We had previously used small animal positron emission tomography (PET) neuroimaging in combination with 11C-Raclopride and fluorine-18 fluorodeoxyglucose (FDG) to examine methamphetamine-induced alterations in brain dopamine and metabolism. Adolescent laboratory rats (30 days old) received baseline microPET scans. The animals then received an injection of methamphetamine, followed by another set of microPET scans. Methamphetamine significantly increased striatal dopamine by approximately 22% and increased FDG uptake cortically, subcortically, and in the cerebellum. There were no effects of methamphetamine on occipital FDG uptake. Acute pretreatment with S-(+)-gamma-vinyl-GABA completely abolished these increases. This constitutes the first finding that racemic gamma-vinyl-GABA's effects on brain mechanisms may be due to actions of the S-(+)-gamma-vinyl-GABA enantiomer. As adults (>90 days old), the animals received another methamphetamine injection followed by microPET scanning. Adolescent exposure to S-(+)-gamma-vinyl-GABA attenuated methamphetamine-induced changes in FDG uptake in these adult animals. We also used a unqiue serial imaging strategy to obtain FDG microPET images both prior to and during the expression of methamphetamine-induced conditioned place preferences. We studied animals during both """"""""forced exposure"""""""" and """"""""free choice exposure"""""""" to the environmental cues previously associated with methamphetamine administration. We found that both types of exposure to amphetamine-paired environmental cues produced significant bilateral activations of motor cortex, temporal cortex, cerebellum, and thalamus. However, """"""""free choice exposure"""""""" preferentially activated the medial forebrain bundle and striatum, while """"""""forced exposure"""""""" preferentially activated the amygdala and sensory cortex. 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 the """"""""risk"""""""" of addiction during pain management with opioid medications, two on hypothesis-driven medication discovery for the treatment of addiction, and one on animal models of addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Intramural Research (Z01)
Project #
1Z01DA000478-04
Application #
7733814
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2008
Total Cost
$311,701
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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Xi, Zheng-Xiong; Gardner, Eliot L (2008) Hypothesis-driven medication discovery for the treatment of psychostimulant addiction. Curr Drug Abuse Rev 1:303-27
Xi, Zheng-Xiong; Gilbert, Jeremy G; Peng, Xiao-Qing et al. (2006) Cannabinoid CB1 receptor antagonist AM251 inhibits cocaine-primed relapse in rats: role of glutamate in the nucleus accumbens. J Neurosci 26:8531-6
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Luo, Feng; Xi, Zheng-Xiong; Wu, Gaohong et al. (2004) Attenuation of brain response to heroin correlates with the reinstatement of heroin-seeking in rats by fMRI. Neuroimage 22:1328-35