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Investigation of the adenosine A(2A) receptor on the enhanced rewarding effects of nicotine and dopamine D2 receptor signaling in a novel heritable model of drug abuse vulnerability Seth E. Turney, Loren D. Peeters, Olivia A. Jennings, Liza J. Wills, Russell W. Brown Many years ago, our laboratory along with a collaborator established that neonatal treatment of the dopamine (DA)D2-like receptor agonist quinpirole (NQ) to rats induces an increase in DAD2 receptor sensitivity throughout the animal’s lifetime, which has validity to schizophrenia (SZ) and a number of clinical conditions. These clinical conditions, which include SZ but also bipolar disorder, obsessive-compulsive disorder, panic disorder, and major depression all demonstrate increased drug abuse vulnerability, especially to cigarette smoking. Based on this permanent change in DAD2 sensitivity, we bred NQ-treated male and female rats with their NQ-treated or neonatal saline (NS)-treated counterparts. This F1 generation also demonstrated increases in DAD2 signaling, both behaviorally as well as through DAD2 signaling mechanisms. We have shown both d enhanced behavioral responding to nicotine on the conditioned place preference (CPP) and behavioral sensitization paradigms. These F1 offspring of NQ-treated rats also demonstrated increases of G-protein dependent and G-protein independent DAD2 signaling. Interestingly, the adenosine A(2A) receptor forms a mutual inhibitory heteromer with the DAD2 receptor. Adenosine is a known neuromodulator that can increase or decrease synaptic transmission in the brain, and there exists a hypothesis that adenosine dysfunction is the primary system which is disrupted in SZ which leads to changes in the dopamine and other neurotransmitter systems. The drug CGS 21680, an A(2A) agonist which stimulates the A(2A) receptor, is known to decrease DAD2 signaling and has been shown to block nicotine behavioral sensitization. A major focus in this project is on the adenosine A(2A) receptor as a novel pharmacological treatment target, since it is known that antipsychotic drugs which are often used to treat SZ and these other clinical conditions which have increased DAD2 signaling produce deleterious side effects, and novel medications are needed. Results here revealed that a 0.09 mg/kg dose of CGS 21680 was effective to block enhanced nicotine CPP and changes in DAD2 G-protein independent signaling in F1 generation rats. Interestingly, CGS 21680 did not affect G-protein dependent signaling in F1 generation animals, suggesting that the mechanism through which it is working may not be through the traditional DAD2 signaling mechanism. Future work is designed to analyze underlying mechanisms of this effect. |
