Monoamine interactions measured by microdialysis in the ventral tegmental area of rats treated systemically with (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin.

Abstract

The effect of (+/-)-8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT), a selective serotonin 5-HT1A agonist, on levels of extracellular norepinephrine (NE), dopamine (DA), and 5-HT (measured simultaneously) was investigated by microdialysis in the ventral tegmental area (VTA) of freely moving rats, and their behavioral activity was monitored. At 50 micrograms/kg s.c., 8-OH-DPAT reduced 5-HT levels but enhanced NE and DA levels in VTA dialysate. These effects were not altered by pretreatment with systemic idazoxan (5 mg/kg i.p.), a selective alpha 2 antagonist, or local sulpiride (10 microM), a selective D2/D3 antagonist. At 500 micrograms/kg s.c., 8-OH-DPAT further enhanced or more persistently reduced dialysate NE or 5-HT content but had little effect on dialysate DA content. Its DA level-increasing effect could be seen dramatically with local infusion of cocaine (30 microM) and, to a lesser extent, sulpiride (10 microM). Depletion of endogenous 5-HT with p-chlorophenylalanine attenuated both the 5-HT level-reducing and DA level-enhancing effects of 8-OH-DPAT without affecting its maximal NE effect and the locomotor-stimulatory effect. Partial depletion of endogenous NE with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine failed to change the monoamine response but diminished the locomotion induced by 8-OH-DPAT. These results suggested that (a) the low dose of 8-OH-DPAT may act at presynaptic 5-HT1A receptors to modulate 5-HT and DA release, while acting at postsynaptic 5-HT1A receptors to modulate NE release; (b) the high dose of 8-OH-DPAT may activate D2 receptors to offset its DA level-increasing effect; and (c) the locomotor-stimulatory effect of 8-OH-DPAT might be mediated primarily by postsynaptic 5-HT1A receptors and the NE system.