Acute fluoxetine treatment potentiates amphetamine hyperactivity and amphetamine-induced nucleus accumbens dopamine release: possible pharmacokinetic interaction.
Amphetamine stimulates locomotor activity, in large part by activating central dopaminergic systems. Serotonin shares on overlapping distribution with dopamine and has been shown to modulate dopaminergic function and dopamine-mediated behaviors. The present study examined whether increasing serotonergic function, via the selective serotonin reuptake inhibitor fluoxetine, would alter the stimulatory effects of amphetamine on locomotor activity and dopamine overflow in the nucleus accumbens. In addition, the present study determined whether fluoxetine treatment would alter the metabolism of amphetamine. Results show that 5.0 mg/kg fluoxetine potentiated the locomotor activity induced by amphetamine (0.5-1.0 mg/ kg), and enhanced the increased dopamine overflow in the nucleus accumbens induced by amphetamine. Fluoxetine treatment also resulted in a higher concentration of amphetamine in the CNS. Together, these findings indicate that acute fluoxetine treatment potentiates the locomotor stimulating and dopamine activating effects of amphetamine. Further, the results indicate that fluoxetine potentiates the effects of amphetamine by decreasing the metabolism of amphetamine, probably through inhibition of cytochrome P450 isozymes.
Sills
T L
TL
Biopsychology Section, Clarke Institute of Psychiatry, Toronto, Canada. terrence@psych.toronto.edu
Greenshaw
A J
AJ
Baker
G B
GB
Fletcher
P J
PJ
D018759:Adrenergic Uptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000661:Amphetamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D018759:Adrenergic Uptake Inhibitors; D000661:Amphetamine; D004298:Dopamine; D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors