Fluoxetine combined with a serotonin-1A receptor antagonist reversed reward deficits observed during nicotine and amphetamine withdrawal in rats.
The symptom of "diminished interest or pleasure" in rewarding stimuli is an affective symptom of nicotine and amphetamine withdrawal, and a core symptom of depression. An operational measure of this symptom is elevation of brain reward thresholds during drug withdrawal. We report here that acute co-administration of fluoxetine, a selective serotonin reuptake inhibitor, and p-MPPI, a serotonin-1A receptor antagonist, alleviated the diminished interest in brain stimulation reward observed during withdrawal from nicotine or amphetamine in rats (i.e., increased reward). By contrast, the same drug combination treatment did not reduce the somatic signs of nicotine withdrawal indicating symptom-specific neurobiological abnormalities. Surprisingly, the same treatment had opposite effects in control rats where reductions in reward were produced, suggesting that animal models should be based primarily on studying specific deficits that are pathognomic of a psychiatric disorder. The reversal of the affective aspects of drug withdrawal by a treatment that enhances serotonin neurotransmission indicates that decreased serotonergic function may mediate the reward decrements characterizing nicotine and amphetamine withdrawal, and that these symptoms may be homologous to a core symptom of non-drug-induced depressions.
Harrison
A A
AA
Scripps Research Institute, Department of Neuropharmacology, La Jolla, CA 92037, USA.
Liem
Y T
YT
Markou
A
A
D000631:Aminopyridines / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D019969:Amphetamine-Related Disorders / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003863:Depression / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D004338:Drug Combinations; D004558:Electric Stimulation; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012201:Reward; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014029:Tobacco Use Disorder / Q000188:drug therapy* / Q000503:physiopathology
D000631:Aminopyridines; D000661:Amphetamine; D004338:Drug Combinations; D005473:Fluoxetine; D008464:Mecamylamine; D009538:Nicotine; D018733:Nicotinic Antagonists; D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C087205:4-(2'-methoxyphenyl)-1-(2'-(N-(2''-pyridinyl)-4-iodobenzamido)ethyl)piperazine