Preclinical Laboratory, Department of Adult Psychiatry and Psychotherapy, Psychiatric University Clinic and University of Zurich, Zurich, Switzerland.
Zurich Neuroscience Center, University of Zurich and ETH, Zurich, Switzerland.
Transl Psychiatry. 2024 Sep 7;14(1):363. doi: 10.1038/s41398-024-03081-w.
Reward processing dysfunctions e.g., anhedonia, apathy, are common in stress-related neuropsychiatric disorders including depression and schizophrenia, and there are currently no established therapies. One potential therapeutic approach is restoration of reward anticipation during appetitive behavior, deficits in which co-occur with attenuated nucleus accumbens (NAc) activity, possibly due to NAc inhibition of mesolimbic dopamine (DA) signaling. Targeting NAc regulation of ventral tegmental area (VTA) DA neuron responsiveness to reward cues could involve either the direct or indirect-via ventral pallidium (VP)-pathways. One candidate is the orphan G protein-coupled receptor GPR52, expressed by DA receptor 2 NAc neurons that project to VP. In mouse brain-slice preparations, GPR52 inverse agonist (GPR52-IA) attenuated evoked inhibitory postsynaptic currents at NAc-VP neurons, which could disinhibit VTA DA neurons. A mouse model in which chronic social stress leads to reduced reward learning and effortful motivation was applied to investigate GPR52-IA behavioral effects. Control and chronically stressed mice underwent a discriminative learning test of tone-appetitive behavior-sucrose reinforcement: stress reduced appetitive responding and discriminative learning, and these anticipatory behaviors were dose-dependently reinstated by GPR52-IA. The same mice then underwent an effortful motivation test of operant behavior-tone-sucrose reinforcement: stress reduced effortful motivation and GPR52-IA dose-dependently restored it. In a new cohort, GRAB-sensor fibre photometry was used to measure NAc DA activity during the motivation test: in stressed mice, reduced motivation co-occurred with attenuated NAc DA activity specifically to the tone that signaled reinforcement of effortful behavior, and GPR52-IA ameliorated both deficits. These findings: (1) Demonstrate preclinical efficacy of GPR52 inverse agonism for stress-related deficits in reward anticipation during appetitive behavior. (2) Suggest that GPR52-dependent disinhibition of the NAc-VP-VTA-NAc circuit, leading to increased phasic NAc DA signaling of earned incentive stimuli, could account for these clinically relevant effects.
奖赏加工功能障碍，例如快感缺失、淡漠，在与应激相关的神经精神障碍中很常见，包括抑郁症和精神分裂症，但目前尚无既定的治疗方法。一种潜在的治疗方法是恢复奖赏预期，这在与奖赏相关的行为中存在缺陷，与伏隔核（NAc）活动减弱有关，可能是由于 NAc 抑制中脑边缘多巴胺（DA）信号。靶向 NAc 调节腹侧被盖区（VTA）DA 神经元对奖赏线索的反应性，可能涉及直接途径或间接途径-通过腹侧苍白球（VP）途径。一个候选物是孤儿 G 蛋白偶联受体 GPR52，由投射到 VP 的 NAc 神经元表达的 DA 受体 2 表达。在小鼠脑切片制剂中，GPR52 反向激动剂（GPR52-IA）减弱了 NAc-VP 神经元的诱发抑制性突触后电流，这可能使 VTA DA 神经元去抑制。应用慢性社会应激导致奖赏学习和努力动机减少的小鼠模型来研究 GPR52-IA 的行为效应。对照和慢性应激小鼠接受了音调偏好行为-蔗糖强化的辨别性学习测试：应激降低了奖赏反应和辨别性学习，而 GPR52-IA 剂量依赖性地恢复了这些预期行为。相同的小鼠随后进行了操作性行为-音调-蔗糖强化的努力动机测试：应激降低了努力动机，GPR52-IA 剂量依赖性地恢复了它。在一个新的队列中，使用 GRAB-传感器光纤光度法测量动机测试期间的 NAc DA 活动：在应激小鼠中，动机降低与特定于信号努力行为强化的音调的 NAc DA 活性减弱有关，GPR52-IA 改善了这两种缺陷。这些发现：（1）证明了 GPR52 反向激动剂在与应激相关的奖赏预期缺陷方面的临床前疗效，在与奖赏相关的行为中。（2）表明 GPR52 依赖性抑制 NAc-VP-VTA-NAc 回路，导致获得性激励刺激的 NAc DA 信号的相位增加，可能解释了这些与临床相关的影响。
