Modulation of Δ 9 ‐tetrahydrocannabinol‐induced hypothermia by fluoxetine in the rat

1 It has been suggested that the dose of Δ 9 ‐tetrahydrocannabinol (Δ 9 ‐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 Δ 9 ‐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 Δ 9 ‐THC; maximum decreases being 0.8±0.2°C to 2.9±0.3°C. This hypothermic response was attenuated by the cannabinoid CB 1 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 Δ 9 ‐THC significantly reduced the Δ 9 ‐THC‐induced hypothermia ( n = 7–8, P <0.05). Contrary to this antagonist‐like effect, fluoxetine administered 40 min after Δ 9 ‐THC significantly potentiated the Δ 9 ‐THC‐induced hypothermia, producing a maximum decrease of 3.2±0.3°C. 4 It is suggested that the effect of fluoxetine on the Δ 9 ‐THC‐induced hypothermic response is dependent on the time of its administration relative to that of Δ 9 ‐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 Δ 9 ‐THC‐induced hypothermia. Conversely, when fluoxetine is adminstered after Δ 9 ‐THC, the reuptake block is thought to potentiate the already activated serotonegic system, hence potentiating the Δ 9 ‐THC‐induced hypothermia.British Journal of Pharmacology (1998) 124 , 1419–1424; doi: 10.1038/sj.bjp.0701980