Effect of chronic treatment with 5-HT1 agonist (8-OH-DPAT and RU 24969) and antagonist (isapirone) drugs on the behavioural responses of mice to 5-HT1 and 5-HT2 agonists

Abstract

1 The effects of chronic (14 day) administration to mice of the 5-HT₁ agonists 8-hydroxy 2-(di-n-propylamino) tetralin (8-OH-DPAT) and 5-methoxy-3 (1,2,3,6-tetrahydropyridin-4-yl) IH indole (RU 24969) on the hypothermic response to 8-OH-DPAT and the locomotor response to RU 24969 have been examined. 2 Chronic administration of 8-OH-DPAT (5 mg kg⁻¹, s.c.) resulted in an attenuated hypothermic response to this drug given subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) but did not alter the locomotor response to RU 24969. 3 Chronic injection of RU 24969 (3 mg kg⁻¹, i.p.) produced an attenuated locomotor response to this drug given i.p. or i.c.v. but not the hypothermic response to 8-OH-DPAT (0.5 mg kg⁻¹, s.c). 4 Chronic administration of the putative presynaptic 5-HT, antagonist isapirone (10 mg kg⁻¹, i.p.) decreased the hypothermic response following 8-OH-DPAT injection but did not alter RU 24969-induced locomotion. 5 Chronic treatment with 8-OH-DPAT (5 mg kg⁻¹, s.c.) produced a modest enhancement of the 5-HT₂ receptor-mediated head-twitch behaviour initiated by 5-hydroxytryptophan injection while chronic isapirone decreased this behavioural response. 5-HT₂ receptor number in frontal cortex was unaltered by isapirone treatment but markedly decreased (34%) by chronic 8-OH-DPAT. 6 These data suggest that chronic administration of the 5-HT, agonists induces tolerance in their respective responses but not cross-tolerance, while chronic isapirone may down-regulate the 5-HT_1A site in a matter analogous to that seen by 5-HT₂ receptors following 5-HT₂ receptor antagonists. 7 The data further demonstrate that chronic treatment with 8-OH-DPAT and isapirone alter postsynaptic 5-HT₂ receptor function although 5-HT₂ receptor number in the frontal cortex did not correlate with the behavioural change.