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Dopamine has been implicated in value-based learning and decision making by signaling reward prediction errors and facilitating cognitive flexibility, incentive motivation, and voluntary movement. Dopamine receptors can roughly be divided into the D1 and D2 subtypes, and it has been hypothesized that these two types of receptors have an opposite function in facilitating reward-related and aversion-related behaviors, respectively. Here, we tested the contribution of striatal dopamine D1 and D2 receptors to processes underlying value-based learning and decision making in rats, employing a probabilistic reversal learning paradigm. Using computational trial-by-trial analysis of task behavior after systemic or intracranial treatment with dopamine D1 and D2 receptor agonists and antagonists, we show that negative feedback learning can be modulated through D2 receptor signaling and positive feedback learning through D1 receptor signaling in the ventral striatum. Furthermore, stimulation of D2 receptors in the ventral or dorsolateral (but not dorsomedial) striatum promoted explorative choice behavior, suggesting an additional function of dopamine in these areas in value-based decision making. Finally, treatment with most dopaminergic drugs affected response latencies and number of trials completed, which was also seen after infusion of D2, but not D1 receptor-acting drugs into the striatum. Together, our data support the idea that dopamine D1 and D2 receptors have complementary functions in learning on the basis of emotionally valenced feedback, and provide evidence that dopamine facilitates value-based and motivated behaviors through distinct striatal regions.

The development of hypothalamic obesity (HO) following craniopharyngioma (CP) and other suprasellar tumors leads to reduced patient quality of life. No treatment algorithms are currently available for management of HO. Depending on which hypothalamic nuclei are destroyed, the pathophysiologic mechanisms and clinical symptoms that contribute to HO differ among patients. Herein, we review the contribution of the hypothalamus to the pathophysiologic mechanisms and symptoms underlying CP-associated HO. Additionally, we performed a systematic search of MEDLINE and Embase to identify all intervention studies for weight management in patients with CP or other suprasellar tumors published until September 2017. The search yielded 1866 publications, of which 40 were included. Of these 40 studies, we identified four modalities for intervention (i.e., lifestyle, dietary, pharmacotherapeutic, or surgical) within six clinical domains (i.e., psychosocial disorders, hyperphagia, sleep disturbances, decreased energy expenditure, hyperinsulinemia, and hypopituitarism). We used the findings from our systematic review, in addition to current knowledge on the pathophysiology of HO, to develop an evidence-based treatment algorithm for patients with HO caused by CP or other suprasellar tumors. Although the individual effects of the HO interventions were modest, beneficial individual effects may be achieved when the pathophysiologic background and correct clinical domain are considered. These two aspects can be combined in an individualized treatment algorithm with a stepwise approach for each clinical domain. Recently elucidated targets for HO intervention were also explored to improve future management of HO for patients with CP and other suprasellar tumors.

The central melanocortin (MC) system mediates its effects on food intake via MC3 (MC3R) and MC4 receptors (MC4R). Although the role of MC4R in meal size determination, satiation, food preference, and motivation is well established, the involvement of MC3R in the modulation of food intake has been less explored. Here, we investigated the role of MC3R on the incentive motivation for food, which is a crucial component of feeding behavior. Dopaminergic neurons within the ventral tegmental area (VTA) have a crucial role in the motivation for food. We here report that MC3Rs are expressed on VTA dopaminergic neurons and that pro-opiomelanocortinergic (POMC) neurons in the arcuate nucleus of the hypothalamus (Arc) innervate these VTA dopaminergic neurons. Our findings show that intracerebroventricular or intra-VTA infusion of the selective MC3R agonist γMSH increases responding for sucrose under a progressive ratio schedule of reinforcement, but not free sucrose consumption in rats. Furthermore, ex vivo electrophysiological recordings show increased VTA dopaminergic neuronal activity upon γMSH application. Consistent with a dopamine-mediated effect of γMSH, the increased motivation for sucrose after intra-VTA infusion of γMSH was blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. Taken together, we demonstrate an Arc POMC projection onto VTA dopaminergic neurons that modulates motivation for palatable food via activation of MC3R signaling.

Stress affects eating behaviour in rodents and humans, suggesting that the regulation of energy balance and the stress response are coupled physiological processes. Neuropeptide Y (NPY) and agouti-related protein (AgRP) are potent food-stimulating neuropeptides that are highly co-localised in arcuate nucleus neurons of the hypothalamus. Recent studies have shown that NPY and AgRP mRNA levels in these neurons respond similarly to fasting and leptin, indicating functional redundancy of the neuropeptide systems in these orexigenic neurons. However, we have found that NPY and AgRP mRNA expression in arcuate nucleus neurons are dissociated immediately following a stressful event. Two hours following a brief session of inescapable foot shocks, AgRP mRNA levels are down-regulated (P< 0.0001). In contrast, NPY mRNA levels are up-regulated (P< 0.0001). To provide physiological relevance for this acute down-regulation of AgRP, an inverse agonist of melanocortin receptors, we have shown that acute intracerebroventricular injection of a melanocortin receptor agonist, α-melanocyte-stimulating hormone (α-MSH), caused a significantly stronger activation of the hypothalamus–pituitary–adrenal-cortical (HPA) axis following a stressful event than in controls. Thus, AgRP and NPY mRNA levels in similar arcuate nucleus neurons are differentially regulated following a stressful event. This may contribute to increased sensitivity for α-MSH to activate the HPA axis following a repeated stressful experience.

Summary 1. VP and OT mediate their wealth of effects via 4 receptor subtypes V1a, V1b, V2, and OT receptors.

In accord with previous studies intracerebroventricular (i.c.v.) injections of ACTH1‐24(1 μg) induced a display of excessive grooming, and increased the plasma concentrations of ACTH and corticosterone. Pituitary‐adrenal activation was blocked by pretreatment with dexamethasone, indicating that the effect of the (i.c.v.) injected peptide was not caused by a peripheral effect on the adrenal cortex.Doses of 1 and 3 μg of a non‐selective melanocortin‐3/4‐receptor antagonist (SHU 9119), or of 5 and 10 μg of a selective melanocortin‐4‐receptor antagonist ([D‐Arg8]ACTH4‐10), coadministered (i.c.v.) with 1 μg ACTH1‐24, inhibited the ACTH1‐24‐induced activation of the hypothalamus‐pituitary‐adrenal‐axis and excessive grooming.In addition, several doses of the selective melanocortin‐3‐receptor agonist Lys‐γ2‐MSH were centrally administered, but neither neuroendocrine, nor excessive grooming responses were observed.These results imply that the melanocortin‐4‐receptor, and not the melanocortin‐3‐receptor, is involved in the ACTH1‐24‐induced rise in plasma levels of ACTH and corticosterone, and excessive grooming.

Cyclic lactam analogs of α-melanocyte stimulating hormone (α-MSH) have been shown to be potent agonists in the frog skin bioassay [Al-Obeidi, F. et al., J. Med. Chem., 32 (1989) 2555], demonstrating melanocortin-1 (MC1) receptor activity. We synthesized cyclic α-MSH(1–13) and α-MSH(4–10) lactam analogs. The peptides were synthesized using Fmoc chemistry. We improved the cyclization procedure: side chains of Asp5and Lys10from the deprotected peptide were coupled in DMF to form a cyclic lactam, using an excess of PyBOP reagent and DIEA as a base. The cyclization reaction was completed within 1 h and was almost quantitative. We also synthesized an α-MSH analog cyclized via a disulphide bridge. The peptides were tested for their selectivity for the rat MC4 receptor. Cyclization and substitutions at position 7 dramatically influenced the selectivity for the rMC4 receptor.