Abstract : Incubation of a crude synaptosomal fraction from rat striatum with GBR 12783 at 37°C produced an inhibition of the specific uptake of [3H]dopamine that increased with time. The inhibition increased when GBR 12783 was present during preincubation and incubation (IC50 = 1.85 ± 0.1 nM) instead of incubation alone (IC50 = 25 ± 3.5 nM). Time‐course studies of uptake inhibition demonstrated that a first collision transporter‐inhibitor complex (TI) was formed immediately after addition of GBR 12783 so that the initial uptake velocity (Vo) decreased for increasing concentrations of inhibitor (Ki≥ 20 nM). TI slowly isomerized to a more stable complex TI* (K*i≤ 5 nM) with a value of t1/2 = 20‐270 s. Fits of data to model 2 in which the steady‐state uptake (VS) is set to zero were generally preferred, suggesting that formation of TI* could tend to irreversibility, as a consequence of a very low reverse isomerization. As expected, k, Vo, and VS tended to steady‐state values in an asymptotic manner for high concentrations of GBR 12783. GBR 12783 at 2.5 nM produced a mixed inhibition of the uptake, with an increase in KM and a decrease in Vmax ; these effects were improved for 10 nM GBR 12783 and at 20°C. These results are discussed in relation to previous data concerning [3H]GBR 12783 binding. The present work gives the first experimental demonstration that dopamine uptake blockers can act according to a two‐step mechanism of inhibition ; this is of great interest, because these inhibitors can oppose the effects of cocaine or amphetamine on the transporter according to a reaction that is partly nondependent on the concentration of the abused agent.
Journal of Neurochemistry – Wiley
Published: Jan 1, 1999
Keywords: ; ; ; ;
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
All the latest content is available, no embargo periods.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud