Enhancement of serotonergic and noradrenergic neurotransmission in the rat hippocampus by sustained administration of bupropion

Previous studies reported that bupropion, an effective antidepressant, exerts modulatory actions on serotonin (5-HT) and norepinephrine (NE) neurons. This study examined effects of bupropion administration on 5-HT and NE neurotransmission in hippocampus. Electrophysiological recordings were obtained from anesthetized Sprague-Dawley rats. Subcutaneously implanted minipumps delivered saline or bupropion (30 mg/kg/day) for 2 and 14 days. Although sustained bupropion administration did not alter the sensitivity of 5-HT1A and alpha(2)-adrenergic receptors, the tonic activation of postsynaptic 5-HT1A receptors by endogenous 5-HT was enhanced in 14-day bupropion-treated rats to a greater extent than in the 2-day and control rats, as revealed by the greater disinhibitory action of the 5-HT1A antagonist WAY-100635 on hippocampus pyramidal neurons. The function of terminal 5-HT1B autoreceptors was not changed as determined by the unaltered effectiveness of different frequencies of stimulation of the ascending 5-HT fibers. The function of alpha(2)-adrenergic receptors on 5-HT terminals was, however, diminished, as indicated by the lesser effect of the alpha(2)-adrenoceptor agonist clonidine. Tonic activation of postsynaptic alpha(2)- and alpha(1)-adrenoceptors by endogenous NE was also increased in 14-day bupropion-treated rats, as indicated by the greater effect of the alpha(2)- and alpha(1)-adrenoceptor antagonists idazoxan and prazosin, respectively, on pyramidal firing. The function of terminal alpha(2)-adrenergic autoreceptors was attenuated since increasing frequency of stimulation of the ascending NE pathway produced a lesser degree of suppression of pyramidal neurons in rats administered bupropion than the control. Enhancement of 5-HT and NE transmissions in hippocampus by prolonged bupropion may account for its effectiveness in major depression.