INCREASED CENTRAL 5‐HYDROXTRYPTAMINE RECEPTOR MECHANISMS IN RATS AFTER CHRONIC NEUROLEPTIC TREATMENT

Abstract

1 The behavioural responses of drugs known to act through central 5-hydroxytryptamine (5-HT) mechanisms have been investigated in rats receiving a neuroleptic (trifluoperazine) in their drinking water for 4 to 6 months. 2 5-Hydroxytryptophan (5-HTP) induced 5-HT-dependent behaviours including head bobbing and lateral head weaving, reciprocal forepaw treading, tremor, backward walking, body writhing and ‘wet-dog’ shakes. In doses of 50 to 150 mg/kg, 5-HTP induced more intense behavioural effects in neuroleptic-treated rats than in the control animals. 3 Similarly the putative 5-HT agonist, quipazine (1 to 20 mg/kg) and the 5-HT releasing drug, fenfluramine (5 to 20 mg/kg), both induced significantly greater motor responses in the chronically neuroleptic-treated rats. 4 A 5-HT uptake inhibitor (femoxetine, 2.5 to 10 mg/kg) had little behavioural effect in either control or trifluoperazine-treated rats. 5 Total specific high-affinity binding of radiolabeled 5-HT was significantly increased in crude membrane fractions prepared from the cortex, striatum and substantia nigra of neuroleptic-treated rats compared to control animals. 6 High-affinity uptake of radiolabeled 5-HT into striatal slices was similar in experimental and control animals. 7 Behavioural and biochemical data would indicate that postsynaptic 5-HT mechanisms are enhanced in rats treated chronically with trifluoperazine. Chronic neuroleptic therapy may thereby induce cerebral 5-HT receptor supersensitivity in addition to the well-documented cerebral dopamine receptor supersensitivity.