Dopamine signaling in reward-related behaviors

Abstract

Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DA mesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural reward such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.

Keywords: dopamine; dopamine receptor; drug addiction; food reward; reward circuit.

FIGURE 1

D1 receptor-mediated ERK activation signaling pathway. D1 receptor-mediated ERK singling involves interaction with the NMDA glutamtate receptor (see text), which is expressed predominantly in the striatum. The stimulation of D1 receptors is not able to mediate ERK phosphorylation per se, but rather requires endogenous glutamate (Pascoli et al., 2011). Stimulation of D1 receptors increases calcium influx through NMDA receptors, which involves phosphorylation of the NMDA receptor NR2B subunit by a Src-family tyrosine kinase (Pascoli et al., 2011). This increased calcium influx activates a number of signaling pathways, including calcium and calmodulin-dependent kinase II (CamKII), which can activate ERK via the Ras-Raf-MEK cascade (Fasano et al., 2009; Shiflett and Balleine, 2011; Girault, 2012). Upon D1 receptor activation, activated PKA can mediate phosphorylation of DARPP-32 and phosphorylated DARPP-32 can act as potent inhibitor of the protein phosphatase (PP-1), which dephosphorylates another phosphatase, the striatal-enriched tyrosine phosphatase (STEP). Dephosphorylation of STEP activates its phosphatase activity, thus allowing STEP to dephosphorylate ERK. DARPP-32 also acts upstream of ERK, possibly by inhibiting PP-1, which prevents PP-1 from dephosphorylating MEK, the upstream kinase of ERK. Thus, D1 receptor activation increases ERK phosphorylation by preventing its dephosphorylation by STEP, but also by preventing the dephosphorylation of the upstream kinase of ERK, indicating that D1 receptor-mediated ERK activation involved a complex regulation by phosphatases and kinases in addition to the cross talk with glutamate receptor signaling. Phosphorylation status is only notified for DARPP32 and STEP in this figure.

FIGURE 2

D2 receptor-mediated ERK activation signaling pathway. D2 receptor-mediated ERK activation is dependent on Gα_i protein coupling. It also appears that D2 receptor-mediated ERK activation requires the transactivation of receptor tyrosine kinase, which consequently activates downstream signaling involving matrix metalloproteinases (MMPs) with ectodomain shedding of EGFR ligand, for example, to finally activate ERK (Choi et al., 1999; Kim et al., 2004; Wang et al., 2005; ). The involvement of arrestin has also been suggested to contribute to D2 receptor-mediated ERK activation (Beom et al., 2004; Kim et al., 2004), which can activate MAPK signaling by mobilizing clathrin-mediated endocytosis in a β-arrestin/dynamin-dependent manner (Kim et al., 2004).