Involvement of somatodendritic 5-HT 1A receptors in Δ 9-tetrahydrocannabinol-induced hypothermia in the rat

Abstract

Previously, it has been reported that modulating serotonergic neurones by use of selective serotonin reuptake inhibitors (SSRI) can alter the hypothermic response produced by Δ 9-tetrahydrocannabinol (Δ 9-THC). The aim of the present study was to investigate the effect that activation or antagonism of 5-hydroxytryptamine (5-HT 1A) receptors has on Δ 9-THC-induced hypothermia. Δ 9-THC (0.5, 2 and 5 mg/kg iv) decreased body temperature in a dose-related manner. Whilst having no significant effect on body temperature when administered 40 min prior to vehicle injection, the 5-HT 1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY 100635; 1 mg/kg sc) significantly potentiated the hypothermia produced by 2 and 5 mg/kg Δ 9-THC. In order to investigate whether this effect was due to antagonism at somatodendritic autoreceptors in midbrain raphe nuclei, WAY 100635 or the 5-HT 1A agonist 8-hydroxy-(di- n-propylamino) tetralin (8-OH-DPAT) was microinjected into either the median raphe nuclei (MRN) or dorsal raphe nuclei (DRN) 40 min prior to Δ 9-THC injection. Following microinjection into the DRN, neither WAY 100635 (0.5 nmol/0.5 μl/10 s) nor 8-OH-DPAT (15.2 nmol/0.5 μl/10 s) had any significant effect on Δ 9-THC-induced hypothermia. However, WAY 100635 when microinjected into the MRN significantly potentiated Δ 9-THC-induced hypothermia, and 8-OH-DPAT microinjected into the MRN significantly inhibited Δ 9-THC-induced hypothermia. It is suggested from these studies that the potentiation of Δ 9-THC-induced hypothermia by WAY 100635 when administered peripherally is mainly due to antagonism at somatodendritic 5-HT 1A autoreceptors in the MRN.