Reciprocal interactions between cocaine and GABA in the VTA of rats self-administering cocaine.

摘要

Few effective pharmacotherapies exist for treatment of cocaine addiction. Major advances in our understanding, though, have emerged from observed changes in the molecular composition of cells in brain regions involved in cocaine abuse.; The ventral tegmental area (VTA) plays a role in the reinforcing effects of most drugs of abuse, including cocaine, and consists of both dopaminergic and GABAergic cell bodies along with afferent terminals containing a variety of neurotransmitters. Dopaminergic projections from the VTA terminate in the nucleus accumbens (NAc), prefrontal cortex, and other brain regions. The primary reinforcing properties of cocaine, though, involve the dopaminergic projection from the VTA to the NAc. GABA acts as the primary inhibitory neurotransmitter in the VTA, and the GABAergic environment in the VTA has been understudied in the realm of cocaine abuse.; The first experiment examined self-administered cocaine's effects on gene expression in VTA dopaminergic cells and found changes in GABA-A subunits as well as evidence of cellular plasticity. The second experiment attempted to validate the findings of the first study at the protein level, but did not demonstrate significant alterations in GABA-A receptor protein in the VTA or its terminal regions. The discrepancy is most likely due to regional protein analysis versus single-cell mRNA analysis.; The remaining studies used behavioral pharmacology to analyze the effects of GABAergic compounds microinjected into the VTA on cocaine self-administration. Picrotoxin negatively impacted the reinforcing efficacy of cocaine in a manner similar to that previously seen with baclofen. The effects of picrotoxin on cocaine self-administration were also blocked by the GABA-B antagonists 2-hydroxysaclofen, suggesting a net effect through GABA-B receptors. Muscimol had no effect on cocaine self-administration.; The present results have implications for treatment strategies for cocaine abuse. The findings support investigations into use of GABAergic compounds for treatment, especially GABA-B agonists. All of the results presented here suggest that cocaine diminishes transmission through the GABA-A receptor on dopaminergic cells in the VTA, and stimulation of the GABA-B receptor, instead, can counteract the reinforcing properties of cocaine.