Weiner Sydney P, Vasquez Carolina, Song Soomin, Zhao Kaiyang, Ali Omar, Rosenkilde Danielle, Froemke Robert C, Carr Kenneth D
Department of Psychiatry, New York University Grossman School of Medicine, 435 East 30th Street, New York, NY 10016, United States.
Diabetes Research Program, New York University Grossman School of Medicine, 435 East 30th Street, New York, NY 10016, United States.
Addict Neurosci. 2024 Mar;10. doi: 10.1016/j.addicn.2024.100142. Epub 2024 Jan 9.
Psychosocial and environmental factors, including loss of natural reward, contribute to the risk of drug abuse. Reward loss has been modeled in animals by removal from social or sexual contact, transfer from enriched to impoverished housing, or restriction of food. We previously showed that food restriction increases the unconditioned rewarding effects of abused drugs and the conditioned incentive effects of drug-paired environments. Mechanistic studies provided evidence of decreased basal dopamine (DA) transmission, adaptive upregulation of signaling downstream of D1 DA receptor stimulation, synaptic upscaling and incorporation of calcium-permeable AMPA receptors (CP-AMPARs) in medium spiny neurons (MSNs) of nucleus accumbens (NAc). These findings align with the still evolving 'reward deficiency' hypothesis of drug abuse. The present study tested whether a compound natural reward that is known to increase DA utilization, environmental enrichment, would prevent the persistent expression of cocaine conditioned place preference (CPP) otherwise observed in food restricted rats, along with the mechanistic underpinnings. Because nearly all prior investigations of both food restriction and environmental enrichment effects on cocaine CPP were conducted in male rodents, both sexes were included in the present study. Results indicate that environmental enrichment curtailed the persistence of CPP expression, decreased signaling downstream of the D1R, and decreased the amplitude and frequency of spontaneous excitatory postsynaptic currents (EPSCs) in NAc MSNs of food restricted male, but not female, rats. The failure of environmental enrichment to significantly decrease food restriction-induced synaptic insertion of CP-AMPARs, and how this may accord with previous pharmacological findings that blockade of CP-AMPARs reverses behavioral effects of food restriction is discussed. In addition, it is speculated that estrous cycle-dependent fluctuations in DA release, receptor density and MSN excitability may obscure the effect of increased DA signaling during environmental enrichment, thereby interfering with development of the cellular and behavioral effects that enrichment produced in males.
社会心理和环境因素，包括自然奖励的缺失，都增加了药物滥用的风险。在动物实验中，通过剥夺社交或性接触、从丰富环境转移到贫瘠环境或限制食物来模拟奖励缺失。我们之前的研究表明，食物限制会增强滥用药物的非条件奖励效应以及药物配对环境的条件性激励效应。机制研究提供了证据，表明基础多巴胺（DA）传递减少，D1 多巴胺受体刺激下游信号适应性上调，伏隔核（NAc）中中等棘状神经元（MSN）的突触放大以及钙通透性 AMPA 受体（CP-AMPARs）的整合增加。这些发现与仍在不断发展的药物滥用“奖励不足”假说相一致。本研究测试了一种已知能增加 DA 利用度的复合自然奖励——环境丰富化，是否能预防在食物受限大鼠中原本会出现的可卡因条件性位置偏好（CPP）的持续表达及其机制基础。由于几乎所有之前关于食物限制和环境丰富化对可卡因 CPP 影响的研究都是在雄性啮齿动物中进行的，本研究纳入了雌雄两性。结果表明，环境丰富化减少了 CPP 表达的持续性，降低了 D1R 下游的信号传导，并降低了食物受限雄性（而非雌性）大鼠 NAc MSN 中自发性兴奋性突触后电流（EPSCs）的幅度和频率。讨论了环境丰富化未能显著减少食物限制诱导的 CP-AMPARs 突触插入的原因，以及这如何与之前的药理学研究结果相符，即阻断 CP-AMPARs 可逆转食物限制的行为效应。此外，推测发情周期依赖性的 DA 释放、受体密度和 MSN 兴奋性波动可能掩盖了环境丰富化期间 DA 信号增加的影响，从而干扰了丰富化在雄性中产生的细胞和行为效应的发展。
