Evaluating Neuro-protective Targets to Revert Cocaine Toxicity

Nilesh Tannu, Department of Psychiatry and Behavioral Sciences, University of Texas Medical School at Houston

Chronic cocaine dependence is associated with structural as well as functional changes in gray matter, including deeper structures such as dorsal and ventral striatum, and amygdale. Some of these changes persist well after abstinence, suggesting a neuro-toxic/degeneration mechanism. Cocaine activates dopamine and glutamate transmission in discrete areas of the brain, specifically the nucleus accumbens (NAc), ventral tegmental area (VTA), prefrontal cortex – regions of the mesolimbic dopamine pathway, which originates in the VTA and projects to several forebrain regions, most notably the NAc.

The learning of cocaine-associated memories involves alterations in molecular signaling with extracellular-signal regulated kinase (ERK) mitogen-activated protein kinase (MAPK) identified as a key molecular substrate for this behavior. PPARγ (peroxisome proliferator-activated receptors) and ERK complex in the cytosol of the hippocampus is disrupted upon ligand activation, suggesting that ligand activation of PPARγ regulates ERK via a protein-protein interaction. Recent studies have shown that ligand-activation of neuronal PPARγ isoform recruits hippocampal ERK activity to rescue hippocampus-dependent memory deficits. The current study will test the hypothesis that PPARγ agonists could provide neuroprotection to cocaine; this may also reduce impulsivity and improve decision-making, which would in turn reduce cocaine use in cocaine dependent subjects. The first phase will foresee analysis of NAc proteomics in rodents chronically treated with cocaine or saline. The second phase will be with two groups of rodents, one treated with cocaine alone and the second treated with cocaine plus pioglitazone. We hypothesize that the NAc biosignature from rats exposed to neuro-toxic doses of cocaine will be used as a benchmark for further studies of neuro-protection afforded by pioglitazone, and may also serve as a prognostic tool in the treatment of cocaine dependence.