Complex effects of mGluR5 antagonism on sociability and stereotypic behaviors in mice: Possible implications for the pharmacotherapy of autism spectrum disorders

Abstract

Balb/c mice display deficits of sociability; for example, they show reduced locomotor activity in the presence of an enclosed or freely-moving social stimulus mouse. Transgenic mice with defective or diminished expression of NMDA receptors manifest impaired sociability, while a partial and full agonist of the obligatory glycine co-agonist binding site on the NMDA receptor improved sociability in the Balb/c mouse strain. Because 2-methyl-6-(phenylethynyl)-pyridine (MPEP), an antagonist of the mGluR5 metabotropic glutamate receptor (mGluR), reduced self-grooming behavior in BTBR T+tfJ (BTBR) mice, another inbred genetic mouse model of autism spectrum disorders (ASDs), and mGluR5 antagonism is emerging as an experimental treatment for the ‘fragile X syndrome,” which has a high prevalence of co-morbid ASDs, we examined the effects of MPEP on sociability and stereotypic behaviors in Balb/c and Swiss Webster mice in a standard paradigm. MPEP had complex effects on sociability, impairing some measures of sociability in both strains, while it reduced the intensity of some spontaneous measures of stereotypic behaviors emerging during free social interaction in Swiss Webster mice. Conceivably, mGluR5 antagonism exacerbates diminished endogenous tone of NMDA receptor-mediated neurotransmission in neural circuits relevant to at least some measures of sociability in Balb/c mice; the mGluR5 receptor contributes to regulation of the phosphorylation status of the NMDA receptor. In any event, although stereotypies are an important therapeutic target in ASDs, medication strategies to attenuate their severity via antagonism of mGluR5 receptors must be pursued cautiously because of their potential to worsen at least some measures of sociability.