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

J Neurochem. 2013 Oct;127(2):187-98. doi: 10.1111/jnc.12373. Epub 2013 Aug 20.


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.

Keywords: GZ-793A; VMAT2; dopamine; lobeline; methamphetamine; microdialysis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • Animals
  • Aromatic Amino Acid Decarboxylase Inhibitors
  • Brain Chemistry / drug effects
  • Chromatography, High Pressure Liquid
  • Data Interpretation, Statistical
  • Dihydroxyphenylalanine / metabolism
  • Dopa Decarboxylase / metabolism
  • Dopamine / biosynthesis
  • Dopamine / metabolism*
  • Dopamine Uptake Inhibitors / antagonists & inhibitors*
  • Electrochemistry
  • Extracellular Space / drug effects
  • Extracellular Space / metabolism
  • Lobeline / analogs & derivatives*
  • Lobeline / pharmacology
  • Male
  • Methamphetamine / antagonists & inhibitors*
  • Microdialysis
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Tyrosine 3-Monooxygenase / metabolism
  • Vesicular Monoamine Transport Proteins / antagonists & inhibitors*


  • Aromatic Amino Acid Decarboxylase Inhibitors
  • Dopamine Uptake Inhibitors
  • N-(1,2-dihydroxylpropyl)-2,6-di-(4-methoxyphenethyl)piperidine
  • Slc18a2 protein, rat
  • Vesicular Monoamine Transport Proteins
  • 3,4-Dihydroxyphenylacetic Acid
  • Methamphetamine
  • Dihydroxyphenylalanine
  • Lobeline
  • Tyrosine 3-Monooxygenase
  • Dopa Decarboxylase
  • Dopamine