THE ROLE OF THE LOCUS-COERULEUS AND N-METHYL-D-ASPARTIC ACID (NMDA) AND AMPA RECEPTORS IN OPIATE WITHDRAWAL

Biochemical, behavioral, and electrophysiologic studies indicate that activation of the noradrenergic cells in the locus coeruleus (LC) play s an important role in the symptoms of opiate withdrawal. Extrinsic fa ctors play a major role in the morphine-withdrawal-induced activation of the LC, but intrinsic factors also play a role. Among the extrinsic factors, a glutamatergic projection from the nucleus paragigantocellu laris plays an important role in the withdrawal-induced activation of the LC. N-methyl-D-aspartic acid (NMDA) receptors play at most a minor role in the withdrawal-induced activation of the LC by glutamate; pre liminary evidence indicates that alpha-amino-3-hydroxy-5-methyl-4-isox azole propionic acid (AMPA) receptors play an important role. Whereas NMDA antagonists produce little to no suppression of the activation of the LC during morphine withdrawal, they do suppress many morphine wit hdrawal symptoms. However, phencyclidinelike side effects may limit th e clinical utility of NMDA antagonists. Experiments examining c-fos ex pression during morphine withdrawal indicate that NMDA antagonists may exert some of their influence on morphine withdrawal symptoms through actions in the forebrain. Pretreatment with the noncompetitive NMDA a ntagonist MK801 blocks morphine withdrawal-induced increased c-fos exp ression in the amygdala, but not in the nucleus accumbens, frontal cor tex, or hippocampus. Pretreatment with the competitive NMDA antagonist LY274614 (or the alpha(2)-adrenergic agonist clonidine) blocks morphi ne withdrawal-induced increased c-fos expression in the amygdala and n ucleus accumbens, but not in the frontal cortex or hippocampus. These results help to elucidate some of the neuroanatomy and neurophysiology underlying morphine withdrawal. Further, NMDA antagonists may not be clinically useful for opiate withdrawal due to their side-effects, but AMPA antagonists may be of great benefit for alleviating opiate withd rawal symptoms in humans.