Effects of VMAT 2 inhibitors lobeline and GZ ‐793A on methamphetamine‐induced changes in dopamine release, metabolism and synthesis in vivo

• Published in: Journal of neurochemistry 2013-10, Vol.127 (2), p.187-198
• Main Authors: Meyer, Andrew C., Neugebauer, Nichole M., Zheng, Guangrong, Crooks, Peter A., Dwoskin, Linda P., Bardo, Michael T.
• Format: Article
• Language: English
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12373

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 ‐(1,2 R ‐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. image 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.