Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425.
Salk Institute for Biological Studies, La Jolla, California 92037.
J Neurosci. 2021 May 26;41(21):4620-4630. doi: 10.1523/JNEUROSCI.1847-20.2021. Epub 2021 Mar 22.
Although cocaine is powerfully rewarding, not all individuals are equally prone to abusing this drug. We postulate that these differences arise in part because some individuals exhibit stronger aversive responses to cocaine that protect them from cocaine seeking. Indeed, using conditioned place preference (CPP) and a runway operant cocaine self-administration task, we demonstrate that avoidance responses to cocaine vary greatly between individual high cocaine-avoider and low cocaine-avoider rats. These behavioral differences correlated with cocaine-induced activation of the rostromedial tegmental nucleus (RMTg), measured using both firing and c-, whereas slice electrophysiological recordings from ventral tegmental area (VTA)-projecting RMTg neurons showed that relative to low avoiders, high avoiders exhibited greater intrinsic excitability, greater transmission via calcium-permeable AMPA receptors (CP-AMPARs), and higher presynaptic glutamate release. In behaving animals, blocking CP-AMPARs in the RMTg with NASPM reduced cocaine avoidance. Hence, cocaine addiction vulnerability may be linked to multiple coordinated synaptic differences in VTA-projecting RMTg neurons. Although cocaine is highly addictive, not all individuals exposed to cocaine progress to chronic use for reasons that remain unclear. We find that cocaine's aversive effects, although less widely studied than its rewarding effects, show more individual variability, are predictive of subsequent propensity to seek cocaine, and are driven by variations in RMTg in response to cocaine that arise from distinct alterations in intrinsic excitability and glutamate transmission onto VTA-projecting RMTg neurons.
虽然可卡因具有强大的奖赏作用，但并非所有个体都同样容易滥用这种药物。我们推测，这些差异部分源于一些个体对可卡因表现出更强的厌恶反应，从而保护他们免受可卡因的影响。事实上，通过条件性位置偏好（CPP）和跑道操作性可卡因自我给药任务，我们证明了个体高可卡因回避者和低可卡因回避者大鼠之间对可卡因的回避反应差异很大。这些行为差异与可卡因诱导的延髓头端腹侧被盖区（RMTg）激活相关，通过放电和 c-Fos 测量均可证实这一点，而来自腹侧被盖区投射到 RMTg 神经元的切片电生理记录显示，与低回避者相比，高回避者表现出更高的内在兴奋性、更高的通过钙通透性 AMPA 受体（CP-AMPAR）的传递，以及更高的突触前谷氨酸释放。在行为动物中，用 NASPM 阻断 RMTg 中的 CP-AMPAR 可减少可卡因回避。因此，可卡因成瘾易感性可能与 VTA 投射到 RMTg 神经元的多个协调的突触差异有关。尽管可卡因具有很强的成瘾性，但并非所有接触过可卡因的个体都会因不明原因发展为慢性使用。我们发现，可卡因的厌恶作用虽然不如其奖赏作用研究广泛，但表现出更大的个体变异性，可预测随后寻求可卡因的倾向，并且由 RMTg 对可卡因的反应中的变化驱动，这些变化源于内在兴奋性和谷氨酸传递到 VTA 投射到 RMTg 神经元的不同改变。
