Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway.

TLDR

The mesolimbic dopaminergic system mediates motivational effects of opioids and other drugs of abuse, and its role in drug‑induced mood changes suggests therapeutic relevance for opiate dependence and affective disorders. The study aimed to identify the specific sites and roles of endogenous opioid peptides in modulating dopamine activity within this system. Using in vivo microdialysis and selective opioid ligands, the authors demonstrated tonically active, functionally opposing mu and kappa opioid systems regulating dopamine release in the nucleus accumbens. Stimulation of mu receptors in the ventral tegmental area increased, while blockade decreased, basal dopamine release, whereas kappa receptor activation in the nucleus accumbens decreased, and blockade increased, dopamine release, indicating that tonic mu and kappa activity maintains basal dopamine levels.

Abstract

The mesolimbic dopaminergic system has been implicated in mediating the motivational effects of opioids and other drugs of abuse. The site of action of opioids within this system and the role of endogenous opioid peptides in modulating dopamine activity therein remain unknown. Employing the technique of in vivo microdialysis and the administration of highly selective opioid ligands, the present study demonstrates the existence of tonically active and functionally opposing mu and kappa opioid systems that regulate dopamine release in the nucleus accumbens, the major terminal area of A10 dopaminergic neurons. Thus, stimulation of mu-type receptors in the ventral tegmental area, the site of origin of A10 dopaminergic neurons, increases dopamine release whereas the selective blockade of this opioid receptor type results in a significant decrease in basal dopamine release. In contrast, stimulation of kappa-type receptors within the nucleus accumbens decreases dopamine release whereas their selective blockade markedly increases basal dopamine release. These data show that tonic activation of mu and kappa receptors is required for the maintenance of basal dopamine release in the nucleus accumbens. In view of the postulated role of the mesolimbic system in the mediation of drug-induced alterations in mood and affect, such findings may have implications for the treatment of opiate dependence and affective disorders.