NEW MODEL OF DRUG ABUSE WITH DEPRESSION COMORBIDITY

滥用药物和抑郁经常并存。这项拟议的实验将使用一个成熟的抑郁症模型来研究与药物滥用和抑郁症相关的神经化学和行为变化。抑郁症的嗅球切除(OBX)模型会产生这样的变化，从而为研究这些疾病的共同神经生物学基础提供了独特的机会。OBX会产生一种与嗅觉障碍无关的行为综合征，类似于人类抑郁症，包括昼夜活动节律丧失，对压力反应过度，进食减少，体重增加减少，性行为减少。OBX综合征可以通过慢性但不是急性抗抑郁药物治疗来逆转。OBX引起的一些行为变化表明患有快感缺乏症。病变诱导的中脑边缘多巴胺系统的可塑性可能介导了这种快感缺失。此外，OBX引起的多巴胺可塑性的性质预测，去球部的大鼠将对苯丙胺的刺激剂和增强作用过敏。先前的研究表明，OBX增加了嗅结节中D1和D2受体的密度。本实验室的初步原位杂交实验表明，OBX增加了嗅结节中D2受体和前脑啡肽原mRNAs的水平。嗅结节此前曾被认为与行为强化和滥用药物的行为有关。实验将验证这样的假设，即去球状突触的大鼠比正常大鼠对兴奋剂和苯丙胺的增强作用更敏感，这是因为嗅结节中的突触后受体超敏。实验还将确定去球部的大鼠是否会以更高的比率自我给予苯丙胺。这些行为研究中所有大鼠的大脑将进行原位杂交组织化学分析，多巴胺受体和前脑啡肽原mRNA水平的增加将作为OBX诱导的嗅结节可塑性的标志。初步数据显示，去球大鼠在苯丙胺敏感性和前脑啡肽原mRNA可塑性方面存在很大的个体差异。因此，这项建议的最终目标将是测试苯丙胺诱导的行为的个体差异和嗅结节中OBX诱导的可塑性的个体差异之间的关系。拟议中的实验可能揭示了苯丙胺敏感性个体差异的一种新机制。这些研究还可能为首个药物自我给药的动物模型提供基础，作为对快感缺乏的代偿反应。

Drug abuse and depression frequently coexist. The proposed experiments will employ a well-established model of depression to study neurochemical and behavioral changes associated with both drug abuse and depression. The olfactory bulbectomy (OBX) model of depression produces such changes, thus providing a unique opportunity to study the common neurobiological bases of these disorders. OBX produces a behavioral syndrome independent of anosmia that resembles human depression, including loss of circadian activity rhythms, hyperreactivity to stress, decreased meal size, decreased weight gain, and decreased sexual behavior. The OBX syndrome is reversed by chronic but not acute antidepressant treatment. Some of the behavioral changes caused by OBX suggest anhedonia. Lesion-induced plasticity in mesolimbic dopamine systems may mediate this anhedonia. Furthermore, the nature of the dopamine plasticity caused by OBX predicts that bulbectomized rats would be hypersensitive to the stimulant and reinforcing effects of amphetamine. Previous research reveals that OBX increases D1 and D2 receptor density in the olfactory tubercle. Preliminary in situ hybridization experiments from this laboratory indicate that OBX increases levels of D2 receptor and prepro-enkephalin mRNAs in the olfactory tubercle. The olfactory tubercle has previously been implicated in behavioral reinforcement and the actions of drugs of abuse. Experiments will test the hypothesis that bulbectomized rats are more sensitive than intact rats to the stimulant and reinforcing effects of amphetamine because of postsynaptic receptor supersensitivity in the olfactory tubercle. Experiments will also determine whether bulbectomized rats will self-administer amphetamine at higher rates. Brains from all rats in these behavioral studies will be analyzed by in situ hybridization histochemistry, and increases in dopamine receptor and prepro-enkephalin mRNA levels will serve as markers for OBX- induced plasticity in the olfactory tubercle. Preliminary data reveal wide individual differences in amphetamine sensitivity and prepro-enkephalin mRNA plasticity in bulbectomized rats. The ultimate objective of this proposal will therefore be to test the relationship between individual differences in amphetamine-induced behaviors and individual differences in OBX-induced plasticity in the olfactory tubercle. The proposed experiments may reveal a novel mechanism for individual differences in amphetamine sensitivity. The studies may also provide the basis for the first animal model of drug self-administration as a compensatory response to anhedonia.