NEW MODEL OF DRUG ABUSE WITH DEPRESSION COMORBIDITY

药物滥用和抑郁症经常并存。拟议的实验将采用一个完善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）模型产生了这样的变化，从而为研究这些疾病的共同神经生物学基础提供了一个独特的机会。OBX产生一种独立于嗅觉缺失的行为综合症，类似于人类抑郁症，包括昼夜节律的丧失、对压力的过度反应、食量减少、体重增加减少和性行为减少。慢性而非急性抗抑郁治疗可逆转OBX综合征。OBX引起的一些行为变化表明快感缺乏症。中边缘多巴胺系统损伤诱导的可塑性可能介导这种快感缺乏。此外，OBX引起的多巴胺可塑性的性质预示着球管切除的大鼠对安非他明的刺激和强化作用会过敏。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增加嗅觉结节中D2受体和前脑啡肽mrna的水平。嗅觉结节先前被认为与行为强化和药物滥用有关。实验将验证一种假设，即由于嗅结节突触后受体超敏，去球鼠对安非他明的刺激和强化作用比完整的大鼠更敏感。实验还将确定被球管切除的大鼠是否会以更高的速率自行服用安非他明。在这些行为研究中，所有大鼠的大脑将通过原位杂交组织化学分析，多巴胺受体和前脑啡肽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，在去球化大鼠中，安非他命敏感性和脑啡肽前体mRNA可塑性存在广泛的个体差异。因此，本研究的最终目的是测试安非他明诱导行为的个体差异与obx诱导的嗅结节可塑性的个体差异之间的关系。本实验可能揭示安非他明敏感性个体差异的新机制。这些研究也可能为第一个药物自我给药作为快感缺乏的代偿反应的动物模型提供基础。

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.