Modulation by fluoxetine of striatal dopamine release following Delta9-tetrahydrocannabinol: a microdialysis study in conscious rats.
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.
Malone
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DT
Department of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy (Monash University), 381 Royal Parade, Parkville 3052, Victoria, Australia.
Taylor
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DA
D000818:Animals; D003243:Consciousness; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D010477:Perfusion; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000077285:Rimonabant; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013997:Time Factors
D004298:Dopamine; D013759:Dronabinol; D005473:Fluoxetine; D010880:Piperidines; D011720:Pyrazoles; D000077285:Rimonabant; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors