Today, the clinical notion of 'memory disorder' is largely synonymous with 'Alzheimer's disease.' Only 50% of all dementias are of the Alzheimer's type though, and dementias represent only the more severe of all learning/memory disorders that derive from heredity, disease, injury or age. Perhaps as many as 30 million Americans suffer some type of clinically recognized memory disorder. To date, therapeutic drugs of only one class have been approved for the treatment of Alzheimer's disease. Fortunately, basic research during the past 25 years has begun to define a 'chemistry of brain plasticity,' which is suggesting new gene targets for the discovery of memory enhancers.

Investigation of the actions of the benzodiazepines has provided insights into the neurochemical mechanisms underlying anxiety, seizures, muscle relaxation, and sedation. Behavioral, electrophysical, pharmacological, and biochemical evidence indicates that the benzodiazepines exert their therapeutic effects by interacting with a high-affinity binding site (receptor) in the brain. The benzodiazepine receptor interacts with a receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter, and enhances its inhibitory effects. The benzodiazepine receptor may also interact with endogenous substances and several naturally occurring compounds, including the purines and nicotinamide, are candidates for this role. Both the purines and nicotinamide possess some benzodiazepine-like properties in vivo, although further work will be required to confirm their possible roles as endogenous benzodiazepines.

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Regulation of tyrosine hydroxylase expression by antidepressant treatments was investigated in the locus coeruleus (LC), the major noradrenergic nucleus in brain. Rats were treated chronically with various antidepressants, and tyrosine hydroxylase levels were measured in the LC by inimunoblot analysis. Representatives of all major classes of antidepressant medication-including imipramine, nortriptyline, tranylcypromine, fluvoxamine, fluoxetine, bupropion, iprindole, and electroconvulsive seizures-were found to de- refs. 11, 12). While these findings suggest that chronic antidepressant treatments may alter the synthesis of norepinephrine in the brain, no consistent reproducible effect of these treatments on the biosynthetic pathway for norepinephrine has, to date, been established. The rate-limiting enzyme in the synthesis of norepinephrine is tyrosine hydroxylase. Tyrosine hydroxylase is an -60-kDa protein abundant in noradrenergic and dopaminergic cell bodies and distributed throughout the brain in terminal fields of these catecholaminergic systems. Activity of the enzyme is regulated rapidly by neurotransmitters and neuronal activity through its phosphorylation by several types of protein kinase (for review, see refs. 13 and 14). More longterm regulation of the enzyme is achieved through changes in its expression, apparently at the level of gene transcription, by a variety of chronic perturbations (15)(16)(17)(18)(19)(20)(21)(22). Such acute and chronic regulation of tyrosine hydroxylase is thought to play a critical role in modulating the functional activity of catecholaminergic neuronal systems in the brain.In the present study, the influence of chronic antidepressant treatments on the expression of tyrosine hydroxylase was examined in the LC. We show here that chronic administration of every major class of antidepressant results in a dramatic downregulation of tyrosine hydroxylase expression specifically in the LC. The results raise the possibility that downregulation of the biosynthetic pathway for norepinephrine contributes to the molecular mechanisms through which antidepressant treatments exert at least some oftheir multiple clinical actions. METHODS 7522The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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