Modulation of brain reward circuitry by exposure to stimulants during development

有大量证据表明，反复接触精神兴奋剂药物会使动物对它们的奖励作用更加敏感，更容易上瘾。然而，我们已经表明，在青春期暴露于兴奋剂使药物滥用在以后的生活中回报减少。由于大脑发育涉及神经化学，解剖学和分子适应的复杂相互作用，因此在生命早期给予兴奋剂可能具有独特的神经生物学效应，尚未完全表征，这可能是导致滥用药物成瘾性降低的原因。拟议的研究计划将检验这一假设，即在生命早期有一段时间，暴露于兴奋剂药物会引起行为和分子变化，这些变化与成年期首次暴露于兴奋剂的受试者所观察到的变化不同。这些实验将研究兴奋剂药物对发育中大脑的奖励回路的持久影响。在所有实验中，大鼠在不同发育期将用刺激剂或盐水（溶剂）预处理。随后，将通过完善的行为模型和神经生物学方法在系统，细胞和分子水平上评估大脑奖励功能。查明防止反复接触毒品的影响的具体机制，例如通过减少毒品的奖赏价值，为开发吸毒成瘾的合理治疗方法提供了一个非常有希望的途径。

There is much evidence to suggest that repeated exposure to psychostimulant drugs makes animals more sensitive to their rewarding effects and more vulnerable to addiction. However, we have shown that exposure to stimulants during the peripubertal period makes drugs of abuse less rewarding later in life. Because brain development involves a complex interplay of neurochemical, anatomical, and molecular adaptations, it is possible that stimulant administration early in life has distinct neurobiological effects, not yet fully characterized, which may be responsible for a decreased vulnerability to the addictive properties of abused drugs. The proposed program of research will test the hypothesis that there is a period early in life during which exposure to stimulant drugs induces behavioral and molecular changes that are different from those observed in subjects first exposed to stimulants during adulthood. The experiments outlined will investigate the lasting effects that stimulant drugs have on the reward circuitry of developing brains. In all experiments, rats will be pretreated with stimulants or saline (vehicle) during different developmental periods. Later on, brain reward function will be assessed by means of well-established behavioral models and neurobiological methods at the system, cellular, and molecular levels. The identification of specific mechanisms that protect against the effects of repeated exposure to drugs, for example, by diminishing the reward value of drugs, provides a highly promising avenue for developing rational treatments for drug addiction.