Alterations in alcohol consumption, withdrawal seizures, and monoamine transmission in rats treated with phentermine and 5-hydroxy-L-tryptophan.
We have previously shown that coadministration of the dopamine (DA) agonist phentermine plus the serotonergic agonist fenfluramine suppresses alcohol intake and withdrawal seizures in rats. In the present study, phentermine and the serotonin (5-HT) precursor, 5-hydroxy-L-tryptophan (5-HTP), were administered alone, or in combination, to rats fed on a 6% alcohol-containing diet or an isocaloric control diet. Following a 9-h withdrawal period from the alcohol-containing diet, phentermine enhanced the effects of 5-HTP on both reduction of alcohol withdrawal seizures as well as changes in striatal serotonin. Food intake was monitored for 24 h after drug treatment, and neurochemical measures were examined at various time points. Phentermine alone reduced food intake in all diet conditions, but this anorectic effect was followed by hyperphagia in control rats. Phentermine plus 5-HTP reduced the consumption of the alcohol-containing diet, while its effects on consumption of control diets were mixed. In vivo microdialysis in rat nucleus accumbens revealed that phentermine increased extracellular DA, whereas 5-HTP caused marked elevations in extracellular 5-HT. Coadministration of phentermine and 5-HTP evoked simultaneous elevations in extracellular DA and 5-HT that mirrored the effects of each drug alone. Collectively, these findings show that coadministered phentermine plus 5-HTP is effective in reducing alcohol intake and suppressing alcohol withdrawal seizures. These therapeutic actions may be related to elevations in synaptic DA and 5-HT in critical brain regions.
Halladay
A K
AK
Department of Pharmacology, Rutgers University, New Brunswick, New Jersey 08901, USA.
Wagner
G C
GC
Sekowski
A
A
Rothman
R B
RB
Baumann
M H
MH
Fisher
H
H
D006916:5-Hydroxytryptophan / Q000627:therapeutic use*; D000428:Alcohol Drinking / Q000188:drug therapy*; D020270:Alcohol Withdrawal Seizures / Q000188:drug therapy*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000009:adverse effects; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000009:adverse effects; D008297:Male; D010645:Phentermine / Q000627:therapeutic use*; D051381:Rats; D020318:Rats, Long-Evans; D013997:Time Factors
D015306:Biogenic Monoamines; D002492:Central Nervous System Depressants; D000697:Central Nervous System Stimulants; D000431:Ethanol; D010645:Phentermine; D006916:5-Hydroxytryptophan