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1 Department of Pharmacology, Chas. Pfizer & Co., Inc., Groton, Connecticut
(
-MT), a potent inhibitor of tyrosine hydroxylase, antagonizes the hyperactivity, the sniffing-licking-gnawing syndrome, the anorexia and the nondiscriminated avoidance rate-stimulating effects of amphetamine, as well as the syndrome produced by 2 amphetamine-like drugs. Theseeffects of -MT appear to be correlated with in vivo inhibition of tyrosine hydroxylase, since other inhibitors, notably m-iodo-L--methyltyrosine and m-bromo-L--methyltyrosine, also antagonize amphetamine. The gross norepinephrine depletion produced by -MT may be related to its antiamphetamine effect, but gross norepinephrine depletion is not itself sufficient for amphetamine antagonism since amine depletors such as DL--methyl-m-tyrosine (-M-m-T) do not antagonize amphetamine. The behavioralprofile of -MT appears unique: -MT differs from chlorpromazine in not profoundly disrupting avoidance behavior and in not altering symptoms produced by intravenous norepinephrine, tryptamine and apomorphine or by a monoamine oxidase (MAO) inhibitor + either 3,4-dihydroxyphenylalanine (dopa) or -M-m-T. It differs from phenobarbital in that -MT exertsno anticonvulsant effect and is not an effective sedative. Its antiamphetamine action clearly distinguishes -MT from norepinephrine depletors which act by a release mechanism. The antiamphetamine effects of -MT and other tyrosine hydroxylase inhibitors suggest that a critical level of norepinephrine at the receptor is required for amphetamine to exert its customary effects. It is speculated that this level derives from a functional pool of norepinephrine in thecentral nervous system, highly susceptible to blockade of norepinephrine biosynthesis at the tyrosine hydroxylase step.
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