Reversal of Methamphetamine Induced Cognitive Deficits and mGlu Receptors

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DESCRIPTION (provided by applicant): Project Summary Meth-induced cognitive impairments observed in addicts after chronic drug use comprise a particularly serious problem in meth addiction and treatment. As such, there is a need for research efforts to develop animal models with translational relevance to the cognitive impairments observed in human meth addiction. Preclinical animal models reveal long-lasting impairments in recognition memory in rats. Specifically, high dose non-contingent meth injections can produce neurotoxicity and disrupt performance on memory tasks. Most object recognition studies have used short term, non-contingent drug delivery approaches to study the impact of meth on recognition memory. Intravenous meth self-administration offers a translational approach as a model of human meth addiction and the impact of chronic meth on cognitive function. The preliminary research shows that contingent long-access meth causes deficits in recognition memory, and that meth intake correlates with this memory deficit 24 hrs later. One purpose of this proposal is to determine whether these deficits in recognition memory involve a glutamatergic mechanism. In order to reverse meth-induced deficits in recognition memory, Specific Aim 1 will use a metabotropic glutamate receptor (mGluR) 2/3 agonist during acquisition of novel object recognition and Specific Aim 2 will use a mGluR5 positive allosteric modulator. Additionally, the experiments in this proposal will identify meth-induced changes in mGluR 2/3 and 5 expression in brain areas related to meth addiction (i.e., nucleus accumbens, dorsal striatum, and prefrontal cortex) and recognition memory (i.e., perirhinal cortex and hippocampus) following abstinence from long- access daily meth. Meth intake, object recognition scores, and receptor levels will be examined for correlations and predictive relationships. Identifying such relationships will provide new insights into meth- induced cognitive deficits, elucidate underlying neuronal mechanisms, and help identify possible therapeutic interventions in this animal model. PUBLIC HEALTH RELEVANCE: Project Narrative The overall purpose of these studies is to determine the relationships between motivated meth-taking behavior over time, meth-induced cognitive impairments, and the underlying neural mechanisms. The use of a translational animal model of meth addiction allows for the study of cognitive and motivational deficits that are manifested in meth addiction. Additionally, identification of neural mechanisms involved with this translational model may help identify promising new pharmacotherapeutic targets for meth-induced cognitive deficits.