The role of α1- and α2-adrenoreceptors on venlafaxine-induced elevation of extracellular serotonin, noradrenaline and dopamine levels in the rat prefrontal cortex and hippocampus

The rote of adrenergic alpha(1)- and alpha(2)-adrenoreceptors in augmentation of venlafaxine-induced elevation of extracellular serotonin (5-HT), noradrenahne (NA) and dopamine (DA) Levels in the rat prefrontal cortex (PFC) and hippocampus (HIPP) was studied by in vivo microdialysis in anaesthetized rats. The alpha(2)-adrenoreceptor antagonist prazosin given alone (0.3 mg/kg, s.c.) induced only a moderate reduction of hippocampal 5-HT and NA levels. The alpha(2)-adrenoreceptor antagonist idazoxan (1.5 mg/kg, s.c.) causes moderate increases in the Levels of 5-HT and DA in the PFC. The mixed 5-HT and NA reuptake inhibitor venlafaxine (10 mg/kg, i.p.) increased the efflux of 5-HT, NA and DA almost equally, to approximately 200% of the control Levels in the PFC. The Levels of 5-HT increased to 310%, an effect approximately twice the effect on NA in the HIPP. Venlafaxine also produced a moderate increase in DA levels in the PFC but had no effect in the HIPP. Pre-treatment with prazosin caused a significant attenuation of the venlafaxine induced 5-HT effect in the PFC, and a moderate increase in DA Levels in the HIPP. Prazosin had no significant effect on the venlafaxine-induced increase of the NA levels in PFC or HIPP. A combined treatment of venlafaxine with idazoxan increased the venlafaxine NA and DA effects in PFC by a factor of two and resulted in a very robust five-fold augmentation of NA and DA concentrations in the HIPP. In summary, idazoxan was found to produce a potent enhancement of the venlafaxine effect to increase extracellular NA and DA levels in the PFC and, in particular, in the HIPP. Idazoxan had no effect on venlafaxine-induced elevation of extracellular 5-HT levels in either PFC or HIPP and prazosin induced a decrease of 5-HT in the PFC. The present data suggest that blockade of alpha(2)-adrenoreceptors may play an important rote in augmentation of the effects of mixed monoamine reuptake inhibitors.