Grants and Contracts Details
Relapse and neurodegeneration are two major therapeutic targets in medications development for methamphetamine (Meth) abuse, however no FDA-approved pharmacotherapy exists for either. Although several compounds have been investigated in humans, only a limited number have shown promise as anti-relapse agents, and among these, evidence for neuroprotection is lacking. The role of glutamate in conditioning and neurotoxicity following Meth use suggests that glutamate receptor inhibition may be an effective strategy to impact both relapse and neurotoxicity. NMDAr antagonism reverses Meth toxicity, and positively impacts responding for psychostimulants in preclinical models of reward and reinstatement. The subpopulation of NMDArs containing NR2B subunits have been identified as valuable pharmacological targets; NR2B-specific antagonists positively impact reward and reinstatement behaviors for other drugs of abuse, and attenuate neurotoxicity following methamphetamine exposure. Recently, new NR2B antagonists which are well-tolerated in humans have become available, potentially yielding compounds which may simultaneously reduce Meth toxicity, and promote abstinence. Aim 1 will test the hypothesis that NR2B-specific antagonists can mitigate toxic effects of Meth, using an organotypic corticostriatal slice culture model. Two compounds will be explored: Ro 25-6981 and CP-1O1 606, both of which inhibit dissociable subpopulations of NR2B- containing NMDArs. Cell death & damage will be indexed by fluorescing propidium iodide, added to some cultures, and cell survival will be indexed via NeuN immunoreactivity. Aim 2 will test the hypothesis that NR2B subunit-specific antagonism can reduce behavioral indices of relapse and craving following Meth administration. To this end we will employ two iterations of the conditioned place preference (CPP) paradigm, examining both conditioning and reinstatement of CPP. The experiment will also allow for the investigation of behavioral sensitization following repeated Meth administrations. It is hypothesized that Ro 25- 6981 and CP-101 ,606 will both attenuate reinstatement, conditioning, and sensitization to Meth. Support for either of these hypotheses will contribute to current medications development for Meth abuse, and would be particularly exciting since compounds tested within this proposal are already being used clinically, eliminating many barriers which might normally impede future clinical investigation.
|Effective start/end date||9/30/10 → 2/28/14|
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.