Effect of the mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) on the acute locomotor stimulant properties of cocaine, D-amphetamine, and the dopamine reuptake inhibitor GBR12909 in mice.
BACKGROUND
Recent evidence suggests that, in addition to ascending monoaminergic systems, glutamate systems also play a role in psychostimulant-induced locomotor activity. The present study was conducted to examine the effects of the selective type-5 metabotropic glutamate receptor (mGluR5) antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) on the acute locomotor stimulant effects of cocaine, D-amphetamine, and the dopamine reuptake inhibitor GBR12909.


METHODS
Male DBA/2J mice were treated with saline or MPEP (1, 5, 20 or 30 mg/kg i.p.) 10 min prior to the administration of cocaine (15 mg/kg or 30 mg/kg i.p.), D-amphetamine (3 mg/kg or 5 mg/kg i.p.) or GBR12909 (10 mg/kg or 20 mg/kg i.p.). Locomotor activity was then monitored in an open-field environment for 30 min. The effects of MPEP alone (1, 5, 20 and 30 mg/kg i.p.) on locomotor activity were also examined.


RESULTS
MPEP dose dependently inhibited the acute locomotor stimulant effects of cocaine, D-amphetamine, and the 10-mg/kg dose of GBR12909. However, MPEP had no effect on the locomotor stimulant effects of the higher (20 mg/kg) dose of GBR12909. When tested alone, MPEP increased locomotor activity at doses of 5 mg/kg and 20 mg/kg.


CONCLUSIONS
Our data suggest that mGluR5 receptors not only mediate spontaneous locomotor activity in DBA/2J mice but also the acute locomotor stimulant effects of cocaine, D-amphetamine and lower doses of GBR12909. However, the fact that MPEP did not attenuate the locomotor stimulant effects of the high (20 mg/kg) dose of GBR12909 suggests complex interactions between metabotropic glutamate receptors, dopamine transporters and possibly other monoamines in the regulation of psychostimulant-induced locomotor activity.
Mcgeehan
Andrew J
AJ
Department of Neurology, Ernest Gallo Clinic and Research Center, University of California at San Francisco, 5858 Horton Street, Suite 200, Emeryville, CA 94608, USA.
Janak
Patricia H
PH
Olive
M Foster
MF
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D015259:Dopamine Agents / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
D014151:Anti-Anxiety Agents; D015259:Dopamine Agents; D018765:Dopamine Uptake Inhibitors; C578936:Grm5 protein, mouse; D010879:Piperazines; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C121465:6-methyl-2-(phenylethynyl)pyridine; C043425:vanoxerine; D000661:Amphetamine; D003042:Cocaine