Mediation of the discriminative stimulus properties of cocaine by mesocorticolimbic dopamine systems

This paper provides a brief review of the scientific evidence implicating the mesocorticolimbic dopamine (DA) system in modulating the discriminative stimulus properties of cocaine in rats. Briefly, systemic administration of DA releasers, reuptake inhibitors, and DA D₁, D₂ and putative D₃ receptor agonists engendered partial to full substitution for the discriminative stimulus effects of cocaine. Dopamine D₁ and D₂ receptor antagonists attenuate this behavioral property of cocaine. Intracranial microinjection studies have indicated certain key limbic nuclei as loci of action for DA in mediating the discriminative stimulus effects of cocaine. Microinjections of cocaine into either DA cell body (i.e., ventral tegmental area, substantia nigra) or DA terminal regions (i.e., prefrontal cortex, central amygdala, caudate putamen) have failed to reproduce the systemic cocaine discriminative stimulus. Only infusion of cocaine into the nucleus accumbens has been demonstrated to substitute fully for the systemic effects of this psychostimulant. Interestingly, microinjections of the DA D₁ receptor antagonist SCH 23390 into either the prefrontal cortex, nucleus accumbens, or central or basolateral amygdala have been demonstrated to block the discriminative stimulus properties of cocaine. Although a determination of the antagonism of the cocaine discriminative stimulus following intra-accumbens microinjection of DA D₂ receptor antagonists has not been made, intra- accumbens administration of the DA D₂ receptor antagonist sulpiride blocked the discriminative stimulus effects of another psychostimulant, amphetamine, 6-Hydroxydopamine lesions of DA terminals in the nucleus accumbens also attenuated the dose-effect curve for systemic administration of cocaine. Taken together, this intracranial evidence suggests that DA D₁ and D₂ receptors in the mesocorticolimbic system are involved in modulating the discriminative stimulus properties of psychostimulants and that the nigrostriatal DA system is not primarily involved.