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

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Abstract
The present study was undertaken to investigate the effect of Δ9‐tetrahydrocannabinol (Δ9‐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 Δ9‐THC when compared with vehicle (n=5–8, P9‐THC. This effect was abolished by pretreatment with the cannabinoid CB1 receptor antagonist, SR 141716 (2.5 mg kg−1 i.p.). Pretreatment with fluoxetine (10 mg kg−1 i.p.) abolished the Δ9‐THC‐induced DA release. Fluoxetine 10 mg kg−1 i.p. administered 40 min after Δ9‐THC had no significant effect on Δ9‐THC‐induced DA release. However, fluoxetine perfused locally into the striatum by adding it to the microdialysis perfusion fluid (10 μM) 40 min after Δ9‐THC significantly potentiated the Δ9‐THC‐induced DA release (n=6–8, P9‐THC is modulated by serotoninergic changes induced by fluoxetine, the effect of which depends on the time of its administration relative to that of Δ9‐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 Δ9‐THC‐induced DA release. The potentiation of Δ9‐THC‐induced DA release by fluoxetine perfusion added 40 min after Δ9‐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