Changes in cortical 5-HT2 receptors following 5-HTP and paroxetine administration in rats.

Rats were pretreated with either carbidopa (25 mg/kg 30 min previously) or phenelzine (50 mg/kg 18 h and 12 mg/kg 90 min previously) before being given 5-HTP (150 or 350 mg/kg) or paroxetine (12 mg/kg). In carbidopa-treated animals, 5-HTP (150 mg/kg) evoked many wet-dog shakes (WDS) without changing receptor numbers, but an increase in the dose of 5-HTP to 350 mg/kg paradoxically increased the number of cortical 5-HT2 receptors. The increase was reversed by pretreating the rats with haloperidol (5 mg/kg), but this did not occur with α-methyl-para-tyrosine (250 mg/kg 16 h and 4 h before carbidopa). Apomorphine (2 mg/kg) in phenelzine-treated rats and apomorphine (10 mg/kg) in untreated rats increased 5-HT2 receptor numbers. The reason for the failure of 5-HTP to rapidly down-regulate 5-HT2 receptors is not known, but is thought to depend in some complex way on the proportion of 5-HTP that is decarboxylated to 5-HT outside serotonergic neurons, thus affecting the dopaminergic mechanism. In phenelzine-treated rats, paroxetine produced a 5-HT-dependent syndrome, which included WDS, and a significant reduction in cortical 5-HT2 receptors within 3 h. WDS were unaffected by administration of propranolol (20 mg/kg) or pindolol (5 mg/kg), confirming that WDS were independent of 5-HT1A receptors. The reduction of 5-HT2 receptors was not associated with migration of the receptors into the "light-density fraction" of the cortex, isolated by density-gradient centrifugation. Introduction Rat cortical 5-HT2 receptors are rapidly down-regulated by administering a 5-HT uptake inhibitor, such as fenfluramine, or 5-methoxydimethyltryptamine to animals pretreated with a monoamine oxidase (MAO) inhibitor[1,2]. This downregulation is temporally associated with a reduced responsiveness of brain-stem and spinal cord 5-HT2 receptors, as evidenced from the reduced number of wet-dog 越 川 憲 明,丸 山佳 子,岡 耕 一,野 村 周 史,森 栄一,小 林 雅文: Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101, JAPAN. * Department of Pharmacology, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, U. K.