The role of alpha1- and alpha2-adrenoreceptors on venlafaxine-induced elevation of extracellular serotonin, noradrenaline and dopamine levels in the rat prefrontal cortex and hippocampus.
The role of adrenergic alpha1- and alpha2-adrenoreceptors in augmentation of venlafaxine-induced elevation of extracellular serotonin (5-HT),noradrenaline (NA) and dopamine (DA) levels in the rat prefrontal cortex (PFC) and hippocampus (HIPP) was studied by in vivo microdialysis in anaesthetized rats. The alpha1-adrenoreceptor antagonist prazosin given alone (0.3 mg/kg, s.c.) induced only a moderate reduction of hippocampal 5-HT and NA levels. The alpha2-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 alpha2-adrenoreceptors may play an important role in augmentation of the effects of mixed monoamine reuptake inhibitors.
Weikop
P
P
Department of Microdialysis, NeuroSearch A/S, Ballerup, Denmark. piw@neurosearch.dk
Kehr
J
J
Scheel-Krüger
J
J
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D003511:Cyclohexanols / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D019329:Idazoxan / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D011224:Prazosin / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013997:Time Factors; D000069470:Venlafaxine Hydrochloride
D000317:Adrenergic alpha-Antagonists; D015306:Biogenic Monoamines; D003511:Cyclohexanols; D004298:Dopamine; D019329:Idazoxan; D009638:Norepinephrine; D011224:Prazosin; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride