Fluoxetine, but not sertraline or citalopram, potentiates the locomotor stimulant effect of cocaine: possible pharmacokinetic effects.
BACKGROUND
The selective serotonin reuptake inhibitor (SSRI) fluoxetine enhances some of the behavioural effects of cocaine, including locomotor stimulation. While this effect has often been interpreted as evidence for a serotonergic component to the behavioural effects of cocaine, direct evidence for this hypothesis is lacking. One alternative explanation is that fluoxetine, by inhibiting cytochrome P450 (CYP) enzymes, interferes with the metabolism of cocaine.


OBJECTIVE
These experiments were undertaken to: 1) compare the effects of fluoxetine with those of two other SSRIs, sertraline and citalopram, on cocaine-induced locomotor activity, 2) examine the effects of fluoxetine on cocaine-stimulated locomotion in rats depleted of serotonin (5-hydroxytryptamine; 5-HT), and 3) determine the effect of fluoxetine on cocaine levels in the brain.


METHODS
Locomotor activity was measured, using photocell based activity monitors, in rats habituated to those monitors. Depletion of 5-HT was achieved by injecting 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal and median raphe nuclei. Cocaine levels in whole brain were measured using high-performance liquid chromatography with ultraviolet detection.


RESULTS
In experiment 1, 5 mg/kg fluoxetine enhanced the ability of 10 and 15 mg/kg cocaine to increase locomotor activity. Neither citalopram nor sertraline (5 and 10 mg/kg) altered the stimulant effect of 10 mg/kg cocaine. Experiment 2 showed that this effect of fluoxetine was also apparent in rats with large and widespread depletion of brain 5-HT levels. The 5-HT depletion also failed to alter the response to cocaine itself. In experiment 3, brain levels of cocaine were elevated in rats pretreated with fluoxetine compared with rats that received cocaine alone.


CONCLUSIONS
Fluoxetine enhanced the ability of cocaine to increase locomotor activity. This effect appears not to depend upon increasing 5-HT function since fluoxetine was also effective in rats with substantial 5-HT depletions, and two other SSRIs did not alter the effects of cocaine. Fluoxetine-treated rats had higher brain levels of cocaine than rats treated with cocaine alone. This effect suggests that fluoxetine slows the metabolism of cocaine, perhaps by inhibition of CYP enzymes involved in metabolizing cocaine. The results also indicate that 5-HT reuptake inhibition may not play a prominent role in mediating the stimulant effects of cocaine.
Fletcher
Paul J
PJ
Section of Biopsychology, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T 1R8, Canada. Paul_Fletcher@camh.net
Sinyard
Judy
J
Salsali
Mahnaz
M
Baker
Glen B
GB
D015116:5,7-Dihydroxytryptamine / Q000633:toxicity; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000032:analysis; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D015283:Citalopram / Q000494:pharmacology; D003042:Cocaine / Q000493:pharmacokinetics / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018490:Serotonin Agents / Q000633:toxicity; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline / Q000494:pharmacology; D014018:Tissue Distribution
D015116:5,7-Dihydroxytryptamine; D015306:Biogenic Monoamines; D015283:Citalopram; D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D005473:Fluoxetine; D018490:Serotonin Agents; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline