5-HT1a agonist +/-8-OH-DPAT modulates basal and stress-induced changes in medial prefrontal cortical dopamine

Serotonergic 5-HT1a agonists have recently been suggested to be effective in the treatment of human anxiety disorders. The neural mechanisms responsible for their clinical efficacy are unknown. In this study, we investigated the effects of +/-8-hydroxy-2(di-n-propylamino)tetralin [+/-8-OH-DPAT], a serotonergic 5-HT1a agonist, on basal and stress-induced changes in dopamine utilization and release in selected forebrain dopamine terminal fields in the rat. Dopamine utilization and release were respectively assessed by neurochemical analysis of ex vivo brain tissue and by microdialysis in the freely moving animal. Systemic +/-8-OH-DPAT at doses below 225 micrograms/kg had not effect in any region except to slightly decrease dopamine utilization in the nucleus accumbens. However, at a dose of 225 micrograms/kg, +/-8-OH-DPAT significantly increased basal dopamine utilization and release in the medial prefrontal cortex, while simultaneously decreasing serotonin release in this area. By contrast, the same dose of +/-8-OH-DPAT decreased extracellular dopamine in the striatum. The effect of +/-8-OH-DPAT on the response of the dopamine system to mild footshock stress was also assessed. This 5-HT1a agonist diminished the magnitude of footshock-induced increases in prefrontal cortical dopamine utilization. These data suggest that 5-HT1a agonists may dose-dependently modulate both basal and stress-induced changes in dopamine utilization in the medial prefrontal cortex. The possible relevance of these findings to the observed clinical efficacy of 5-HT1a agonists in anxiety disorders is discussed.