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The Role of 1- and 2-Adrenoreceptors on Venlafaxineinduced Elevation of Extracellular Serotonin, Noradrenaline and Dopamine Levels in the Rat Prefrontal Cortex and Hippocampus

Department of Microdialysis, NeuroSearch A/S, Ballerup, Denmarkpiw{at}neurosearch.dk

J. Kehr

Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden

J. Scheel-Krüger

Department of Pharmacology NeuroSearch A/S, Ballerup, Denmark

The role of adrenergic ₁- and ₂-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 ₁-adrenoreceptor antagonist prazosin given alone (0.3 mg/kg, s.c.) induced only a moderate reduction of hippocampal 5-HT and NA levels. The ₂-adrenoreceptor antagonistidazoxan (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-foldaugmentation 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, inparticular, 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 ₂-adrenoreceptors may play an important role inaugmentation of the effects of mixed monoamine reuptake inhibitors.

Key Words: 2-adrenoreceptors • antidepressants • autoreceptors • hippocampus • microdialysis • monoamines • prefrontal cortex • venlafaxine

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