Preclinical Research and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St., Toronto, Ontario M5T 1R8, Canada; Dept. Psychiatry, University of Toronto, Toronto, ON, Canada; Dept. Psychology, University of Toronto, Toronto, ON, Canada.
Preclinical Research and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St., Toronto, Ontario M5T 1R8, Canada.
Schizophr Res. 2018 Apr;194:98-106. doi: 10.1016/j.schres.2017.02.028. Epub 2017 Mar 17.
Nicotine use and dependence is very high in patients with schizophrenia. One possible reason is that altered dopamine or glutamate activity in schizophrenia enhances the reinforcing effectiveness of nicotine. We used animal models to test the hypothesis that a hyperdopaminergic state (induced by repeated intermittent injections of amphetamine) or altered glutamate function (subchronic injection of phencyclidine, PCP) facilitates spontaneous acquisition of nicotine self-administration in rats. In Experiment 1 animals in an amphetamine-induced sensitized state (AISS) did not differ from saline-injected controls in their acquisition and maintenance of nicotine self-administration. This effect was replicated in experiment 2, but it was also found that AISS rats and saline-injected controls showed higher rates of nicotine self-administration compared to uninjected controls. This difference was maintained across several fixed ratio and progressive ratio schedules of reinforcement. In Experiment 3 PCP treated rats and their saline-injected controls did not differ in nicotine self-administration. However, both groups showed consistently increased responding for nicotine on FR and PR schedules compared to an uninjected control group. Injection-stress appeared to influence the outcomes of these experiments in two ways. Firstly, injection stress potentially masked the impact of the AISS and PCP treatment on nicotine self-administration. Secondly, injection stress itself may have been sufficient to induce plastic changes in dopamine and glutamate systems, and these changes enhanced the acquisition and maintenance of nicotine self-administration. Further investigation is needed into the role of stress in the development of nicotine use and dependence, in the aetiology of schizophrenia and in their co-morbidity.
尼古丁使用和依赖在精神分裂症患者中非常高。一个可能的原因是，精神分裂症中多巴胺或谷氨酸活性的改变增强了尼古丁的强化效果。我们使用动物模型来测试以下假设：超多巴胺状态（通过重复间歇性安非他命注射诱导）或谷氨酸功能改变（亚慢性氯胺酮注射，PCP）促进大鼠尼古丁自我给药的自发获得。在实验 1 中，处于安非他命诱导敏感状态（AISS）的动物在尼古丁自我给药的获得和维持方面与生理盐水注射对照没有差异。该实验在实验 2 中得到了复制，但也发现 AISS 大鼠和生理盐水注射对照与未注射对照相比表现出更高的尼古丁自我给药率。这种差异在几个固定比率和递增比率强化方案中得以维持。在实验 3 中，PCP 处理的大鼠及其生理盐水注射对照在尼古丁自我给药方面没有差异。然而，与未注射对照组相比，这两组在 FR 和 PR 方案中对尼古丁的反应都持续增加。注射应激似乎以两种方式影响这些实验的结果。首先，注射应激可能掩盖了 AISS 和 PCP 治疗对尼古丁自我给药的影响。其次，注射应激本身可能足以引起多巴胺和谷氨酸系统的可塑性变化，这些变化增强了尼古丁自我给药的获得和维持。需要进一步研究应激在尼古丁使用和依赖的发展、精神分裂症的病因及其共病中的作用。
