A POSSIBLE ROLE OF CENTRAL NORADRENERGIC NEURONS IN WITHDRAWAL STATES FROM ALCOHOL

The possibility that central noradrenergic neurons may play a role in the expression of withdrawal states from alcohol is implicit in several recent biochemical theories of alcoholic dependence. *,Z These hypotheses attempt to explain the action of alcohol on the brain as mediated, in part, by catecholaminergic mechanisms. They suggest that acetaldehyde, formed from the metabolism of ethanol, condenses with catecholamines in situ in nerve terminals to produce pharmacologically active agents, either morphinelike alkaloids2 or tetrahydroisoquinolines. ' These agents, it is proposed, may act like false transmitters at catecholaminergic receptors: By either reducing or augmenting the effectiveness of adrenergic transmission or by modifying the sensitivity of adrenergic receptors they could lead to the behaviors characteristic of dependence on the drug. If abnormal function of catecholaminergic neurons underlies states of dependency on alcohol, it would be necessary to demonstrate that altered activity of central catecholaminergic receptors can result in integrated patterns of behavior similar to the withdrawal state. Although several animal models of withdrawal from ethanol are presently a ~ a i l a b l e , ~ ~ there have been no studies directed towards establishing the relationship between catecholaminergic neurons and this behavior. There is at present, 1 believe, indirect evidence to suggest that excessive activation of central catecholaminergic receptors, probably noradrenergic, may produce a state of behavioral excitement simulating the withdrawal state of delirium tremens in man. In this paper I would like to briefly present the arguments to support the contention. In the cat, several drugs, including L-dopa, can produce a state of intense behavioral excitement with many of the behavioral and autonomic components associated with delirium tremens. Following the administration of L-dopa alone or after facilitation by inhibitors of monoamine oxidase, cats exhibit a syndrome of motor restlessness, tremor, widespread sympathetic activation, intermittent hissing, snarling and screeching, hyperventilation, increased release of adrenal medullary hormones, hyperpyrexia, and hallucinatory The syndrome may be attenuated, but not abolished, by administration of disulfiram.7 This drug inhibits the activity of the enzyme dopamine P-hydroxylase and thus reduces the production of norepinephrine; this suggests that noradrenergic mechanisms are important in the expression of the excited state. A similar state of intense autonomic and behavioral arousal with neurally mediated release of adrenal catecholamines can be produced in the cat by administration of morphine.I0-l3 It also is evoked by recurrent electrical Stimulation of the amygdalaI4 and by acute d e c ~ r t i c a t i o n , ~ ~ l ~ the latter procedure resulting in behavior termed sham rage.15J8 Common to all of these evoked states of excitement is the fact that the concentration of NE in the brain is reduced without significant changes in the concentration of the other monoamine transmitters, dopamine (DA) or serotonin (5HT). 10-14*17~18