Recent studies in Dr. Conn's laboratory suggest that potentiators of the metabotropic glutamate receptor mGluR5 may provide a novel approach for the treatment of the psychotic symptoms and cognitive impairments observed in individuals with schizophrenia. In particular, these mGluR5 potentiators do not activate the mGluR5 receptor directly, but dramatically potentiate the response to glutamate. The proposal involves the characterization of the cellular physiology, functional brain penetrance and in vivo efficacy of the selective mGluR5 allosteric potentiator CDPPB. In the initial studies, we will determine whether CDPPB potentiates synaptic responses to mGluR5 activation in the pyramidal cells of the CA1 region of the hippocampus, a brain region implicated in the pathophysiology of schizophrenia. Next we will determine the in vivo receptor occupancy of CDPPB in order to understand the functional brain penetrance of this compound. Based on these occupancy studies, we will select doses and time points for further characterization of CDPPB in several behavioral models predictive of antipsychotic activity and enhancement of cognition. ? ? ?
| Brady, Ashley E; Jones, Carrie K; Bridges, Thomas M et al. (2008) Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats. J Pharmacol Exp Ther 327:941-53 |
