Modulation by fluoxetine of striatal dopamine release following Δ9-tetrahydrocannabinol:: a microdialysis study in conscious rats

1 The present study was undertaken to investigate the effect of Delta(9)-tetrahydrocannabinol (Delta(9)-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 0.55 mg kg(-1) Delta(9)-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 Delta(9)-THC. This effect was abolished by pretreatment with the cannabinoid CB, receptor antagonist, SR 141716 (2.5 mg kg(-1) i.p.). 3 Pretreatment with fluoxetine (10 mg kg(-1) i.p.) abolished the dg-THC-induced DA release. Fluoxetine 10 mg kg(-1) i.p. administered 40 min after Delta(9)-THC had no significant effect an Delta(9)-THC-induced DA release. However, fluoxetine perfused locally into the striatum by adding it to the microdialysis perfusion fluid (10 mu M) 40 min after Delta(9)-THC significantly potentiated the Delta(9)-THC-induced DA release (n = 6-8, P<0.05). 4 These results suggest that DA release induced by Delta(9)-THC is modulated by serotoninergic changes induced by fluoxetine, the effect of which depends on the time of its administration relative to that of Delta(9)-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 Delta(9)-THC-induced DA release. The potentiation of Delta(9)-THC-induced DA release by fluoxetine perfusion added 40 min after Delta(9)-THC may be due to an acute increase in 5-HT produced by reuptake inhibition.