Molecular mechanisms of amphetamine-induced behavioral sensitization

反复服用安非他明或可卡因等精神刺激剂会导致在随后的接触中对药物的行为反应增加，这一现象被称为敏化。行为敏化被认为与药物成瘾以及精神分裂症的一些精神症状有关。虽然敏化的持久性表明与中枢多巴胺系统相关的神经元属性的长期适应；然而，这些变化背后的分子机制尚不清楚。我们先前报道了苯丙胺致敏大鼠伏隔核中一种名为Synaxin-1的蛋白质水平的变化。由于Synaxin-1参与了神经递质的释放以及调节突触的可塑性，我们的工作表明，该蛋白的变化可能是致敏动物神经元变化的关键机制。在拟议的研究中，我们的目的是进一步了解Synaxin影响安非他明敏化的机制。例如，我们想知道安非他明致敏动物伏隔核内哪些神经元显示出Synaxin-1的变化，以及对该蛋白的操纵是否会影响致敏行为。此外，我们还想进一步探索安非他明的影响是否可以推广到其他精神刺激剂，如可卡因。更好地了解慢性药物使用后神经元的变化可能有助于开发新的药理药物，以防止这些药物对行为的有害影响。

Repeated administration of psychostimulants like amphetamine or cocaine results in an increased behavioral response to the drugs at subsequent exposure, a phenomenon called sensitization. Behavioral sensitization is suggested to be associated with drug addiction as well as some psychotic symptoms of schizophrenia.  The enduring nature of sensitization suggests long-term adaptations in the property of neurons associated with central dopamine systems; however, the molecular mechanisms underlying these changes are poorly understood. We have previously reported changes in the levels of a protein called syntaxin-1 in the nucleus accumbens of amphetamine sensitized rats.  As syntaxin-1 is involved in mediating neurotransmitter release as well as in regulating synaptic plasticity, our work suggests that alterations in this protein may be a key mechanism mediating neuronal changes in sensitized animals. In the proposed research, our aim is to further understand the mechanisms by which syntaxin affects amphetamine sensitization.  For example, we want to know which neurons within nucleus accumbens of amphetamine-sensitized animals show changes in syntaxin-1 and whether manipulations of the protein will affect sensitized behaviour.   Further we want to explore if the effects of amphetamine are generalizable to other psychostimulants such as cocaine.  A better understanding of neuronal changes following chronic drug use may help in developing novel pharmacological agents to prevent the harmful effects of these drugs on behavior.