Behavioral Pharmacology Group, Laboratory of Animal Morphology and Pathology, State University of North Fluminense Darcy Ribeiro, Avenida Alberto Lamego, 2000, Campos dos Goytacazes, 28013-600, RJ, Brazil.
Pharmacol Biochem Behav. 2010 Sep;96(3):325-32. doi: 10.1016/j.pbb.2010.06.002. Epub 2010 Jun 18.
Neuroplasticity is a key factor in restoration of brain function following neuropathology associated with disease or drug exposure. Here we examined the potential for chronic treatment with the selective D1 receptor antagonist SCH39166 to reverse the profound and enduring cognitive impairment associated with amphetamine (AMPH) sensitization in the nonhuman primate and to stimulate re-growth of atrophied pyramidal dendrites in the dorsolateral prefrontal cortex of these animals. Four rhesus monkeys with sustained cognitive impairment (>1year following AMPH sensitization) were treated for up to 8months with SCH39166. Cognitive testing was performed before, during, and for up to 1(1/2) year following treatment. Significant improvement in working memory performance was observed only after cessation of the D1 antagonist treatment but then was sustained for the duration of the post-treatment testing period. Postmortem quantitative assessment of Golgi-impregnated pyramidal neurons in BA9 showed that apical dendritic length and trunk spine density were increased in D1 antagonist treated monkeys relative to AMPH-sensitized and AMPH-naïve monkeys. These findings, which suggest that the deleterious consequences of AMPH sensitization can be reversed by modulation of D1 receptor signaling, have implications for treating the underlying neural basis of cognitive deficits in both schizophrenia and substance abuse.
神经可塑性是神经病理学相关疾病或药物暴露后大脑功能恢复的关键因素。在这里，我们研究了长期使用选择性 D1 受体拮抗剂 SCH39166 逆转与安非他命（AMPH）敏化相关的非人类灵长类动物严重且持久的认知障碍的潜力，并刺激这些动物背外侧前额皮质中萎缩的锥体树突的再生长。四只认知障碍持续存在（AMPH 敏化后超过 1 年）的恒河猴接受了长达 8 个月的 SCH39166 治疗。在治疗前、治疗期间和治疗结束后长达 1（1/2）年进行认知测试。仅在停止 D1 拮抗剂治疗后才观察到工作记忆性能的显著改善，但随后在整个治疗后测试期间持续。对 BA9 中高尔基浸渍锥体神经元的定量评估表明，与 AMPH 敏化和 AMPH 未敏化的猴子相比，D1 拮抗剂处理的猴子的树突棘长度和主干密度增加。这些发现表明，通过调节 D1 受体信号可以逆转 AMPH 敏化的有害后果，这对治疗精神分裂症和药物滥用的认知缺陷的潜在神经基础具有重要意义。
