Investigating the Metabotropic Glutamate Receptor 1 Subtype for Motivational Dysfunction in Schizophrenia
Schizophrenia is a debilitating disorder that affects approximately 1% of the population. Schizophrenic patients suffer from a spectrum of symptoms that can be grouped into positive, negative, and cognitive symptom clusters. Current antipsychotics are efficacious in treating the positive symptoms, but are unable to attenuate and may even exacerbate negative symptoms. Therefore, there is a critical need to develop novel therapeutics. Substantial evidence has implicated the metabotropic glutamate receptor 1 (mGlu1) in the pathophysiology of schizophrenia. Recent data from our laboratory has demonstrated that activation of mGlu1 reduces striatal dopamine release and is efficacious in preclinical models that predict antipsychotic efficacy. Interestingly, the reductions in dopamine release seen in the striatum are not seen in other dopaminergic regions, such as the accumbens, indicating that mGlu1 may selectively modulate striatal dopamine release. Traditional antipsychotics, which reduce dopamine release in both the striatum and accumbens, have been correlated with amotivation, therefore it is critical to investigate whether mGlu1 activation influences motivated behavior. To test this hypothesis, mice have been trained on operant response paradigms that are validated assays of motivation. Our results show that activation of mGlu1 does not impair motivated behavior as assessed by traditional progressive ratio schedules and can increase selection of high effort alternatives in an effort-based decision making tasks. Taken together, these studies demonstrate that selective activation of mGlu1 is efficacious for positive symptoms and does not influence motivated behavior. Thus, targeting mGlu1 may offer promising advances that could lead to a new therapeutic approach schizophrenia.