Modulation of brain reward circuitry by exposure to stimulants during development

有很多证据表明，反复接触精神兴奋剂药物会使动物对它们的奖励效果更敏感，更容易上瘾。然而，我们已经证明，在青春期周围接触兴奋剂会使滥用药物的人在以后的生活中得不到回报。因为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，所以在生命早期服用兴奋剂可能具有明显的神经生物学效应，但尚未完全确定，这可能是导致滥用药物成瘾特性的脆弱性降低的原因。拟议的研究计划将检验这样一种假设，即在生命早期的一段时间里，接触兴奋剂药物会引起行为和分子的变化，这些变化与成年后首次接触兴奋剂的受试者所观察到的不同。概述的实验将调查兴奋剂对发育中的大脑奖赏回路的持久影响。在所有的实验中，大鼠将在不同的发育时期用兴奋剂或生理盐水（媒介）进行预处理。随后，我们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的奖励功能。确定防止反复接触毒品的具体机制，例如通过减少毒品的奖励价值，为开发合理的药物成瘾治疗方法提供了一条非常有希望的途径。

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.