During the present reporting period, we continued our work with methamphetamine exposure and found that a single moderately-high dose of methamphetamine causes depletion of striatal dopamine levels, decreases in tyrosine hydroxylase and dopamine turnover, and significant increases in striatal glial fibrillary acidic protein levels. In contrast, methamphetamine did not alter dopamine transporter (DAT) levels, suggesting no severe degeneration of striatal dopamine terminals. The decreases in dopamine cellular markers were also preceded by excessive release of dopamine, but not glutamate, in the ventral striatum immediately after methamphetamine administration. Importantly, these doses of methamphetamine caused dose-dependent increases in cocaine self-administration under low fixed-ratio reinforcement conditions, and a dose-dependent decrease in """"""""break-point"""""""" for cocaine self-administration under progressive-ratio reinforcement. Further, we found that methamphetamine administration dose-dependently attenuates striatal dopamine response to acute cocaine admnistration. These findings indicate that a single injection of methamphetamine causes significant depletion of ventral striatal dopamine and a reduction in striatal dopaminergic response to cocaine, which subsequently augments cocaine-taking behavior in a compensatory manner. These new findings are congruent with previous work, in which we found that methamphetamine administration increases the incentive motivational value of cocaine, as assessed using the conditioned place preference preclinical model. We also contributed major review articles to the addiction medicine literature during this this reporting period - including one on brain mechanism-based medication development for the treatment of nicotine dependence, and one on animal models of addiction. We also embarked upon a study of the anti-nicotine-addiction compound Varenicline, and found that it attenuates nicotine-enhanced brain-stimulation reward by activation of alpha-4-beta-2 nicotinic receptors in the brain. This study adds very significantly to understanding the mechanisms of action of an already-approved and already-introduced pharmacotherapy for nicotine addiction that is now widely available for prescription use by physicians in the United States. Such mechanistic knowledge can aid in the search for new and effective pharmacotherapeutic compounds for the treatment of nicotine addiction and dependence.
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