Modulation by fluoxetine of striatal dopamine release following Δ 9 ‐tetrahydrocannabinol: a microdialysis study in conscious rats

The present study was undertaken to investigate the effect of Δ 9 ‐tetrahydrocannabinol (Δ 9 ‐THC) and possible serotoninergic involvement on the extracellular level of dopamine (DA) in the striatum using microdialysis in conscious, freely‐moving rats. A dose‐dependent increase in striatal DA release occurred after i.v. administration of 0.5–5 mg kg −1 Δ 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 Δ 9 ‐THC. This effect was abolished by pretreatment with the cannabinoid CB 1 receptor antagonist, SR 141716 (2.5 mg kg −1 i.p.). Pretreatment with fluoxetine (10 mg kg −1 i.p.) abolished the Δ 9 ‐THC‐induced DA release. Fluoxetine 10 mg kg −1 i.p. administered 40 min after Δ 9 ‐THC had no significant effect on Δ 9 ‐THC‐induced DA release. However, fluoxetine perfused locally into the striatum by adding it to the microdialysis perfusion fluid (10 μ M ) 40 min after Δ 9 ‐THC significantly potentiated the Δ 9 ‐THC‐induced DA release ( n =6–8, P <0.05). These results suggest that DA release induced by Δ 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 Δ 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 Δ 9 ‐THC‐induced DA release. The potentiation of Δ 9 ‐THC‐induced DA release by fluoxetine perfusion added 40 min after Δ 9 ‐THC may be due to an acute increase in 5‐HT produced by reuptake inhibition.British Journal of Pharmacology (1999) 128 , 21–26; doi: 10.1038/sj.bjp.0702753