DA THERAPY AND BRAIN NEUROTROPHIC ACTIVITY

多巴胺能药物在精神分裂症和帕金森病治疗中的应用 疾病(PD)与并发症有关，这些并发症往往会 其他有效的药物治疗(即迟发性运动障碍(TD)和丧失 分别为疗效)。使用一种新的方法来研究这些 药物，我们已经证明了动物的无细胞纹状体提取物 长期使用多巴胺能药物改变人的生长发育 含有多巴胺(DA)神经元的中脑细胞培养：DA 拮抗剂治疗加强，而DA激动剂治疗减少， 纹状体提取物对培养物生长有影响。这些数据表明 药物敏感的纹状体源性神经营养因子或神经抑制因子 影响培养中DA神经元的生长。这些研究导致了 一种运营性假说，即“促进增长效应” 无细胞纹状体提取物对中脑培养物的作用相反 与DA语气有关。“我们打算直接使用 改变治疗剂量和疗程的传统方法 公认的多巴胺能药物(氟哌啶醇和左旋多巴) 行为模型(行为过敏症和6-羟基多巴胺 旋转)。DA生化，螺哌利多受体密度，以及 这些药物引起的刻板印象和旋转行为改变 治疗将代表DA音调的依赖措施。一位高度 灵敏的低细胞密度培养系统将用于药物鉴定 引起纹状体促生长活性改变的治疗方法 (GPA)。是否使用免疫细胞化学染色和细胞培养 DA和GABA神经元以及星形胶质细胞的计数。这一GPA的影响 将通过评估DA来评估HAS对培养的神经元萌发的影响 和GABA摄取。然后将使用DA音调的从属测量来 预测GPA(定义为细胞计数和/或递质摄取) 多元回归分析。确定具有统计意义的 使用此方程的逆关系将直接支持 运营性假设。这项分析将需要两年时间才能完成。在……里面 第三年的建议，其他不同的多巴胺能药物 然后将对药理特征和临床活动进行评估 使用该模型系统。这些分析将进一步支持或驳斥 运营性假说以及开始解决潜在的 药物治疗与副作用之间的关系。 如果这些药物敏感的生长因子影响DA神经元的生长 在活体内以类似的方式(正如我们的初步结果似乎 提示)，由此导致的突触结构的改变可能 导致多巴胺能药物治疗的并发症。 因此，与DA拮抗剂治疗相关的增加DA神经元的生长 可能对TD有贡献，同时与DA相关的DA神经元生长减少 激动剂治疗可能有助于帕金森病的进展。结果是 因此，这项提议预计将影响目前的 治疗策略在精神分裂症和帕金森病治疗中的应用

Dopaminergic drugs used in the treatment of schizophrenia and Parkinson's disease (PD) are associated with complications which often compromise otherwise efficacious drug therapy (i.e., tardive dyskinesia (TD) and loss of efficacy, respectively). Using a novel approach for studying these drugs, we have demonstrated that cell-free striatal extracts from animals chronically treated with dopaminergic drugs alter the growth of mesencephalic cell cultures containing dopamine (DA) neurons: DA antagonist treatment enhanced, while DA agonist treatment reduced, the effect striatal extracts had on culture growth. These data suggest that drug-sensitive striatal-derived neurotrophic or neuroinhibitory factors influence the growth of DA neurons in culture. These studies have led to an operational hypothesis which states that "the growth promoting effect cell-free striatal extracts have on mesencephalic cultures is inversely related to DA tone." We intend to test this hypothesis directly using the traditional approach of varying the dose and duration of treatment with dopaminergic drugs (haloperidol and levodopa) in well established behavioral models (behavioral hypersensitivity and 6-hydroxydopamine rotation). DA biochemistry, spiroperidol receptor density, as well as stereotypical and rotational behavior alterations induced by these drug treatments will represent the dependent measures of DA tone. A highly sensitive low cell density culture system will be used to identify drug therapies which induce alterations in striatal growth promoting activity (GPA). Whether or not cultures using immunocytochemical stains and cell counts of DA and GABA neurons, as well as astrocytes. The effect this GPA has on neuron sprouting in the cultures will be evaluated by assessing DA and GABA uptake. The dependent measures of DA tone will then be used to predict GPA (defined as cell counts and/or transmitter uptake) using multiple regression analysis. Identifying a statistically significant inverse relationship using this equation will directly support the operational hypothesis. This analysis will take two years to complete. In the third year of the proposal, other dopaminergic drugs with differing pharmacological profiles and clinical activities will then be evaluated using this model system. These analyses will further support or refute the operational hypothesis as well as begin to address the potential relationships between drug treatment and side effects. If these drug sensitive growth factors were to influence DA neuron growth in vivo in a similar fashion (as our preliminary results appear to suggest), the resulting alterations in synaptic architecture could contribute to the complications which attend dopaminergic drug therapy. Thus, increased DA neuron growth associated with DA antagonist treatment could contribute to TD while reduced DA neuron growth associated with DA agonist therapy could contribute to the progression of PD. The results of this proposal would therefore be expected to influence the current therapeutic strategies employed in the treatment of schizophrenia and PD.