INDIRECT SEROTONERGIC AGONISTS ATTENUATE NEURONAL OPIATE WITHDRAWAL

Withdrawal from opiates in dependent subjects produces strongly aversive psychological and autonomic responses which contribute to the chronic ingestion of opiates and the high incidence of relapse after withdrawal.19,20 A variety of evidence indicates that hyperactivity of noradrenergic locus coeruleus (LC) neurons is an important brain substrate of opiate withdrawal.17-20 In particular, only a few agents have been found to be clinically useful in alleviating these symptoms and treating opiate dependence, all of which potently attenuate the activation of noradrenergic neurons in the LC evoked by opiate withdrawal.17-20 However, current pharmacotherapies, especially methadone and clonidine, have serious side effects, including hypotension, sedation and their own withdrawal reactions.17-21,28 Our goal was to find an alternative pharmacological treatment to reduce the magnitude of LC hyperactivity during opiate withdrawal. Previous studies indicated that brain serotonin (5-HT) systems may be involved in opiate withdrawal. 9,12-23,26,30,31,34,37 Two results from our laboratory led us to study the effect of enhanced serotonergic neurotransmission on withdrawal-induced LC hyperactivity: (i) a substantial part of such LC hyperactivity is mediated by an excitatory amino acid input to the locus coeruleus,2 and (ii) 5-HT selectively attenuates excitation of LC neurons mediated by excitatory amino acids .4 Here, we report that agents which increase serotonergic neurotransmission attenuate the hyperactivity of LC neurons induced by naloxone-precipitated withdrawal from chronic morphine exposure in rats. The 5-HT releaser/uptake blocker, d-fenfluramine, as well as the 5-HT reuptake blockers fluoxetine or sertraline, significantly attenuated the withdrawal-induced hyperactivity of LC neurons. Additional results suggest that enhanced serotonergic neurotransmission with such drugs diminishes an augmented excitatory amino acid input to LC neurons that is responsible for most of their hyperactivity during opiate withdrawal. These findings point to the possibility that indirectly acting serotonergic agonists, many of which are already widely available for human use, may be beneficial in the treatment of opiate abuse.