ANTIAMPHETAMINE EFFECTS FOLLOWING INHIBITION OF TYROSINE HYDROXYLASE

Abstract

(α-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 α-MT appear to be correlated with in vivo inhibition of tyrosine hydroxylase, since other inhibitors, notably m -iodo-L-α-methyltyrosine and m -bromo-L-α-methyltyrosine, also antagonize amphetamine. The gross norepinephrine depletion produced by α-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-α-methyl- m -tyrosine (α-M- m -T) do not antagonize amphetamine. The behavioralprofile of α-MT appears unique: α-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 α-M- m -T. It differs from phenobarbital in that α-MT exertsno anticonvulsant effect and is not an effective sedative. Its antiamphetamine action clearly distinguishes α-MT from norepinephrine depletors which act by a release mechanism. The antiamphetamine effects of α-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.