Pocivavsek Ana, Icenogle Laura, Levin Edward D
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
Psychopharmacology (Berl). 2006 Nov;188(4):597-604. doi: 10.1007/s00213-006-0416-1. Epub 2006 May 20.
Nicotinic systems in the hippocampus play important roles in memory function. Decreased hippocampal nicotinic receptor concentration is associated with cognitive impairment in schizophrenia and Alzheimer's disease.
We modeled in rats the cognitive effects of chronic decrease in hippocampal alpha7 or alpha4beta2 receptors with 4-week continuous bilateral local infusions of the alpha7 nicotinic antagonist methyllycaconitine (MLA) or the alpha4beta2 antagonist dihydro-beta-erythroidine (DHbetaE). The working memory effects of these infusions were assessed by performance on the radial-arm maze. To test the effect of antipsychotic medication, we gave acute injections of clozapine and to determine the impact of nicotine, which is widely used by people with schizophrenia approximately half of the rats received chronic systemic infusions of nicotine.
Chronic ventral hippocampal DHbetaE infusion caused a significant (p < 0.001) working memory impairment. Acute systemic clozapine (2.5 mg/kg) caused a significant (p < 0.005) working memory impairment in rats given control aCSF hippocampal infusions. Clozapine significantly (p < 0.025) attenuated the memory deficit caused by chronic hippocampal DHbetaE infusions. Chronic ventral hippocampal infusions with MLA did not significantly affect the working memory performance in the radial-arm maze, but it did significantly (p < 0.05) potentiate the memory impairment caused by 1.25 mg/kg of clozapine. Chronic systemic nicotine did not significantly interact with these effects.
The state of nicotinic receptor activation in the ventral hippocampus significantly affected the impact of clozapine on working memory with blockade of alpha7 nicotinic receptors potentiating clozapine-induced memory impairment and blockade of alpha4beta2 receptors reversing the clozapine effect from impairing to improving memory.
海马体中的烟碱系统在记忆功能中发挥重要作用。海马体烟碱受体浓度降低与精神分裂症和阿尔茨海默病的认知障碍有关。
我们通过连续4周双侧局部注射α7烟碱拮抗剂甲基lycaconitine（MLA）或α4β2拮抗剂二氢-β-刺桐碱（DHbetaE），在大鼠中模拟海马体α7或α4β2受体慢性减少的认知效应。通过放射状臂迷宫实验评估这些注射的工作记忆效应。为了测试抗精神病药物的效果，我们急性注射氯氮平，并为了确定尼古丁的影响（约一半的大鼠接受尼古丁慢性全身注射，精神分裂症患者广泛使用尼古丁）。
慢性腹侧海马体注射DHbetaE导致显著（p < 0.001）的工作记忆损害。急性全身注射氯氮平（2.5 mg/kg）在接受对照人工脑脊液海马体注射的大鼠中导致显著（p < 0.005）的工作记忆损害。氯氮平显著（p < 0.025）减轻了慢性海马体注射DHbetaE引起的记忆缺陷。慢性腹侧海马体注射MLA对放射状臂迷宫中的工作记忆表现没有显著影响，但它确实显著（p < 0.05）增强了1.25 mg/kg氯氮平引起的记忆损害。慢性全身注射尼古丁与这些效应没有显著相互作用。
腹侧海马体中烟碱受体的激活状态显著影响氯氮平对工作记忆的影响，α7烟碱受体的阻断增强了氯氮平诱导的记忆损害，而α4β2受体的阻断使氯氮平的作用从损害记忆转变为改善记忆。
