Involvement of dopamine D3 receptor in impulsive choice decision-making in male rats

• Published in: Neuropharmacology Vol. 257; p. 110051
• Main Authors: Shen, Hui, Ma, Zilu, Hans, Emma, Duan, Ying, Bi, Guo-Hua, Chae, Yurim C., Bonifazi, Alessandro, Battiti, Francisco O., Newman, Amy Hauck, Xi, Zheng-Xiong, Yang, Yihong
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2024
• Subjects: Animals; Choice Behavior - drug effects; Choice Behavior - physiology; D3 receptor; D3 receptor agonist; D3 receptor antagonist; Decision Making - drug effects; Decision Making - physiology; Decision-making; Delay Discounting - drug effects; Delay Discounting - physiology; Dopamine; Dopamine Antagonists - pharmacology; FOB02-04; Impulsive Behavior - drug effects; Impulsive Behavior - physiology; Impulsive choice; Impulsivity; Male; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1 - antagonists & inhibitors; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - metabolism; Receptors, Dopamine D3 - metabolism; Reward; Reward delay discounting task; VK4-116; Decision-making; D3 receptor; Impulsivity; Dopamine; D3 receptor antagonist; Reward delay discounting task; Impulsive choice; D3 receptor agonist; FOB02-04; VK4-116
• ISSN: 0028-3908; 1873-7064; 1873-7064
• DOI: 10.1016/j.neuropharm.2024.110051

Impulsive decision-making has been linked to impulse control disorders and substance use disorders. However, the neural mechanisms underlying impulsive choice are not fully understood. While previous PET imaging and autoradiography studies have shown involvement of dopamine and D2/3 receptors in impulsive behavior, the roles of distinct D1, D2, and D3 receptors in impulsive decision-making remain unclear. In this study, we used a food reward delay-discounting task (DDT) to identify low- and high-impulsive rats, in which low-impulsive rats exhibited preference for large delayed reward over small immediate rewards, while high-impulsive rats showed the opposite preference. We then examined D1, D2, and D3 receptor gene expression using RNAscope in situ hybridization assays. We found that high-impulsive male rats exhibited lower levels of D2 and D3, and particularly D3, receptor expression in the nucleus accumbens (NAc), with no significant changes in the insular, prelimbic, and infralimbic cortices. Based on these findings, we further explored the role of the D3 receptor in impulsive decision-making. Systemic administration of a selective D3 receptor agonist (FOB02-04) significantly reduced impulsive choices in high-impulsive rats but had no effects in low-impulsive rats. Conversely, a selective D3 receptor antagonist (VK4-116) produced increased both impulsive and omission choices in both groups of rats. These findings suggest that impulsive decision-making is associated with a reduction in D3 receptor expression in the NAc. Selective D3 receptor agonists, but not antagonists, may hold therapeutic potentials for mitigating impulsivity in high-impulsive subjects. •Impulsive choice decision is linked to impulse control disorders (ICDs), but its neural mechanisms are unclear.•High-impulsive rats showed reduced dopamine D1, D2, and particularly D3, receptor gene expression in the nucleus accumbens.•D3 receptor activation by FOB02-04 reduced impulsive choice in high-impulsive rats.•D3 receptor blockade by VK4-114 increased impulsive and omission choices.•Findings suggest a role of D3 receptor in ICDs, with selective D3 agonists holding therapeutic potentials.