Activation of dopamine D4 receptors in the nucleus accumbens shell increases motivation for palatable food and homeostatic feeding, whereas systemic blockade reduces feeding behavior in rats

Abstract

Objective The nucleus accumbens shell is a key region involved in motivation and reinforcement behavior associated with the consumption of palatable foods. However, it has not been studied whether D4 dopaminergic receptors regulate homeostatic feeding and reward-dependent behaviors. The objective of this study was to evaluate the effects of activation of D4 dopaminergic receptors within nucleus accumbens shell and systemic D4 blockade on motivation for palatable food and homeostatic feeding in male Wistar rats. Methods Adult male Wistar rats were tested in operant conditioning paradigms using sucrose pellets under fixed-ratio (FR1 and FR5) and progressive-ratio schedules to assess motivation for palatable food. Homeostatic feeding was evaluated by measuring standard chow intake in satiated rats during the first hour of the dark phase. Using stereotaxic surgery, a unilateral guide cannula was implanted into the NAcSh for the microinjection of the selective D4R agonist PD-168,077 (0.1 μg) and the D4R antagonist L-745,870 (0.1 μg). Additionally, PD-168,077 (1 mg/kg, i.p.) and L-745,870 (0.1 mg/kg, i.p.) were administered systemically. Lever presses, reinforcers earned, breakpoint, and chow intake were recorded. Results Intra-nucleus accumbens shell injection of PD-168,077 significantly increased motivation for palatable food, as reflected by greater lever pressing, reinforcers earned, and breakpoint, and increased standard chow intake. These effects were abolished by local pretreatment with L-745,870. Systemic administration of L-745,870 reduced both chow intake and operant responding for palatable food, decreasing lever pressing and breakpoint. Conclusion Dopamine D4 receptors in the nucleus accumbens shell promote both motivational and consummatory aspects of feeding. In contrast, systemic D4 receptor blockade suppresses homeostatic feeding and motivation for palatable food, supporting an important role for D4 receptors in the regulation of feeding behavior.