title: Evidence that amphetamine and Na+ gradient reversal increase striatal synaptosomal dopamine synthesis through carrier-mediated efflux of dopamine.
abstract: Amphetamine (AMPH) releases dopamine (DA) from striatal synaptosomes and concomitantly increases DA synthesis. Since AMPH may release DA through carrier-mediated diffusion via reversal of the DA uptake system, the increase in DA synthesis might depend on a functioning uptake carrier. Consistent with such a mechanism, the uptake inhibitors nomifensine (NMF) and benztropine (BZT) completely prevented the AMPH-induced increase in DA synthesis at concentrations known to inhibit DA uptake. Changes in the Na+ gradient across the synaptosomal membrane also promote DA release, since DA and Na+ are cotransported by the neuronal uptake carrier. Incubation of synaptosomes in medium containing decreasing Na+ increased DA synthesis inversely proportional to Na+ over the range 128 to 20 mM. Similarly, incubations in the presence of 10(-4) M ouabain to inhibit Na+, K+-ATPase and allow intracellular accumulation of Na+ also increased DA synthesis. These changes in DA synthesis could also be prevented by BZT and were non-additive with the AMPH-induced increase in DA synthesis. However, a concentration of ouabain (10(-6) M) which by itself did not increase DA synthesis, and does not promote DA release, potentiated the AMPH-induced increase in DA synthesis. Further, the increased DA synthesis promoted by all three manipulations was only marginally dependent on the presence of Ca2+ in the incubation medium. However, at 5 and 10 mM Na+, a second component of increased DA synthesis was observed which was insensitive to BZT, but was prevented by Ca2+ removal. These results suggest that the increase in DA synthesis, and presumably DA release promoted by AMPH, lowered Na+, and ouabain, depend on the availability of the DA carrier at the internal face of the neuronal membrane and the intracellular content of Na+. The second component of increased DA synthesis which is evident at 5 and 10 mM Na+ is discussed in terms of a possible Ca2+-mediated change in DA synthesis which is independent of the DA carrier.
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001590:Benztropine / Q000494:pharmacology; D001693:Biological Transport, Active; D003342:Corpus Striatum / Q000166:cytology*; D004298:Dopamine / Q000096:biosynthesis*; D004357:Drug Synergism; D004533:Egtazic Acid / Q000494:pharmacology; D008297:Male; D009627:Nomifensine / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism*
chemical_list: D009627:Nomifensine; D001590:Benztropine; D004533:Egtazic Acid; D010042:Ouabain; D012964:Sodium; D000661:Amphetamine; D004298:Dopamine