Dt. Malone et Da. Taylor, MODULATION OF DELTA(9)-TETRAHYDROCANNABINOL-INDUCED HYPOTHERMIA BY FLUOXETINE IN THE RAT, British Journal of Pharmacology, 124(7), 1998, pp. 1419-1424
1 It has been suggested that the dose of Delta(9)-tetrahydrocannabinol
(Delta(9)-THC) that induces hypothermia in the rat increases the rele
ase of brain 5-hydroxytryptamine (5-HT). In light of this, we investig
ated the hypothermia produced by Delta(9)-THC, and the effect the sele
ctive serotonin reuptake inhibitor fluoxetine has on this response. 2
A significant dose-dependent decrease in body temperature occurred aft
er i.v. administration of 0.5 to 5 mg kg(-1) Delta(9)-THC; maximum dec
reases being 0.8 +/- 0.2 degrees C to 2.9 +/- 0.3 degrees C. This hypo
thermic response was attenuated by the cannabinoid CB1 receptor antago
nist SR 141716. 3 Fluoxetine (10 mg kg(-1) i.p.) alone caused a decrea
se 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 poten
tiated the Delta(9)-THC-induced hypothermia, producing a maximum decre
ase of 3.2+/-0.3 degrees C. 4 It is suggested that the effect of fluox
etine on the Delta(9)-THC-induced hypothermic response is dependent on
the time of its administration relative to that of Delta(9)-THC. Pret
reatment with fluoxetine increases extracellular 5-HT due to reuptake
inhibition. Increased extracellular 5-HT can activate autoreceptors wh
ich may decrease serotonergic activity, thereby reducing the Delta(9)-
THC-induced hypothermia. Conversely, when fluoxetine is adminstered af
ter Delta(9)-THC, the reuptake block is thought to potentiate the alre
ady activated serotonegic system, hence potentiating the Delta(9)-THC-
induced hypothermia.