Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation

Molecular Psychiatry (2013) 18, 10251033& 2013 Macmillan Publishers Limited All rights reserved 1359-4184/13

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ORIGINAL ARTICLE

Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation

P Trilieff1,2, B Feng3, E Urizar3, V Winiger1, RD Ward1,3, KM Taylor3, D Martinez2,3, H Moore2,3, PD Balsam2,3,4, EH Simpson2,3 and JA Javitch2,3,5

A decrease in dopamine D2 receptor (D2R) binding in the striatum is one of the most common ndings in disorders that involve a dysregulation of motivation, including obesity, addiction and attention decit hyperactivity disorder. As disruption of D2R signaling in the ventral striatumincluding 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 exible 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 specically increases an animals 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.

Molecular Psychiatry (2013) 18, 10251033; doi:http://dx.doi.org/10.1038/mp.2013.57

Web End =10.1038/mp.2013.57 ; published online 28 May 2013

Keywords: dopamine; D2 receptor; motivation; nucleus accumbens; reward; viral vector

INTRODUCTIONThe mesoaccumbens dopamine (DA) pathway modulates motivation.13 In the nucleus accumbens (NAc), DA mediates its effects through D1- and D2-like receptors. A decrease in D2 receptor (D2R) availability in the striatum, including the NAc, is a common imaging phenotype in disorders that involve the dysregulation of motivation, including obesity,4 addiction5 and attention decit hyperactivity disorder.6 Moreover, imaging studies in human subjects have shown that striatal D2R levels correlate with characteristics such as sensation seeking and motivation.79 These studies clearly establish...