D-amphetamine and γ-butyrolactone alteration of dopamine synthesis in the terminals of nigrostriatal and mesolimbic neurons : Possible role of various autoreceptor sensitivities

Abstract

The rate of synthesis of dopamine (DA) was estimated in vivo in terminals of nigrostriatal and mesolimbic neurons by measuring the accumulation of dihydroxyphenylalanine (DOPA_ in the striatum and in the nucleus accumbens and olfactory tubercle of male rats following the administration of an inhibitor of aromatic L-amino acid decarboxylase. Low to moderate doses of d-amphetamine (0.5 to 1.0 mg/kg) increased DA synthesis in the striatum but were without effect in the nucleus accumbens and olfactory tubercle; a higher dose (5.0 mg/kg) did not alter DA synthesis in any of the brain regions. Despite the lack of effect of d-amphetamine per se in the nucleus accumbens and olfactory tubercle, in both of these regions, as well as in the striatum, this drug was effective in reversing the decreased DA synthesis induced by a monoamine oxidase inhibitor (nialamide) or a DA agonist (apomorphine). γ-Butyrolactone (GBL) increased DA synthesis in the striatum, nucleus accumbens and olfactory tubercle, but it was less potent, less effective, and had a shorter duration of action in the latter two regions. d-Amphetamine, like GBL, may exert part of its effect on DA synthesis by reducing impulse flow in ascending DA neurons, since a low dose of d-amphetamine (0.125 mg/kg) potentiated the GBL-induced increase in DA synthesis in striatum, nucleus accumbens and olfactory tubercle. Regional differences in the actions of GBL and d-amphetamine on DA synthesis may be related to differences in receptor-mediated mechanisms that regulate the synthesis of this amine in neurons terminating in the striatum versus those terminating in nucleus accumbens and olfactory tubercle. At least one difference appears to be in the sensitivity of DA autoreceptors in these regions. The dose of apomorphine needed to reverse the GLB-induced increase of DA synthesis in nucleus accumbens and olfactory tubercle was approximately 1/10 that necessary to cause the same effect in the striatum. Pretreatment with a DA antagonist (haloperidol) potentiated the GBL-induced stimulation of DA synthesis in nucleus accumbens and olfactory tubercle, but not in the striatum. These results suggest that the reduced abilities of GBL and amphetamine to increase DA synthesis in nucleus accumbens and olfactory tubercle may result from a greater sensitivity of autoreceptors on mesolimbic DA neurons permitting a tighter regulatory control over DA synthesis in these neurons.