Effects of VMAT2 inhibitors lobeline and GZ‐793A on methamphetamine‐induced changes in dopamine release, metabolism and synthesis in vivo

Abstract

Vesicular monoamine transporter-2 (VMAT2) inhibitors reduce methamphetamine (METH) reward in rats. The current study determined the effects of VMAT2 inhibitors lobeline (LOB; 1 or 3 mg/kg) and N-(1,2R-dihydroxylpropyl)-2,6-cis-di(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A; 15 or 30 mg/kg) on METH-induced (0.5 mg/kg, SC) changes in extracellular dopamine (DA) and its metabolite dihydroxyphenylacetic acid (DOPAC) in the reward-relevant nucleus accumbens (NAc) shell using in vivo microdialysis. The effect of GZ-793A (15 mg/kg) on DA synthesis in tissue also was investigated in NAc, striatum (STR), medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC). In NAc shell, METH produced a time-dependent increase in extracellular DA and decrease in DOPAC. Neither LOB nor GZ-793A alone altered extracellular DA; however, both drugs increased extracellular DOPAC. In combination with METH, LOB did not alter the effects of METH on DA; however, GZ-793A, which has greater selectivity than LOB for inhibiting VMAT2, reduced the duration of the METH-induced increase in extracellular DA. Both LOB and GZ-793A enhanced the duration of the METH-induced decrease in extracellular DOPAC. METH also increased tissue DA synthesis in NAc and STR, whereas GZ-793A decreased synthesis; no effect of METH or GZ-793A on DA synthesis was found in mPFC or OFC. These results suggest that selective inhibition of VMAT2 produces a time-dependent decrease in DA release in NAc shell as a result of alterations in tyrosine hydroxylase activity, which may play a role in the ability of GZ-793A to decrease METH reward.

Nucleus accumbens hyperpolarization-activated cyclic nucleotide-gated channels modulate methamphetamine self-administration in rats

“…***P < 0.001, *P < 0.05, compared to the −30 min; ### P < 0.001, # P < 0.05, compared to vehicle-methamphetamine group, two-way repeated measures ANOVA followed by Bonferroni's test. Veh vehicle, NS normal saline, METH methamphetamine play an important role in the initial phase of its reinforcement, and increased extracellular dopamine concentrations underlie the psychostimulatory and reinforcing effects of methamphetamine (Le Cozannet et al 2013;Meyer et al 2013;Munzar et al 2004;Narita et al 2003;Shoblock et al 2003). Thus, locomotor activity test and in vivo microdialysis experiments were performed, and they revealed that HCN channel blockade reduced the psychostimulatory effects of methamphetamine and the relevant dopamine transmission in the NAc.…”

“…Previous research has primarily focused on actions of methamphetamine on dopamine transporters that facilitate dopamine reverse transport and inhibit dopamine uptake and on its interaction with vesicular monoamine transporter-2 to increase the amount of cytosolic dopamine available for reverse transport by dopamine transporters. In addition, methamphetamine inhibits the activity of mitochondrial enzyme monoamine oxidase, and it elevates the activity of tyrosine hydroxylase to increase extracellular dopamine levels (Fleckenstein et al 2007;Hyman et al 2006;Meyer et al 2013;Nickell et al 2014). Nevertheless, the mechanisms underlying methamphetamine addiction have not been clarified.…”

The Vesicular Monoamine Transporter-2

“…For example, GZ-793A was 50-fold selective for inhibiting VMAT2 function over DAT or SERT, suggesting that GZ-793A would have low abuse liability at relevant doses. Importantly, GZ-793A inhibited METH-evoked DA release from superfused striatal slices (Horton, Siripurapu, Zheng, et al, 2011), and GZ-793A reduced the duration of the METH-induced increase in extracellular DA in nucleus accumbens in microdialysis studies (Meyer et al, 2013). Taking a more molecular approach, GZ-793A was found recently to inhibit METH-evoked DA release from isolated striatal synaptic vesicles via a surmountable allosteric inhibition and to interact with VMAT2 at several distinct sites on the protein, both extravesicular and intravesicular (Horton, Nickell, Zheng, Crooks, & Dwoskin, 2013).…”

Corticosterone enhances N-methyl-d-aspartate receptor signaling to promote isolated ventral tegmental area activity in a reconstituted mesolimbic dopamine pathway

“…Briefly, binding was carried out after 21 days of culturing to match the in vitro aging cultures employed in drug exposure studies (below). High pressure liquid chromatography (HPLC) analysis of extracellular dopamine in co-cultures was assessed after Meyer et al (2013) without modification, with the exception that 1 mL of artificial cerebrospinal fluid was placed on top of each insert for collected 45 minutes prior stabilization for HPLC analysis. In addition, immunohistochemistry for tyrosine hydroxylase (the rate limiting enzyme in the synthesis of dopamine) and myelin basic protein (to stain myelinated axon fibers) was also conducted on control-treated co-cultures.…”