PDF(Pubmed)
Abstract：
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.
摘要：
社会心理和环境因素，包括自然奖励的损失，增加了药物滥用的风险。奖励损失是通过从社交或性接触中移除动物来建模的，从富裕住房向贫困住房的转移，或者限制食物。我们先前表明，食物限制会增加滥用药物的无条件奖励作用和药物配对环境的条件刺激作用。机制研究提供了基础多巴胺（DA）传播减少的证据，D1DA受体刺激下游信号的适应性上调，伏隔核（NAc）的中等多刺神经元（MSN）中的钙通透性AMPA受体（CP-AMPAR）的突触升级和掺入。这些发现与仍在发展中的药物滥用的“奖励不足”假说相一致。本研究测试了已知会增加DA利用率的复合自然奖励是否，环境富集，会阻止可卡因条件性位置偏爱（CPP）的持续表达，否则在食物限制的大鼠中观察到，以及机械基础。因为几乎所有先前关于食物限制和环境富集对可卡因CPP的影响的调查都是在雄性啮齿动物中进行的，本研究包括两种性别.结果表明，环境富集限制了CPP表达的持久性，D1R下游的信号减少，并降低了食物受限男性的NAcMSN中自发兴奋性突触后电流（EPSC）的幅度和频率，但不是女性，大鼠。环境富集未能显着降低食物限制诱导的CP-AMPAR的突触插入，讨论了这可能与先前的药理学发现相符，即阻断CP-AMPAR逆转了食物限制的行为效应。此外,据推测，DA释放的发情周期依赖性波动，受体密度和MSN兴奋性可能掩盖了环境富集过程中DA信号增强的影响，从而干扰男性产生的细胞和行为效应的发展。
