The inability of serotonin to stimulate dopamine release in the nucleus accumbens, thereby leading to anhedonia and lack of motivation, may therefore be an essential factor in the onset of depression and a target for modulation by antidepressant drugs.

b-endorphin is an endogenous opioid peptide that has been hypothesized to be involved in the behavioral effects of drugs of abuse including psychostimulants. Using microdialysis, we studied the effect of cocaine on extracellular levels of b-endorphin in the nucleus accumbens, a brain region involved in the reinforcing effects of psychostimulant drugs. Experimenter-delivered cocaine (2 mg/kg, i.v.) increased extracellular b-endorphin immunoreactive levels in the nucleus accumbens, an effect attenuated by 6-hydroxy-dopamine lesions or systemic administration of the D 1 -like receptor antagonist, SCH-23390 (0.25 mg/kg, i.p.). The effect of cocaine on b-endorphin release in the nucleus accumbens was mimicked by a local perfusion of dopamine (5 lM) and was blocked by coadministration of SCH-23390 (10 lM).Self-administered cocaine (1 mg/kg/infusion, i.v.) also increased extracellular b-endorphin levels in the nucleus accumbens. In addition, using functional magnetic resonance imaging, we found that cocaine (1 mg/kg, i.v.) increases regional brain activity in the nucleus accumbens and arcuate nucleus. We demonstrate an increase in b-endorphin release in the nucleus accumbens following experimenter-delivered and self-administered cocaine mediated by the local dopaminergic system. These findings suggest that activation of the b-endorphin neurons within the arcuate nucleus-nucleus accumbens pathway may be important in the neurobiological mechanisms underlying the behavioral effects of cocaine.

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Although the involvement of both endogenous opioid and serotonergic systems in modulation of pain and emotion was suggested, the neurochemical interaction between these systems in the brain has not previously been studied directly. Herein, the effects of the local application of serotonin (5-HT) and fluoxetine (a 5-HT reuptake inhibitor) on extracellular levels of ␤-endorphin in the arcuate nucleus and nucleus accumbens were assessed in freely moving rats using in vivo microdialysis. The mean basal concentrations of ␤-endorphin in dialysates obtained from the arcuate nucleus and nucleus accumbens were 259.9 and 143.3 pM, respectively. Specific lesion of the serotonergic system by 5,7-dihydroxytryptamine (5,7-DHT) caused a significant decrease in these dialysate ␤-endorphin levels. When 5-HT (0.25-5 M) was added to the perfusion solution, the levels of ␤-endorphin in the dialysate from the arcuate nucleus increased (186 -296% of baseline), in a concentrationdependent manner. In the nucleus accumbens, 0.5 and 2 M 5-HT in the perfusion fluid did not affect the levels of ␤-endorphin in the dialysate, whereas 5 and 10 M 5-HT caused an increase of ϳ190% of baseline. When fluoxetine (250 M) was present in the perfusing solution, the levels of ␤-endorphin in the dialysates from the arcuate nucleus and nucleus accumbens increased two-to threefold. This effect was not obtained in the 5,7-DHT-lesioned rats. Thus, 5-HT, either endogenously or exogenously delivered, appears to facilitate the release of ␤-endorphin in the arcuate nucleus and nucleus accumbens. This indication of an interaction between serotonergic and endorphinic systems may be relevant for assessing pain and mood disorder circuits and the mode of action of antidepressant drugs. Key Words: ␤-EndorphinFluoxetine-Microdialysis-Serotonin-Nucleus accumbens-Arcuate nucleus.

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