However one major challenge will be to understand how the
However, one major challenge will be to understand how the diverse actions of D2Rs in multipartite, dopamine-sensitive circuits are coordinated to produce specific behaviors across species. It is possible that emerging techniques for imaging neuronal activity in different neuronal population in behaving animals may illuminate patterns and temporal dynamics of D2R actions in each region (Cui et al., 2013; Gallo et al., 2018; Lemos et al., 2016).
While there are some inconsistencies between PET imaging in gamma-Glu-Cys australia disorders and preclinical work on D2Rs that must be reconciled, it is likely that D2R alterations may confer vulnerability to developing neuropsychiatric disorders and specific endophenotypes. It is also possible that D2R alterations arise after developing a disorder, as in chronic substance abuse or obesity (Friend et al., 2017). In either case, further work will be needed to understand the factors and cellular mechanisms leading to these alterations (Trifilieff et al., 2017).
Pharmacological interventions aimed at D2Rs have been effective in treating certain symptoms, but not others, and may even cause serious side effects (Wang et al., 2018). New generations of efficacious therapeutics that have minimal side effects will need to consider the widespread expression of D2Rs, as well as the heterogeneity of D2R signaling and function throughout the brain. For example, such efforts will have to account for region-specific differences in the coupling to downstream effectors, such as G proteins (Marcott et al., 2018) and their functional interactions with β-arrestins (Urs et al., 2016). The continued evolution of functionally-selective D2R ligands, aided now by the recent unveiling of the crystal structure of D2R bound by the antipsychotic risperidone (Wang et al., 2018), may offer new hope in this endeavor (Peterson et al., 2015). In striatum, the selective expression of A2ARs in D2-SPNs may be leveraged to design A2AR-based approaches aimed at counteracting the effects of decreased D2R and overactive indirect pathway function (Nunes et al., 2013).
Funding source(s) This work was supported by NIH MH107648 to E.G.
Conflicts of interest
Introduction Maternal behavior in rats involves dramatic changes in the perceptional, emotional and motivational responses of female rats towards infant rats (Numan and Young, 2016). Through mother-infant interaction, the enduring mother–infant bond (maternal bond) is formed, which drives a mother rat to display a strong preference to pups and pup-related cues over other stimuli. This maternal attraction towards pups is mediated in part by the mesolimbic and mesocortical dopamine pathways, the brain\'s reward system (Numan, 2007). Functional disturbances of these systems, such as lesions of nucleus accumbens (NAc), medial prefrontal cortex (mPFC) or ventral tegmental area (VTA) (Afonso et al., 2007; Hansen, 1994; Hansen et al., 1991; Li and Fleming, 2003; Pereira and Morrell, 2011), or disruption of connection between the medial preoptic area (MPOA) and VTA (Numan and Smith, 1984), or blockade of dopamine receptors in these regions (Keer and Stern, 1999; Numan et al., 2005), reduces active maternal responses (e.g., pup retrieval and pup licking in the home cage). Blockade of D1 and D2 receptors also prevents the development of pup-induced conditioned place preference (Fleming et al., 1994). On the other hand, stimulation of the dopamine systems by certain dopamine receptor agonists (e.g. apomorphine, quinpirole) is also disruptive (Stern and Protomastro, 2000; Zhao and Li, 2010). Thus, it appears that a balanced dopamine neurotransmission is critical for the normal expression of maternal behavior. Based on the detailed behavioral analysis of dopamine-induced alterations in maternal behavior, dopamine action on D2 receptors (possibly D1 too) exerts a regulatory control over a mother rat\'s (positively) emotional and motivation responses towards pups (Numan and Young, 2016; Zhao and Li, 2009c).