NEW MODEL OF DRUG ABUSE WITH DEPRESSION COMORBIDITY

抑郁症合并症的药物滥用新模式

• 批准号: 6175790
• 负责人: PHILIP V HOLMES
• 金额: $ 5.81万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-25 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6175790
• 关键词: amphetamines; comorbidity; depression; disease /disorder model; dopamine receptor; drug abuse; experimental brain lesion; histochemistry /cytochemistry; in situ hybridization; laboratory rat; messenger RNA; neural plasticity; neurochemistry; olfactory lobe; receptor sensitivity; self medication; substance abuse related behavior

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.

药物滥用和抑郁症经常共存。 提出的实验将采用良好的抑郁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。 抑郁症的嗅球切除术（OBX）模型会产生这种变化，从而提供了一个独特的机会来研究这些疾病的常见神经生物学基础。 OBX会产生独立于厌食的行为综合征，类似于人类抑郁症，包括昼夜节律节奏的丧失，对压力的过度反应性，饮食量降低，体重增加减少和性行为减少。 OBX综合征通过慢性抗抑郁药治疗反转。 OBX引起的一些行为变化表明Anhedonia。 病变诱导的中唇胶多巴胺系统的可塑性可能会介导这种麻醉症。此外，由OBX引起的多巴胺可塑性的性质预测，鳞去性大鼠对苯丙胺的刺激性和增强作用过敏。 先前的研究表明，OBX增加了嗅觉结节中的D1和D2受体密度。 该实验室的原位原位杂交实验表明，OBX增加了嗅觉结节中D2受体和前脑脑mRNA的水平。 以前，嗅觉结节涉及行为加强和滥用药物的作用。 实验将检验以下假设：由于嗅觉结节中突触后受体超敏，因此对苯丙胺的刺激性和增强作用比完整的大鼠更敏感。实验还将确定鳞去性大鼠是否会以较高的速率自动辅助苯丙胺。 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，多巴胺受体的增加和前脑脑蛋白mRNA水平将作为嗅觉结节中OBX可塑性的标志物。 初步数据揭示了苯丙胺敏感性和内孔 - 源自源自大鼠的持久性差异。 因此，该提案的最终目标将是测试苯丙胺诱导的行为的个体差异与OBX诱导的嗅觉可塑性的个体差异之间的关系。 提出的实验可能揭示了一种新的机制，即苯丙胺敏感性的个体差异。 这些研究还可以为第一个药物自我给药的第一个动物模型提供基础，以作为对阿尼多尼亚的补偿性反应。

项目成果

Dopamine overflow is increased in olfactory bulbectomized rats: an in vivo microdialysis study.

嗅球切除大鼠的多巴胺溢出增加：一项体内微透析研究。

• DOI: 10.1016/j.physbeh.2004.01.003
• 发表时间: 2004
• 期刊: Physiology & behavior.
• 作者: Masini,CherV;Holmes,PhilipV;Freeman,KimberlyG;Maki,AlexandraC;Edwards,GaylenL
• 通讯作者: Edwards,GaylenL