The antipsychotic-like effects of positive allosteric modulators of metabotropic glutamate mGlu4 receptors in rodents

Br J Pharmacol. 2013 Aug;169(8):1824-39. doi: 10.1111/bph.12254.

Abstract

Background and purpose: Because agonists at metabotropic glutamate receptors exert beneficial effects in schizophrenia, we have assessed the actions of Lu AF21934 and Lu AF32615, two chemically distinct, selective and brain-penetrant positive allosteric modulators (PAMs) of the mGlu4 receptor, in several tests reflecting positive, negative and cognitive symptoms of schizophrenia in rodents.

Experimental approach: Hyperactivity induced by MK-801 or amphetamine and head twitches induced by 2,5-dimethoxy-4-iodoamphetamine (DOI) in mice were used as models for positive symptoms. Disruption of social interaction and spatial delayed alternation tests induced by MK-801 in rats were used as models for negative and cognitive symptoms of schizophrenia, respectively.

Key results: Lu AF21934 (0.1-5 mg·kg(-1) ) and Lu AF32615 (2-10 mg·kg(-1) ) dose-dependently inhibited hyperactivity induced by MK-801 or amphetamine. They also antagonized head twitches and increased frequency of spontaneous excitatory postsynaptic currents (EPSCs) in brain slices, induced by DOI. In mice lacking the mGlu4 receptor (mGlu4 (-/-) ) mice, Lu AF21934 did not antagonize DOI-induced head twitches. MK-801-induced disruption in the social interaction test was decreased by Lu AF21934 at 0.5 mg·kg(-1) and by Lu AF32615 at 10 mg·kg(-1) . In the delayed spatial alternation test, Lu AF21934 was active at 1 and 2 mg·kg(-1) , while Lu AF32615 was active at 10 mg·kg(-1) .

Conclusions and implications: We propose that activation by PAMs of the mGlu4 receptor is a promising approach to the discovery of novel antipsychotic drugs.

Keywords: Lu AF21934; Lu AF32615; mGlu receptors; positive allosteric modulation; schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Amphetamine
  • Anilides / pharmacology*
  • Animals
  • Antipsychotic Agents / pharmacology*
  • Cyclohexanecarboxylic Acids / pharmacology*
  • Disease Models, Animal
  • Dizocilpine Maleate
  • Dose-Response Relationship, Drug
  • Excitatory Postsynaptic Potentials / drug effects
  • Hyperkinesis / drug therapy
  • Male
  • Mice
  • Motor Activity / drug effects
  • Rats
  • Receptors, Metabotropic Glutamate / drug effects*
  • Schizophrenia / chemically induced
  • Schizophrenia / drug therapy*

Substances

  • Anilides
  • Antipsychotic Agents
  • Cyclohexanecarboxylic Acids
  • N1-(3,4-dichlorophenyl)-cyclohexane-1,2-dicarboxamide
  • Receptors, Metabotropic Glutamate
  • Dizocilpine Maleate
  • Amphetamine