Accumbens dopamine D2 receptors increase motivation by decreasing inhibitory transmission to the ventral pallidum

• Published in: Nature communications 2018-03, Vol.9 (1), p.1086-13, Article 1086
• Main Authors: Gallo, Eduardo F., Meszaros, Jozsef, Sherman, Jeremy D., Chohan, Muhammad O., Teboul, Eric, Choi, Claire S., Moore, Holly, Javitch, Jonathan A., Kellendonk, Christoph
• Format: Article
• Language: English
• Subjects: 13/44; 13/51; 14/19; 14/35; 42; 631/378/1662; 631/378/3920; 631/378/87; 64/110; 64/60; 9/74; Animals; Basal Forebrain - metabolism; Brain; Brain slice preparation; Dopamine; Dopamine D2 receptors; Female; Humanities and Social Sciences; Inhibitory Postsynaptic Potentials; Male; Mice, Inbred C57BL; Motivation; Motivation - physiology; multidisciplinary; Neostriatum; Neurons; Neurons - metabolism; Nucleus accumbens; Nucleus Accumbens - metabolism; Pallidum (ventral); Receptors; Receptors, Dopamine D2 - metabolism; Science; Science (multidisciplinary); Spiny neurons; Up-Regulation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03272-2

Dopamine D2 receptors (D2Rs) in the nucleus accumbens (NAc) regulate motivated behavior, but the underlying neurobiological mechanisms remain unresolved. Here, we show that selective upregulation of D2Rs in the indirect pathway of the adult NAc enhances the willingness to work for food. Mechanistic studies in brain slices reveal that D2R upregulation attenuates inhibitory transmission at two main output projections of the indirect pathway, the classical long-range projections to the ventral pallidum (VP), as well as local collaterals to direct pathway medium spiny neurons. In vivo physiology confirms the reduction in indirect pathway inhibitory transmission to the VP, and inhibition of indirect pathway terminals to VP is sufficient to enhance motivation. In contrast, D2R upregulation in the indirect pathway does not disinhibit neuronal activity of the direct pathway in vivo. These data suggest that D2Rs in ventral striatal projection neurons promote motivation by weakening the canonical output to the ventral pallidum. Dopamine D2 receptor activity in the nucleus accumbens is associated with regulation of motivated responding. Here the authors show that overexpression of D2 receptors specifically in ventral striatal projection neurons leads to an increase in the willingness to work by reducing inhibitory transmission to ventral pallidal neurons.