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

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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−1 i.p.) 40 min before Δ9‐THC significantly reduced the Δ9‐THC‐induced hypothermia (n = 7–8, P9‐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. British Journal of Pharmacology (1998) 124, 1419–1424; doi:10.1038/sj.bjp.0701980