PHARMACOLOGICAL CHARACTERIZATION OF ALPHA(2)-ADRENOCEPTOR REGULATED SEROTONIN RELEASE IN THE RAT HIPPOCAMPUS

The purpose of the present study was to confirm the functional regulation by alpha(2)-adrenoceptors of the release of serotonin (5-HT) from the rat hippocampus in vivo. Under several pharmacological conditions, extracellular levels of 5-HT were estimated by assaying its concentrations in the perfusate by high performance liquid chromatography with electrochemical detection. Extracellular 5-HT in the hippocampus was reduced by tetrodotoxin (10 mu M) co-perfusion, but increased by perfusion of a selective 5-HT re-uptake inhibitor, fluoxetine (10 mu M). Addition of potassium (K+, 120 mM) to the perfusion fluid evoked an approximately 3-fold increase in 5-HT release. When the alpha(2)-adrenoceptor agonist UK14,304 (0.1-10 mu M) was added to the perfusion solution, the K+-evoked 5-HT release was significantly inhibited in a concentration-dependent manner. This inhibitory action of UK14,304 was reversed by pretreatment with an alpha(2)-adrenoceptor antagonist, idazoxan (5 mg/kg, i.p.). In rats which were catecholaminergically denervated with 6-hydroxydopamine, UK14,304 (10 mu M) still inhibited the K+-evoked 5-HT release. Treatment with pertussis toxin (PTX) did not alter the K+-evoked release of 5-HT but abolished the inhibitory effect of UK14,304. These findings suggest that 5-HT release is functionally modulated via alpha(2)-adrenoceptors located on the serotonergic nerve terminals in the rat hippocampus and furthermore, the possibility that the inhibitory of alpha(2)-adrenoceptors is linked to G-proteins which are substrates of PTX.