Modulation of Δ9-tetrahydrocannabinol-induced hypothermia by fluoxetine in the rat

Abstract

1. It has been suggested that the dose of Δ9-tetrahydrocannabinol (Δ9-THC) that induces hypothermia in the rat increases the release of brain 5-hydroxytryptamine (5-HT). In light of this, we investigated the hypothermia produced by Δ9-THC, and the effect the selective serotonin reuptake inhibitor fluoxetine has on this response. 2. A significant dose-dependent decrease in body temperature occurred after i.v. administration of 0.5 to 5 mg kg-1 Δ9-THC; maximum decreases being 0.8 ± 0.2°C to 2.9 ± 0.3°C. This hypothermic response was attenuated by the cannabinoid CB1 receptor antagonist SR 141716. 3. Fluoxetine (10 mg kg-1 i.p.) alone caused a decrease in body temperature of 0.6 ± 0.1°C (n = 32, P < 0.05) after 40 min. However, pretreatment with fluoxetine (10 mg kg-1 i.p.) 40 min before Δ9-THC significantly reduced the Δ9-THC-induced hypothermia (n = 7-8, P < 0.05). Contrary to this antagonist-like effect, fluoxetine administered 40 min after Δ9-THC significantly potentiated the Δ9-THC-induced hypothermia, producing a maximum decrease of 3.2 ± 0.3°C. 4. It is suggested that the effect of fluoxetine on the Δ9-THC-induced hypothermic response is dependent on the time of its administration relative to that of Δ9-THC. Pretreatment with fluoxetine increases extracellular 5-HT due to reuptake inhibition. Increased extracellular 5-HT can activate autoreceptors which may decrease serotonergic activity, thereby reducing the Δ9-THC-induced hypothermia. Conversely, when fluoxetine is adminstered after Δ9-THC, the reuptake block is thought to potentiate the already activated serotonegic system, hence potentiating the Δ9-THC-induced hypothermia.