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 ...

Drug addiction is a chronic relapsing disease in which drug administration becomes the primary stimulus that drives behavior regardless of the adverse consequence that may ensue. As drug use becomes more compulsive, motivation for natural rewards that normally drive behavior decreases. The discontinuation of drug use is associated with somatic signs of withdrawal, dysphoria, anxiety, and anhedonia. These consequences of drug use are thought to contribute to the maintenance of drug use and to the reinstatement of compulsive drug use that occurs during the early phase of abstinence. Even, however, after prolonged periods of abstinence, 80-90% of human addicts relapse to addiction, suggesting that repeated drug use produces enduring changes in brain circuits that subserve incentive motivation and stimulus-response (habit) learning. A major goal of addiction research is the identification of the neural mechanisms by which drugs of abuse produce these effects. This article will review data showing that the dynorphin/kappa-opioid receptor (KOPr) system serves an essential function in opposing alterations in behavior and brain neurochemistry that occur as a consequence of repeated drug use and that aberrant activity of this system may not only contribute to the dysregulation of behavior that characterizes addiction but to individual differences in vulnerability to the pharmacological actions of cocaine and alcohol. We will provide evidence that the repeated administration of cocaine and alcohol up-regulates the dynorphin/KOPr system and that pharmacological treatments that target this system may prove effective in the treatment of drug addiction.

Dopaminergic afferents arising from the ventral tegmental area (VTA) are crucial elements in the neural circuits that mediate arousal, motivation, and reinforcement. Two major targets of these afferents are the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). Whereas dopamine (DA) in the mPFC has been implicated in working memory and attentional processes, DA in the NAc is required for responding to reward predictive cues. These distinct functions suggest a role for independent firing patterns of dopaminergic neurons projecting to these brain regions. In fact, DA release in mPFC and NAc can be differentially modulated. However, to date, electrophysiological studies have largely overlooked heterogeneity among VTA neurons. Here, we provide direct evidence for differential neurotransmitter control of DA neural activity and corresponding DA release based on projection target. opioid receptor agonists inhibit VTA DA neurons that project to the mPFC but not those that project to the NAc. Moreover, DA levels in the mPFC, but not the NAc, are reduced after local infusion of opioid receptor agonists into the VTA. These findings demonstrate that DA release in specific brain regions can be independently regulated by opioid targeting of a subpopulation of VTA DA neurons. Selective control of VTA DA neurons projecting to the mPFC has important implications for understanding addiction, attention disorders, and schizophrenia, all of which are associated with DA dysfunction in the mPFC.GABA ͉ reward ͉ motivation ͉ nucleus accumbens ͉ ventral tegmental area T he dopaminergic neurons of the ventral tegmental area (VTA) play a critical role in motivation and reinforcement (1-3). Two major projection targets of VTA dopamine (DA) neurons are the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). DA plays different roles in these two projection targets, contributing to working memory processes in the mPFC (4, 5) and motivated responding in the NAc (6). Despite evidence that DA levels in the mPFC and NAc are differentially modulated during various behavioral conditions (7,8), electrophysiological studies have focused on the functional similarities among the VTA neurons.The VTA is an important site for opioid control of goaldirected behaviors (9). We previously showed that opioid receptor (KOP-R) agonists directly inhibit a subset of DA neurons in the VTA through activation of a G-protein-coupled, inwardly rectifying potassium channel (10). This finding, in conjunction with previous reports that limbic and cortical projections arise from largely separate populations of VTA neurons (11, 12), led us to hypothesize that postsynaptic KOP-R agonist effects on VTA neurons segregate on the basis of projection target. To address this question, we made whole-cell, patchclamp recordings in VTA neurons that were retrogradely labeled from the NAc or the mPFC and tested their postsynaptic sensitivity to KOP-R agonists. Neurons were filled with biocytin, and, after recording, brain slices were fixed and immunohistochemi...

An involvement of the mesolimbic dopamine (DA) system in mediating the motivational effects of opioids has been suggested. Accordingly, the present study employed the technique of in vivo microdialysis to examine the effects of selective mu-, delta-, and kappa- opioids on DA release in the nucleus accumbens (NAC) of anesthetized rats. Microdialysis probes were inserted into the NAC and perfusates were analyzed for DA and its metabolites, dihydroxyphenylacetic acid (DO-PAC) and homovanillic acid (HVA), using a reverse-phase HPLC system with electrochemical detection for separation and quantification. Intracerebroventricular (i.c.v.) administration of selective mu-opioid [D-Ala2, N-methyl-Phe4, Gly5-ol]-enkephalin (DAMGO) or delta-opioid [D-Pen2, D-Pen5]-enkephalin (DPDPE) agonists, at doses that function as positive reinforcers in rats, resulted in an immediate and significant increase in extracellular DA. DOPAC and HVA levels were also significantly increased. The effects of DAMGO were blocked by the selective mu-antagonist D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) whereas those of DPDPE were blocked by the delta-antagonist allyl2-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174,864). In contrast to mu- and delta-agonists, the kappa-agonist N-CH3-Tyr-Gly-Gly-Phe-Leu-Arg-N-CH3-Arg-D-Leu-NHC2H5 (E-2078), a dynorphin analog that produces aversive states, decreased DA release in a biphasic manner. Norbinaltorphimine, a selective kappa-antagonist, could block this effect. These results demonstrate that mu-, delta-, and kappa-opioid agonists differentially affect DA release in the NAC and this action is centrally mediated.