PROJECT SUMMARY/ABSTRACT The type 5 metabotropic glutamate receptor (mGluR5) plays a critical role in various aspects of drug addiction. Pharmacological or genetic inactivation of mGluR5 receptors reduces drug reward, reinforcement, and relapselike behaviors. On the other hand, pharmacological potentiation of mGluR5 function via positive allosteric modulators (PAMs) produces pro-cognitive effects such as facilitated extinction learning and reversal of druginduced cognitive impairments. However, there are numerous challenges and limitations to pharmacological activation of mGluR5 receptors, which significantly limit their utilization as research tools for investigating receptor function in drug addiction. Such challenges include poor spatiotemporal control over receptor activation, a lack of cell-type specificity, poor selectivity of orthosteric mGluR5 agonists, and suboptimal physiochemical properties of mGluR5 PAMs. These technical challenges can be overcome by the successful development of optogenetic tools that allow for precise spatiotemporal and cell-type specific activation of mGluR5 receptor signaling. We have therefore developed and performed a preliminary characterization of a lentiviral vector that expresses light-activated mGluR5 receptor (OptoXR-mGluR5). The expression of OptoXRmGluR5 is under the control of calcium/calmodulin-dependent kinase IIa (CaMKIIa) promoter, allowing for selective expression in cortical glutamatergic neurons, and the vector also encodes enhanced yellow fluorescent protein (eYFP) reporter protein for visualization of expression. Our preliminary characterization of this lentivirus in the rat cerebral cortex in vivo demonstrates its cell-type specificity and acute light-induced activation of mGluR5 signaling. However, the effects of OptoXR-mGluR5 activation in animal models of addiction-related behaviors and cognitive dysfunction have not yet been assessed. In addition, the ability of repeated stimulation of OptoXR-mGluR5 to consistently activate mGluR5 signaling, which would be necessary for various behavioral studies, has not yet been demonstrated. Therefore, the overarching goals of the studies proposed in this application are to examine effects of acute OptoXR-mGluR5 activation on drug-induced cognitive dysfunction, and to further develop and optimize this optogenetic tool for studies involving repeated stimulation. These goals will be achieved under two independent Specific Aims. In Specific Aim 1, we will assess the ability of acute optical stimulation of OptoXR-mGluR5 receptors to reverse drug-induced cognitive dysfunction. In Specific Aim 2, we will develop novel optogenetic tools for repeated activation of mGluR5 signaling. Successful development and optimization of optogenetic tools for mGluR5 activation will allow for an unprecedented level of investigation into the role of these receptors in various aspects of drug addiction. Optogenetic tools for mGluR5 activation may also provide insight into pathophysiological mechanisms and novel therapeutic avenues for other neuropsychiatric disorders in which mGluR5 receptors are implicated, including Alzheimers disease, Fragile X syndrome, and schizophrenia.
|Effective start/end date||3/1/14 → 8/31/17|
- HHS: National Institutes of Health (NIH): $383,093.00