Effects of Imipramine and Serotonin-2 Agonists and Antagonists on Serotonin-2 and Beta-adrenergic Receptors Following Noradrenergic or Serotonergic Denervation

The effects of chronic (14 day) administration of the tricyclic antidepressant imipramine, the serotonin-2 (5-HT2) antagonist ketanserin, and the serotonin agonist quipazine on 5-HT2 receptor binding parameters and 5-HT2-mediated behavior were examined in rats with or without prior serotonergic denervation [via 5,7-dihydroxytryptamine (5,7-DHT)] or noradrenergic denervation [via N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4)]. Chronic administration of imipramine, ketanserin, or quipazine produced a marked reduction in the number of 5-HT2 binding sites which was accompanied by reductions in the 5-HT2-mediated quipazine-induced head shake response. In animals receiving DSP4 or 5,7-DHT lesions and continuous vehicle treatment, beta-adrenergic receptor binding sites were significantly up-regulated while 5-HT2 receptor binding sites did not change. Imipramine normalized the lesion-induced increases in beta-adrenergic binding observed in DSP4 and 5,7-DHT-lesioned rats but failed to down-regulate beta-adrenergic binding sites below non-lesioned control levels. Chronic imipramine, ketanserin, and quipazine reduced quipazine-induced head shakes and down-regulated 5-HT2 binding sites in rats with noradrenergic denervation. While imipramine, ketanserin, and quipazine all down-regulated 5-HT2 binding sites in animals with serotonergic denervation, only imipramine's ability to reduce quipazine-induced head shakes was attenuated in 5,7-DHT-lesioned rats. The present results suggest that imipramine-induced down-regulation of 5-HT2 receptors may not involve presynaptic 5-HT mechanisms, and imipramine-induced alterations in 5-HT2 sensitivity as reflected in the quipazine-induced head shake may, in part, be influenced by beta-adrenergic receptors.