The effect of various drugs was studied on the naloxone-precipitated withdrawal syndrome of morphine-dependent rats. Quipazine and metachlorophenylpiperazine, two agents mimicking serotonin at central receptors, markedly lowered the frequency of jumping in abstinent rats; m-chlorophenylpiperazine significantly blocked diarrhea as well. Ptosis and diarrhea but not jumping were significantly reduced by clonidine. None of the withdrawal signs considered was significantly affected by propranolol or haloperidol. A significant reduction in the number of 3H-serotonin binding sites was found in the brainstem of morphine-dependent rats, but no change was observed in the number of serotonin receptors in the cortex. The hypothesis is proposed that in morphine dependent rats a central serotoninergic hypofunction, probably related to a decrease in the number of serotonin receptors in the brainstem, occurs as a consequence of persistent activation of central serotonin function by long-term treatment with morphine. This mechanism appears to play a major role in the compulsive jumping shown by morphine-dependent rats after naloxone injection. Alpha2 adrenergic sites may play a role in the manifestation of other withdrawal signs examined in this study.
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