These authors contributed equally to this work.
Effects of VMAT2 inhibitors lobeline and GZ-793A on methamphetamine-induced changes in dopamine release, metabolism and synthesis in vivo
Article first published online: 20 AUG 2013
© 2013 International Society for Neurochemistry
Journal of Neurochemistry
Volume 127, Issue 2, pages 187–198, October 2013
How to Cite
J. Neurochem.(2013) 127, 187–198
- Issue published online: 4 OCT 2013
- Article first published online: 20 AUG 2013
- Accepted manuscript online: 22 JUL 2013 06:54AM EST
- Manuscript Accepted: 15 JUL 2013
- Manuscript Revised: 29 JUN 2013
- Manuscript Received: 1 FEB 2013
- National Institute on Drug Abuse. Grant Numbers: U01 DA13519, T32 DA016176, UL1TR000117
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, medial prefrontal cortex and orbitofrontal cortex. 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 striatum, whereas GZ-793A decreased synthesis; no effect of METH or GZ-793A on DA synthesis was found in medial prefrontal cortex or orbitofrontal cortex. 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.
We determined if inhibition of the vesicular monoamine transporter (VMAT2) alters METH-induced changes in dopamine (DA) release, metabolism, and synthesis in vivo. Our results suggest that selective inhibition of VMAT2 produces a time-dependent decrease in DA release as a result of alterations in tyrosine hydroxylase (TH) activity, which may play a role in the ability of the VMAT2 inhibitor GZ-793A to decrease METH reward.