Modulation of delta9-tetrahydrocannabinol-induced hypothermia by fluoxetine in the rat.

1. It has been suggested that the dose of delta9-tetrahydrocannabinol (delta9-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 delta4-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) delta9-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 delta9-THC significantly reduced the delta9-THC-induced hypothermia (n=7-8, P < 0.05). Contrary to this antagonist-like effect, fluoxetine administered 40 min after delta9-THC significantly potentiated the delta9-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 delta9-THC-induced hypothermic response is dependent on the time of its administration relative to that of delta9-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 delta9-THC-induced hypothermia. Conversely, when fluoxetine is administered after delta9-THC, the reuptake block is thought to potentiate the already activated serotonergic system, hence potentiating the delta9-THC-induced hypothermia.