ELECTROPHYSIOLOGIC EVIDENCE FOR DESENSITIZATION OF ALPHA(2)-ADRENOCEPTORS ON SEROTONIN TERMINALS FOLLOWING LONG-TERM TREATMENT WITH DRUGS INCREASING NOREPINEPHRINE SYNAPTIC CONCENTRATION

Previous results from our laboratory have indicated that small intrave nous doses of the alpha(2)-adrenergic agonist clonidine increase serot onin (5-HT) neurotransmission by attenuating the release of endogenous norepinephrine (NE), as a result of the activation of alpha(2)-adrene rgic autoreceptor on NE neurons, and that high doses of clonidine decr ease 5-HT neurotransmission by directly activating alpha(2)-adrenergic heteroreceptors on 5-HT terminals. The aim of the present study was t o assess whether antidepressant treatments that increase the synaptic concentration of NE or 5-HT alter the ability of clonidine to modulate 5-HT neurotransmission through these two alpha(2)-adrenoceptors. Rats were treated for 3 weeks with 0.75 mg/kg per day of befloxatone (a re versible inhibitor of monoamine oxidase A), 10 mg/kg per day of nisoxe tine (a selective NE reuptake inhibitor), 10 mg/kg per day of paroxeti ne (a selective 5-HT reuptake inhibitor) or saline using subcutaneous osmotic minipumps (removed 48 hours before the experiment). No signifi cant change in the effect of the small dose of clonidine (10 mu g/kg, IV) was found following the befloxatone, the nisoxetine, or the paroxe tine treatments. The reduction of 5-HT neurotransmission by the high d ose of clonidine (400 mu g/kg, IV) was no longer present in rats treat ed with nisoxetine or befloxatone, but was unaltered in those treated with paroxetine. Furthermore, in rats pretreated with the NE neurotoxi n 6-hydroxydopamine, a long-term treatment with befloxatone failed to alter the reducing effect of the high dose of clonidine but abolished the reducing effect of the low dose of clonidine. These results sugges t that antidepressant drugs that increase NE synaptic concentration in duce a desensitization of alpha(2)-heteroreceptor on 5-HT terminals.