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

Authors

  • Andrew C. Meyer,

    1. Department of Psychiatry, University of Vermont, Burlington, Vermont, USA
    Search for more papers by this author
    • These authors contributed equally to this work.
  • Nichole M. Neugebauer,

    1. Department of Psychiatry and Behavioral Neurosciences, University of Chicago, Chicago, Illinois, USA
    Search for more papers by this author
    • These authors contributed equally to this work.
  • Guangrong Zheng,

    1. Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
    Search for more papers by this author
  • Peter A. Crooks,

    1. Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
    Search for more papers by this author
  • Linda P. Dwoskin,

    1. Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky, USA
    Search for more papers by this author
  • Michael T. Bardo

    Corresponding author
    1. Department of Psychology, University of Kentucky, Lexington, Kentucky, USA
    • Address correspondence and reprint requests to Michael T. Bardo, Center for Drug Abuse Research Translation (CDART), BBSRB, Room 447, 741 S. Limestone, University of Kentucky, Lexington, KY 40536-0509, USA. Email: mbardo@uky.edu

    Search for more papers by this author

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, 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.

Ancillary