Opioid Modulation of Mesocorticolimbic Neurotransmission

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Acute systemic administration of KOR agonists decreases DA levels in the NAc and dorsal striatum (75,76). In vitro studies assessing the modulation of electrically evoked [3H] DA by opioid receptor activation revealed that in the NAc, olfactory tubercle, and PFC, DA release can be inhibited by activation of KOR (77,78). Evidence that the acute systemic administration of selective KOR agonists decreases dialysis levels of DA in the NAc and dorsal striatum has also been obtained (75). In vivo microdialysis studies in the rat have also shown that the intra-NAc infusion of the selective KOR agonist U-69593 decreases basal DA overflow in the NAc, whereas the selective blockade of KOR in this region significantly increases basal DA overflow (22). Infusion of KOR ligands into the VTA fails to modify basal DA overflow in the NAc, indicating the existence of a tonically active KOR system in the NAc that regulates basal DA tone in the NAc. In view of the localization of KOR on DA terminals, these effects have been attributed to a direct effect on DA neurons. However, the NAc shell receives significant glutamatergic input (79), and KORs are present on the presynaptic terminals of presumed excitatory synapses as well as on the dendrites of medium spiny neurons (60,80). This anatomical arrangement raises the possibility that the behavioral effects of KOR activation in the NAc are due, in part, to the regulation of glutamatergic excitatory transmission. Indeed, NAc KOR activation produces a dose-dependent inhibition of glutamatergic excitatory postsynaptic currents (EPSCs). KOR activation also causes an increase in the paired-pulse ratio as well as a decrease in the frequency of spontaneous miniature events, consistent with a decrease in presynaptic glutamate release (81). A KOR-mediated inhibition of calcium-dependent glutamate release has also been observed in the dorsal and ventral striatum (82,83).

A recent study has shown that KOR also modulates DA uptake in the NAc. Using the technique of quantitative microdialysis, which permits simultaneous assessment of drug-induced alterations in DA uptake and extracellular DA levels, Thompson et al. (84) have shown that acute KOR activation increases DA uptake. This effect is delayed, occurring 1-2 h after drug administration, is dose-dependent, and is reversed by a selective KOR antagonist. These data are particularly interesting in view of ultrastruc-

tural studies (A. Svingos, personal communication) showing collocalization of KOR and DA transporter in axon terminals, small axons of NAc neurons, and suggest that KOR agonists regulate mesoaccumbens DA neurotransmission by two distinct mechanisms, inhibition of release and stimulation of uptake. In contrast to acute KOR activation, a decrease in DA uptake is observed 24-72 h following repeated KOR antagonist treatment. This effect is due to a decrease in the maximum capacity of uptake rather than a change in the affinity. As discussed below, these effects on DA uptake and release are functionally opposite to those produced by the acute and repeated administration of psychostimulants and provide an anatomical basis for the modulation of behavioral sensitization by KOR ligands.

In contrast to KOR agonists, systemically administered MOR agonists increase DA overflow in the NAc (75). Infusion of MOR agonists into the VTA produces similar effects indicating an involvement of VTA opioid receptors in producing this effect (22,85), but see (86). Since MOR induces membrane hyperpolarization, this increase is consistent with the location of MOR on VTA GABA interneurons and disinhibition of DA neurotransmission (67). Anatomical and neurophysiological studies indicate that MOR activation may also stimulate the activity of mesoaccumbens DA neurons, indirectly, by enhancing the response of NAc medium spiny neurons to the excitatory effects of NMDA (87). Medium spiny neurons that contain enkephalin and GABA project to the ventral pallidum and onto GABA interneurons in the VTA. An increase in their output would enhance DA release in the NAc. Consistent with this hypothesis, a recent dialysis study showed that the intra- NAc infusion of the MOR agonists DAMGO and fentanyl increases DA overflow in the NAc (86). In contrast to MOR activation, the blockade of MOR receptors in the VTA has been reported to decrease DA overflow in the NAc (22). This finding is consistent with the existence of a tonically active VTA MOR system that functionally opposes the actions of the NAc KOR system.

Like MOR agonists, the intracerebroventricular infusion of the DOR agonist, DPDPE stimulates DA overflow in the NAc (76). A similar effect is also observed in response to intra-VTA infusions, suggesting that the activation of either MOR or DOR receptors in the VTA increases DA release in the NAc (85). Infusion of the enkephalinase inhibitor thiorphan also increases DA overflow, suggesting that the VTA is one site mediating DOR agonist-induced increases in DA neurotransmission (88). Interestingly, however, other studies have shown that the DOR agonists deltorphin and DPDPE are also effective in increasing DA levels when dialyzed into the NAc, suggesting that DOR activation in the VTA or NAc can modulate mesoaccumbens DA neurotransmission (86,89).

Recent studies have shown that OFQ/N can also modulate DA levels in the NAc. Like KOR agonists, this peptide inhibits locomotor activity (51). In accordance with this inhibitory effect, the intracerebroventricular or intra-VTA infusion of OFQ/N reduces DA overflow in the NAc (90,91). This effect is associated with an increase in GABA and glutamate overflow in the VTA. Administration of the GABAa receptor antagonist bicuculline into the VTA prevents the effect of OFQ/N on NAc DA levels, suggesting that GABAergic interneurons located in the VTA may mediate this effect. Since, however, ORL1 activation, like MOR activation, induces membrane hyperpolarization (92), it appears that OFQ/N reduces the release of another neurotransmitter that inhibits GABA release in the VTA. Likely candidates in this regard are the enkephalin fibers that project to the VTA and synapse with GABA neurons (93).

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