Murphy B L, Arnsten A F, Jentsch J D, Roth R H
Department of Pharmacology, Yale Medical School, New Haven, Connecticut 06510-8001, USA.
J Neurosci. 1996 Dec 1;16(23):7768-75. doi: 10.1523/JNEUROSCI.16-23-07768.1996.
The anxiogenic benzodiazepine inverse agonist FG7142 increases dopamine turnover in rodent prefrontal cortex but not in other dopamine terminal field areas. FG7142-induced increases in prefrontal cortical dopamine receptor stimulation impair prefrontal-dependent, but not nonprefrontal-dependent, cognitive tasks in rats and monkeys. The degree of impairment correlates with levels of prefrontal cortical dopamine turnover in rats and can be blocked in rats and monkeys with dopamine receptor antagonists, suggesting that increased dopamine turnover is directly related to the cognitive deficits. The current study examined nondopaminergic drug effects on FG7142-perturbed biochemistry and cognition. Both the noradrenergic alpha-2 agonist clonidine and the glycine/NMDA antagonist (+)HA966 prevented the FG7142-induced increase in dopamine turnover in rodent prefrontal cortex. Infusion of (+)HA966 into the ventral tegmental area (VTA) also blocked this increase in dopamine turnover, indicating that critical modulatory effects of (+)HA966 on FG7142-induced changes in dopamine turnover are occurring at the level of mesoprefrontal dopamine neuron cell bodies. Systemic (+)HA966 and clonidine, but not propranolol or D-cycloserine, prevented FG7142-associated spatial working memory deficits in rats and monkeys. These results support the idea of a critical range of dopamine turnover for optimal prefrontal cortical cognitive functioning, with excessive dopamine turnover leading to cognitive impairment. These studies also provide evidence for the regulation of prefrontal cortical dopamine turnover and cognition by multiple neurotransmitter systems and suggest that the VTA is an important regulatory site for these effects.
致焦虑的苯二氮䓬反向激动剂FG7142可增加啮齿动物前额叶皮质中的多巴胺周转率，但在其他多巴胺终末场区域则不然。FG7142诱导的前额叶皮质多巴胺受体刺激增加会损害大鼠和猴子依赖前额叶的认知任务，但不影响非前额叶依赖的认知任务。损害程度与大鼠前额叶皮质多巴胺周转率水平相关，并且可被多巴胺受体拮抗剂在大鼠和猴子中阻断，这表明多巴胺周转率增加与认知缺陷直接相关。本研究考察了非多巴胺能药物对FG7142干扰的生物化学和认知的影响。去甲肾上腺素能α-2激动剂可乐定和甘氨酸/NMDA拮抗剂(+)HA966均可阻止FG7142诱导的啮齿动物前额叶皮质多巴胺周转率增加。将(+)HA966注入腹侧被盖区(VTA)也可阻断多巴胺周转率的这种增加，表明(+)HA966对FG7142诱导的多巴胺周转率变化的关键调节作用发生在中前额叶多巴胺神经元细胞体水平。全身性给予(+)HA966和可乐定可预防大鼠和猴子中与FG7142相关的空间工作记忆缺陷，但普萘洛尔或D-环丝氨酸则不能。这些结果支持了这样一种观点，即存在一个关键的多巴胺周转率范围，以实现最佳的前额叶皮质认知功能，多巴胺周转率过高会导致认知障碍。这些研究还为多种神经递质系统对前额叶皮质多巴胺周转率和认知的调节提供了证据，并表明VTA是这些作用的一个重要调节位点。
