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A decrease in dopamine D2 receptor (D2R) binding in the striatum is one of the most common findings in disorders that involve a dysregulation of motivation, including obesity, addiction and attention deficit hyperactivity disorder. As disruption of D2R signaling in the ventral striatum-including the nucleus accumbens (NAc)-impairs motivation, we sought to determine whether potentiating postsynaptic D2R-dependent signaling in the NAc would improve motivation. In this study, we used a viral vector strategy to overexpress postsynaptic D2Rs in either the NAc or the dorsal striatum. We investigated the effects of D2R overexpression on instrumental learning, willingness to work, use of reward value representations and modulation of motivation by reward associated cues. Overexpression of postsynaptic D2R in the NAc selectively increased motivation without altering consummatory behavior, the representation of the value of the reinforcer, or the capacity to use reward associated cues in flexible ways. In contrast, D2R overexpression in the dorsal striatum did not alter performance on any of the tasks. Thus, consistent with numerous studies showing that reduced D2R signaling impairs motivated behavior, our data show that postsynaptic D2R overexpression in the NAc specifically increases an animal's willingness to expend effort to obtain a goal. Taken together, these results provide insight into the potential impact of future therapeutic strategies that enhance D2R signaling in the NAc. [ABSTRACT FROM AUTHOR]

A common polymorphism (val158met) in the gene encoding catechol-O-methyltransferase (COMT) has been shown to affect dopamine (DA) tone in cortex and cortical functioning. D1 receptors are the main DA receptors in the cortex, and studies have shown that decreased levels of cortical DA are associated with upregulation of D1 receptor availability, as measured with the positron-emission tomography (PET) radiotracer [11C]NNC112. We compared [11C]NNC 112 binding in healthy volunteers homozygous for the Val allele compared with Met carriers. Subjects were otherwise matched for parameters known to affect [11C]NNC 112 binding. Subjects with Val/Val alleles had significantly higher cortical [11C]NNC 112 binding compared with Met carriers, but did not differ in striatal binding. These results confirm the prominent role of COMT in regulating DA transmission in cortex but not striatum, and the reliability of [11C]NNC 112 as a marker for low DA tone as previously suggested by studies in patients with schizophrenia.Molecular Psychiatry (2008) 13, 821–827; doi:10.1038/mp.2008.19; published online 4 March 2008 [ABSTRACT FROM AUTHOR]