition phas e. DOPAC and HVA levels in the left and right sides of the medial pref rontal cortex were positively and negatively correlated, respectively, with self-administration rates during the asymptotic phase; left/righ t 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 resul ts suggest that the normal variability in drug seeking behavior is at least in part attributable to individual differences in the activity o f brain dopamine systems. Furthermore, different mechanisms appear to be responsible for the acquisition and maintenance phases of cocaine s elf-administration: dopamine release in the nucleus accumbens appears to be a critical component of both mechanisms, with an optimal level o f dopamine appearing to be a major predisposing factor: dopamine relea se in the striatum appears to modulate acquisition; and there appears to be a left-right lateralized influence of the medial prefrontal cort ex on maintenance. Although previous data have indicated that dopamine rgic 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 h ow these dopaminergic brain regions act and interact.