Premium
GZ ‐793A, a lobelane analog, interacts with the vesicular monoamine transporter‐2 to inhibit the effect of methamphetamine
Author(s) -
Horton David B.,
Nickell Justin R.,
Zheng Guangrong,
Crooks Peter A.,
Dwoskin Linda P.
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12371
Subject(s) - tetrabenazine , dopamine , chemistry , vesicular monoamine transporter , methamphetamine , reserpine , dopamine uptake inhibitors , monoamine neurotransmitter , pharmacology , dopamine transporter , biophysics , biochemistry , dopaminergic , endocrinology , serotonin , biology , receptor
( R )‐3‐[2,6‐ cis ‐Di(4‐methoxyphenethyl)piperidin‐1‐yl]propane‐1,2‐diol (GZ‐793A) inhibits methamphetamine‐evoked dopamine release from striatal slices and methamphetamine self‐administration in rats. GZ‐793A potently and selectively inhibits dopamine uptake at the vesicular monoamine transporter‐2 (VMAT2). This study determined GZ‐793A's ability to evoke [ 3 H]dopamine release and inhibit methamphetamine‐evoked [ 3 H]dopamine release from isolated striatal synaptic vesicles. Results show GZ‐793A concentration‐dependent [ 3 H]dopamine release; nonlinear regression revealed a two‐site model of interaction with VMAT2 (High‐ and Low‐EC 50 = 15.5 nM and 29.3 μM, respectively). Tetrabenazine and reserpine completely inhibited GZ‐793A‐evoked [ 3 H]dopamine release, however, only at the High‐affinity site. Low concentrations of GZ‐793A that interact with the extravesicular dopamine uptake site and the High‐affinity intravesicular DA release site also inhibited methamphetamine‐evoked [ 3 H]dopamine release from synaptic vesicles. A rightward shift in the methamphetamine concentration‐response was evident with increasing concentrations of GZ‐793A, and the Schild regression slope was 0.49 ± 0.08, consistent with surmountable allosteric inhibition. These results support a hypothetical model of GZ‐793A interaction at more than one site on the VMAT2 protein, which explains its potent inhibition of dopamine uptake, dopamine release via a High‐affinity tetrabenazine‐ and reserpine‐sensitive site, dopamine release via a Low‐affinity tetrabenazine‐ and reserpine‐insensitive site, and a low‐affinity interaction with the dihydrotetrabenazine binding site on VMAT2. GZ‐793A inhibition of the effects of methamphetamine supports its potential as a therapeutic agent for the treatment of methamphetamine abuse.GZ‐793A inhibits methamphetamine‐evoked dopamine release from synaptic vesicles through a surmountable allosteric mechanism and interacts with several sites on the vesicular monoamine transporter‐2 (VMAT2), including high‐ and‐low affinity intravesicular dopamine release sites, high‐affinity extravesicular dopamine uptake sites and low‐affinity extravesicular dihydrotetrabenazine binding sites. VMAT2 interactions likely underlie the ability of GZ‐793A to attenuate the neurochemical and behavioral effects of methamphetamine.