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Previous data have shown that the repeated administration of kappa-opioid receptor agonists attenuates the acute behavioral effects of cocaine. The site and mechanism by which kappa-agonists interact with this psychostimulant, however, are unknown. Accordingly, the present microdialysis study characterized the effects of prior, repeated administration of the selective kappa-opioid receptor agonist U69593 on basal and cocaine-evoked DA levels within the nucleus accumbens (NAC) and caudate putamen (CPU). ⋯ These data demonstrate that prior, repeated administration of a selective kappa-opioid receptor agonist attenuates the locomotor-activating effects of cocaine and increases cocaine-evoked DA overflow in terminal projection areas of mesostriatal and mesolimbic DA neurons. These findings indicate that the behavioral interactions of kappa-agonists with cocaine observed in this and previous studies cannot be attributed to a presynaptic inhibition of DA release. Rather, they suggest that postsynaptic or non-DA mechanisms mediate the interaction of these agents with cocaine.
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The core of the nucleus accumbens (NAcc core) is the principal input structure to the basal ganglia circuitry for the prelimbic and medial orbital areas (PL/MO) of the prefrontal cortex. As is now well recognized in the rat, the main basal ganglia output of this prefrontal channel is the dorsomedial part of the substantia nigra pars reticulata (SNR) and not the ventral pallidum as previously suggested. There is evidence suggesting that the ventral pallidum is rather involved with the subthalamic nucleus (STN) in an indirect NAcc-SNR pathway. ⋯ Furthermore, the stimulation of the VPl induced an inhibition in a majority of the STN cells identified, by the antidromic activation method, as projecting to SNR (76.6%) and/or back to the VPl (72.7%). In conclusion, these data further demonstrate the existence of an indirect striato-nigral pathway in the PL/MO channel and indicate that VPl is involved in an inhibitory feedback circuit, which modulates the discharge of medial STN. These results indicate that the medial STN is implicated in the limbic/cognitive functions of the basal ganglia.
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The administration of psychostimulants increases dopamine (DA) release within the nucleus accumbens (NAC), a terminal projection site of mesolimbic DA neurons, originating in the ventral tegmental area (VTA). Recent evidence demonstrates that two subdivisions of the NAC, the dorsolateral core and the ventromedial shell, can be distinguished by morphological and immunohistochemical differences, as well as by their distinct anatomical connections. It has been suggested that these two subregions subserve different functions that are related to goal-directed behaviors, stimulus-reward associations, and reinforcement induced by addictive drugs. ⋯ The highest dose of AMPH significantly increased dialysate 5-HT levels over baseline only in the caudal shell of the NAC. The basal dialysate 5-HT levels did not significantly differ between the three subterritories of the NAC. These results emphasize the heterogeneity and functional compartmentalization within the NAC, the differential regulation of neurochemical and motor responses across the anteroposterior axis of the NAC, and the preferential effect of AMPH in the rostral shell subterritory of the NAC.
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Cognition and acquisition of novel motor skills and responses to emotional stimuli are thought to involve complex networking between pyramidal and local GABAergic neurons in the prefrontal cortex. There is increasing evidence for the involvement of cortical norepinephrine (NE) deriving from the nucleus locus coeruleus (LC) in these processes, with possible reciprocal influence via descending projections from the prefrontal cortex to the region of the LC. We used in vivo intracellular recording in rat prefrontal cortex to determine the synaptic responses of individual neurons to single electrical stimulation of the mesencephalic region including the nucleus LC. ⋯ In contrast, in single sections, noradrenergic terminals immunoreactive for DBH rarely contacted LY-filled somata and dendrites. These results support the conclusion that IPSPs observed following single electrical stimulation of the LC region are mediated by GABA, with little involvement of NE. These IPSPs, arising from antidromic invasion of mPFC cells innervating the LC, may improve the signal-to-noise ratio and favor a better responsiveness of neighboring neurons to NE released in the mPFC.
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Chronoamperometry was used in combination with monoamine-selective electrodes to monitor, in nucleus accumbens (NAcc) and prefrontal cortex (PFC) of freely behaving rats, changes in dopamine (DA)-like electrochemical signals elicited by unilateral ventral tegmental microinjections of the selective mu-opioid receptor agonist D-Ala, N-Me-Phe-Gly-Ol-Enkephalin (DAMGO; 0.01, 0.1, and 1.0 nmol). The results show that DAMGO dose-dependently increased electrochemical signals both in Nacc and PFC within a few minutes of injection. While DAMGO elicited signal increases of comparable amplitudes in both regions, the increases recorded in PFC were significantly longer lasting than those in NAcc; at the highest dose tested (1.0 nmol), DAMGO produced signal increases that lasted (mean +/- sem) 129 +/- 7.3 min in PFC and 96 +/- 12.5 min in NAcc. ⋯ However, differences in the time courses of DAMGO-induced contraversive circling and signal increases in NAcc suggest that the behavioral stimulant effect of ventral tegmental mu-opioid receptor activation may not be mediated exclusively by meso-NAcc DA neurons. The results of this study suggest that enkephalins modulate the activity of meso-PFC DA neurons and that behaviorally relevant activation of mu-opioid receptors in the ventral tegmental area increases DA transmission in PFC to a same, if not to a greater extent as in NAcc. These findings are discussed in relation to evidence indicating that the response of meso-NAcc DA neurons to a variety of stimuli, including drugs of abuse, is indirectly regulated by a DA-sensitive neurons in PFC.