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

1 It has been suggested that the dose of Delta(9)-tetrahydrocannabinol (Delta(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 Delta(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) Delta(9)-THC; maximum decreases being 0.8 +/- 0.2 degrees C to 2.9 +/- 0.3 degrees 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 degrees C (n = 32, P<0.05) after 40 min. However, pretreatment with fluoxetine (10 mg kg(-1) i.p.) 40 min before Delta(9)-THC significantly reduced the Delta(9)-THC-induced hypothermia (n=7-8, P<0.05). Contrary to this antagonist-like effect, fluoxetine administered 40 min after Delta(9)-THC significantly potentiated the Delta(9)-THC-induced hypothermia, producing a maximum decrease of 3.2+/-0.3 degrees C. 4 It is suggested that the effect of fluoxetine on the Delta(9)-THC-induced hypothermic response is dependent on the time of its administration relative to that of Delta(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 Delta(9)-THC-induced hypothermia. Conversely, when fluoxetine is adminstered after Delta(9)-THC, the reuptake block is thought to potentiate the already activated serotonegic system, hence potentiating the Delta(9)-THC-induced hypothermia.