Modulation by fluoxetine of striatal dopamine release following Delta9-tetrahydrocannabinol: a microdialysis study in conscious rats.

Delta9-tetrahydrocannabinol (THC) increased dopamine release in the striatum of conscious, freely-moving rats in a dose-dependent manner, with maximum increases of 42% to 97% above baseline occurring 20 minutes after intravenous administration. This effect was blocked by a cannabinoid CB1 receptor antagonist and by pretreatment with the antidepressant fluoxetine. However, fluoxetine administered after THC or perfused locally into the striatum potentiated the dopamine release. The authors suggest that THC-induced dopamine release is modulated by serotoninergic changes, with fluoxetine's effect depending on timing of administration.

Study at a glance

Abstract

1. The present study was undertaken to investigate the effect of Delta9-tetrahydrocannabinol (Delta9-THC) and possible serotoninergic involvement on the extracellular level of dopamine (DA) in the striatum using microdialysis in conscious, freely-moving rats. 2. A dose-dependent increase in striatal DA release occurred after i.v. administration of 0.5 - 5 mg kg-1 Delta9-THC when compared with vehicle (n=5 - 8, P<0.05). Maximum increases, ranging from 42.1+/-5. 4% to 97.4+/-5.9% (means+/-s.e.mean) of basal levels occurred 20 min after Delta9-THC. This effect was abolished by pretreatment with the cannabinoid CB1 receptor antagonist, SR 141716 (2.5 mg kg-1 i.p.). 3. Pretreatment with fluoxetine (10 mg kg-1 i.p.) abolished the Delta9-THC-induced DA release. Fluoxetine 10 mg kg-1 i.p. administered 40 min after Delta9-THC had no significant effect on Delta9-THC-induced DA release. However, fluoxetine perfused locally into the striatum by adding it to the microdialysis perfusion fluid (10 microM) 40 min after Delta9-THC significantly potentiated the Delta9-THC-induced DA release (n=6 - 8, P<0.05). 4. These results suggest that DA release induced by Delta9-THC is modulated by serotoninergic changes induced by fluoxetine, the effect of which depends on the time of its administration relative to that of Delta9-THC. Fluoxetine induces an acute increase in extracellular 5-HT through reuptake inhibition, which can activate autoreceptors which may decrease serotoninergic neuronal activity. This may be the reason fluoxetine pretreatment abolished the Delta9-THC-induced DA release. The potentiation of Delta9-THC-induced DA release by fluoxetine perfusion added 40 min after Delta9-THC may be due to an acute increase in 5-HT produced by reuptake inhibition.