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 us 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.