Effects of d-amphetamine and dopamine synthesis inhibitors on dopamine and acetylcholine neurotransmission in the striatum. II. Release in the presence of vesicular transmitter stores.
The release of endogenous dopamine (DA) elicited by electrical stimulation and by d-amphetamine (AMPH) from superfused striatal slices of untreated rabbits was examined. AMPH (0.3-10 microM) produced a concentration-dependent increase in basal DA efflux (30-fold increase at 10 microM) and stimulation-evoked (SE) DA overflow (11-fold increase at 10 microM). Although AMPH had little effect on the basal efflux of dihydroxyphenylacetic acid (DOPAC), the drug was an effective inhibitor of the SE overflow of the DA metabolite (66% inhibition at 0.3 microM). AMPH increased significantly the total basal efflux of endogenous compounds (DA + DOPAC) only at high concentrations (3-10 microM) whereas the total SE overflow of total endogenous compounds was decreased at all concentrations of AMPH tested. AMPH inhibited SE [3H]acetylcholine (ACh) release in a concentration-dependent manner (71% inhibition at 10 microM). Inhibition of DA synthesis with alpha-methyl-p-tyrosine (100 microM) or 3-iodotyrosine (100 microM) reduced both the basal efflux and SE overflow of endogenous DA and DOPAC; synthesis inhibition had greater effects on the SE overflow. Neither synthesis inhibitor altered SE [3H]ACh release. alpha-Methyl-p-tyrosine and 3-iodotyrosine reduced the absolute values of the basal efflux and SE overflow of DA elicited by AMPH by approximately 60%; however, the inhibition of SE [3H]ACh release produced by AMPH was attenuated only slightly (approximately 20%). Synthesis inhibitors also reduced tissue DA levels (approximately 30%). These results suggest that: basal efflux of endogenous DA from superfused rabbit striatal slices may derived both from DA newly synthesized in the cytoplasm and from spontaneous leakage of DA from storage vesicles. In addition, synthesis may provide a continuous supply of DA to vesicles that are used for exocytotic DA release during electrical stimulation. However, the depletion of tissue DA produced by synthesis inhibitors as well as other extraneous pharmacological actions of these drugs makes firm conclusions difficult. AMPH increases the synaptic concentration of DA by accelerating the basal efflux as well as the SE overflow of unchanged DA. At concentrations less than 1 microM AMPH has no effect on basal efflux of DA or DOPAC but reduces SE overflow of DOPAC via an unknown mechanism. At higher concentrations (greater than or equal to 1 microM) acceleration of carrier-mediated DA efflux coupled with displacement of DA from vesicular stores, as well as interference with the uptake of exocytotically released DA produces a marked increase in synaptic DA which in turn inhibits SE ACh release.(ABSTRACT TRUNCATED AT 400 WORDS)
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D003913:Dextroamphetamine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008781:Methyltyrosines / Q000494:pharmacology; D007470:Monoiodotyrosine / Q000494:pharmacology; D011817:Rabbits; D012636:Secretory Rate / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*
D018492:Dopamine Antagonists; D008781:Methyltyrosines; D015102:3,4-Dihydroxyphenylacetic Acid; D007470:Monoiodotyrosine; D000109:Acetylcholine; D003913:Dextroamphetamine; D004298:Dopamine