Basic brain mechanisms underlying drug addiction, craving, and relapse

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Due to diversion of laboratory personnel and resources to the dopamine D3 receptor, GABA, and cannabinoid research projects during the reporting period (01 Oct 06 to 30 Sept 07), only limited progress was made on this research project. During the reporting period, we 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. We also contributed 3 major review articles to the addiction medicine literature during this this reporting period - one on the "risk" of addiction during pain management with opioid medications, one on hypotheis-driven medication discovery for the treatment of psychostimulant addiction, and one on animal models of addiction.