Madjid Nather, Tottie Elin Elvander, Lüttgen Maria, Meister Björn, Sandin Johan, Kuzmin Alexander, Stiedl Oliver, Ogren Sven Ove
Departmentt of Neuroscience, Division of Behavioral Neuroscience, Karolinska Institutet, Stockholm, Sweden.
J Pharmacol Exp Ther. 2006 Feb;316(2):581-91. doi: 10.1124/jpet.105.092262. Epub 2005 Oct 13.
The effects of 5-hydroxytryptamine 1A (5-HT(1A)) receptor ligands on aversive learning were examined in the passive avoidance (PA) task in mice. Anxiety and autonomic functions were investigated using the elevated plus-maze and heart rate measurements. The main findings from this study are as follows. 1) Pretraining administration of the 5-HT(1A) receptor agonist 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide] facilitated PA retention at low doses (0.01 and 0.03 mg/kg) but impaired PA retention at higher doses (0.1-1.0 mg/kg), consistent with previous findings in the rat. 2) Similar to the acetylcholinesterase inhibitor physostigmine, pretraining administration of the 5-HT(1A) receptor antagonists [(R)-3-N,N-dicyclobutylamino-8 fluoro-3,4-dihydro-3H-1-benzopyran-5-carboxamide hydrogen(2R,3R)-tartrate monohydrate] NAD-299 (0.1-2 mg/kg) and [N-2-4-(2-methoxyphenyl)-1-piperazinylethyl-N-(2-pyridinyl)cyclohexane carboxamide trihydrochloride] WAY-100635 (0.3-3 mg/kg) enhanced PA retention. 3) The impairment (1 mg/kg) but not the facilitation (0.03 mg/kg) induced by 8-OH-DPAT was fully blocked by NAD-299 (0.3 mg/kg). 4) 5-HT(1A) receptor ligands given immediate post-training failed to alter PA retention. 5) NAD-299 (0.3-1 mg/kg) blocked the impairment of PA retention caused by a) the nonselective muscarinic receptor antagonist scopolamine and b) the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen maleate]. 6) A subthreshold dose of scopolamine completely blocked the facilitatory effect of NAD-299 on PA retention. 7) Anxiety-related behaviors and autonomic function were unchanged by NAD-299. 8) In situ hybridization showed that septal neurons expressing 5-HT(1A) receptor mRNA were codistributed with markers for cholinergic, GABAergic, and glutamatergic neurons. These results indicate that systemic administration of 5-HT(1A) receptor antagonists can facilitate cognitive performance, most likely by enhancing hippocampal/cortical cholinergic and glutamatergic neurotransmissions. Selective 5-HT(1A) receptor antagonists may be useful in the treatment of cognitive deficits such as Alzheimer's disease.
在小鼠的被动回避（PA）任务中，研究了5-羟色胺1A（5-HT(1A)）受体配体对厌恶学习的影响。使用高架十字迷宫和心率测量来研究焦虑和自主神经功能。本研究的主要发现如下。1）5-HT(1A)受体激动剂8-OH-DPAT[8-羟基-2-（二正丙基氨基）四氢萘氢溴酸盐]在训练前低剂量（0.01和0.03mg/kg）给药时促进PA记忆，但在高剂量（0.1-1.0mg/kg）给药时损害PA记忆，这与先前在大鼠中的研究结果一致。2）与乙酰胆碱酯酶抑制剂毒扁豆碱类似，5-HT(1A)受体拮抗剂[(R)-3-N,N-二环丁基氨基-8-氟-3,4-二氢-3H-1-苯并吡喃-5-羧酰胺氢(2R,3R)-酒石酸盐一水合物]NAD-299（0.1-2mg/kg）和[N-2-4-(2-甲氧基苯基)-1-哌嗪基乙基-N-(2-吡啶基)环己烷甲酰胺三盐酸盐]WAY-100635（0.3-3mg/kg）在训练前给药增强了PA记忆。3）NAD-299（0.3mg/kg）完全阻断了8-OH-DPAT诱导的损害（1mg/kg），但未阻断促进作用（0.03mg/kg）。4）训练后立即给予的5-HT(1A)受体配体未能改变PA记忆。5）NAD-299（0.3-1mg/kg）阻断了由以下因素引起的PA记忆损害：a）非选择性毒蕈碱受体拮抗剂东莨菪碱和b）非竞争性N-甲基-D-天冬氨酸受体拮抗剂MK-801[(5R,10S)-(+)-5-甲基-10,11-二氢-5H-二苯并(a,d)环庚烯-5,10-亚胺氢马来酸盐]。6）阈下剂量的东莨菪碱完全阻断了NAD-299对PA记忆的促进作用。7）NAD-299未改变与焦虑相关的行为和自主神经功能。8）原位杂交显示，表达5-HT(1A)受体mRNA的隔区神经元与胆碱能、GABA能和谷氨酸能神经元的标志物共分布。这些结果表明，全身性给予5-HT(1A)受体拮抗剂可促进认知表现，最可能是通过增强海马体/皮质胆碱能和谷氨酸能神经传递。选择性5-HT(1A)受体拮抗剂可能对治疗认知缺陷如阿尔茨海默病有用。
