Depletion of brain serotonin following intra-raphe injections of 5,7-dihydroxytryptamine does not alter d-amphetamine self-administration across different schedule and access conditions.
OBJECTIVE
These experiments investigated the effects of selective serotonin (5-HT) depletion on intravenous self-administration of d-amphetamine.


METHODS
Depletion of brain 5-HT levels was induced by injecting the serotonergic neurotoxin 5,7-dihydroxytryptamine (5, 7-DHT) into the dorsal and median raphe nuclei. Rats were then trained to self-administer d-amphetamine according to various schedule and access conditions via chronically indwelling intravenous catheters.


RESULTS
Large reductions of brain 5-HT did not alter responding for a training dose of 120 microgram/kg d-amphetamine delivered according to a fixed ratio 1 schedule during 3-h sessions. When the dose of d-amphetamine was altered (0, 3.75, 7. 5, 15, 30, 60 microgram/kg per infusion) a characteristic inverted U-shaped dose response function was obtained. The 5-HT depleted rats showed increased responding for the lower doses of d-amphetamine, with a large significant increase in responding for the 7.5 microgram/kg dose. In these same rats, the suppressive effect of 10 mg/kg fluoxetine on d-amphetamine (60 microgram/kg) self-administration was prevented. The 5,7-DHT lesion also did not alter responding for d-amphetamine (120 microgram/kg) in longer (8 h) daily access sessions. Responding for d-amphetamine delivered on a progressive ratio schedule, in which response requirements increased for each successive infusion of d-amphetamine, was also determined in 5-HT depleted rats. The number of d-amphetamine infusions was not different from the number of infusions earned by sham-lesioned rats across a range of doses of d-amphetamine (7.5-60 microgram/kg). In a final experiment, spontaneous acquisition of self-administration of low doses of d-amphetamine (10 and 30 microgram/kg) was measured in 5-HT depleted and control rats. Again, self-administration behaviour in the 5-HT depleted rats did not differ from controls.


CONCLUSIONS
These results provide no evidence that reducing 5-HT function alters the primary reinforcing effects of self-administered amphetamine. The increase in self-administration of a low dose of amphetamine observed in experiment 1 probably involves some other process such as increased resistance to extinction.
Fletcher
P J
PJ
Departments of Psychiatry, University of Toronto, Centre for Addiction and Mental Health, Clarke Division, 250 College Street, Toronto, Ontario, Canada M5T 1R8. fletcher@psych.toronto.edu
Korth
K M
KM
Chambers
J W
JW
D015116:5,7-Dihydroxytryptamine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D003913:Dextroamphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007267:Injections; D008297:Male; D009042:Motivation; D011903:Raphe Nuclei / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule; D012646:Self Administration; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology*; D013268:Stimulation, Chemical
D000697:Central Nervous System Stimulants; D018490:Serotonin Agents; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D003913:Dextroamphetamine