Alpha-methyl-para-tyrosine effects in mice selectively bred for differences in sensitivity to ethanol

The responses of catecholamine systems in long sleep (LS) and short sleep (SS) mice to alpha-methyl-p-tyrosine (AMPT) have been examined. Marked differences were found between LS and SS mice in the dose necessary for maximal brain catecholamine depletion and in the time-course of the catecholamine depletion. Brain catecholamines in the LS mice were depleted by lower doses of AMPT and the levels remained depressed for longer periods of time in this line of mice. These differences may be explained only partially by an increased susceptibility of the LS mice to the hypothermia and toxic effects caused by AMPT administration, as they persist with non-toxic AMPT dosage regimens and under conditions where the degree of hypothermia is comparable in both lines of mice. In addition, there were no differences between the Ki values for the effect of AMPT on the tyrosine hydroxylase from striata of these mouse lines. The primary cause of the heightened response to AMPT in LS mice would appear to be pharmacokinetic in nature, as brain and plasma peak levels of AMPT in LS mice were greater and the levels remained higher for a longer time. The depletion of brain tyrosine by AMPT combined with the lower affinity of the LS striatal tyrosine hydroxylase for the substrate tyrosine may also contribute to the heightened response in LS mice.