Modification of quasi-morphine withdrawal with serotonin agonists and antagonists: evidence for a role of serotonin in the expression of opiate withdrawal.
Methylxanthines produce a quasi-morphine withdrawal syndrome (QMWS) in opiate naive rats. Additionally, methylxanthine-induced suppression of conditioned behavior in rats is reversed by the alpha 2 adrenergic agonist clonidine which also attenuates true opiate withdrawal and the QMWS. Therefore, the operant behavioral effects of 3-isobutyl-1-methylxanthine (IBMX) provide a model with which to study mechanisms involved in the expression of opiate withdrawal. In order to examine the role of serotonin (5-HT) in the rate-decreasing effects of IBMX on operant behavior, the 5-HT precursor 5-hydroxytryptophan, and 5-HT reuptake blocker fluoxetine were administered in combination with IBMX to rats performing a fixed-ratio 30 operant for food reinforcement. Both drugs failed to reverse the behavioral suppression caused by relatively low doses of IBMX, suggesting that elevated 5-HT neurotransmission contributes to, rather than attenuates, the QMWS. The relatively selective 5-HT2 antagonists mianserin and pirenperone blocked the IBMX-induced suppression, whereas the classic 5-HT antagonist methysergide had no effect. The results indicate that the operant behavioral effects of IBMX and possibly the QMWS may be mediated by serotonergic mechanisms.
Kleven
M S
MS
Department of Pharmacology, University of Minnesota Medical School, Minneapolis 55455.
Sparber
S B
SB
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000818:Animals; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D008784:Methysergide / Q000494:pharmacology; D008803:Mianserin / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control* / Q000523:psychology
D010880:Piperidines; D012702:Serotonin Antagonists; D005473:Fluoxetine; D008803:Mianserin; D012701:Serotonin; D009020:Morphine; D006916:5-Hydroxytryptophan; D015056:1-Methyl-3-isobutylxanthine; D008784:Methysergide; C034177:pirenperone