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

Abstract

The mesolimbic dopaminergic system has been implicated in mediating the motivational effects of oploids 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 it and K opioid systems that regulate dopamine release in the nucleus accumbens, the major terminal area of A10 dopaminergic neurons. Thus, stimulation of J-type receptors in the ventral tegmental area, the site of origin of A10 dopminergic 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 K-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 pA and ic 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.There is evidence that exogenous opioids can influence the activity of mesolimbic dopaminergic neurons and it has been postulated that such actions underlie the motivational (1, 2) and locomotor effects (3, 4) of these agents, as well as the development of various aspects of opiate dependence (5-7).The behavioral effects of opioids differ depending on the opioid receptor type with which they interact. Thus, systemically applied P-receptor agonists function as positive reinforcers and increase locomotor activity. In contrast, K-receptor agonists have aversive and sedating effects (8, 9). Opposing effects of these agents are also observed at the neurochemical level within the mesolimbic dopaminergic system: A agonists increase, whereas K agonists decrease, dopamine release in the nucleus accumbens (10, 11), the major terminal projection site of mesolimbic dopaminergic neurons. The behavioral effects of opioids noted above are abolished following 6-hydroxydopamine lesions of the mesolimbic system or selective blockade of the dopamine receptors therein (2, 4, 9, 12, 13), suggesting that mesolimbic dopaminergic neurons are necessary for the expression of these actions. Specifically, it has been hypothesized that the opposing effects of A and K agonists on mesolimbic dopaminergic release underlie their different effects on motivation and motor behavior.Neither the site of action of exogenous opioid agonists within this system in affecting dopamine release nor the role of endogenous opioid systems in regulating mesolimbic dopaminergic system activity is known. The latter issue has, until recently, been complicated by the ...

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