抗抑郁药对新生大鼠海马细胞的保护作用

目的：研究不同种类的抗抑郁药对谷氨酸和过氧化氢所致新生大鼠海马细胞损伤的保护作用。方法：建立Glu对新生大鼠海马神经细胞的急、慢性损伤模型及H2O2对大鼠海马神经细胞的急性损伤模型。观察文拉法辛、度洛西汀、氟西汀、地西帕明和DOV对海马神经细胞是否有保护作用，并采用流式细胞仪测定细胞内钙浓度，初步探讨急性Glu损伤及各类抗抑郁药物的神经保护作用和细胞内钙超载的相关性。     

五味子对去卵巢小鼠的记忆保持和海马NOS神经元表达的影响

目的：研究五味子（Fructus Schisandrae Chinensis）改善记忆与类雌激素作用的关系，并探讨相关的作用机制。方法：采用一次性被动回避反应行为学方法研究五味子对去卵巢小鼠记忆能力的影响；NADPH—d酶组化染色观察五味子对小鼠海马亚区一氧化氮合酶（NOS）阳性神经元形态及数日的影响。结果：去卵巢可明显降低小鼠的记忆能力，同时降低海马各区NOS阳性神经元数目。五味子醇提物具有改善去卵巢小鼠记忆保持的能力，显著增加海马各区NOS阳性神经元数目；五味子脂提物却明显抑制去卵巢小鼠的记忆保持，相应降低海马各区NOS阳性神经元的数目。结论：五味子改善记忆保持与类雌激素作用有关，其类雌激素作用的主要成分存在于乙醇提取物中，但五味子脂提物存在拮抗类雌激素的作用。影响海马各区NOS阳性神经元的合成及分布可能是五味子醇提物的类雌激素作用机制之一。     

蛋白质组学方法在研究阿片类物质依赖机理中的应用

阿片类物质成瘾（依赖）的机理十分复杂。大脑中有关组织中蛋白质表达改变可能与阿片类物质依赖产生密切相关。海马是一个调节学习记忆功能的重要脑组织，近年来研究表明它在阿片等毒品成瘾机理中也有重要作用。研究海马组织蛋白表达改变与阿片类物质成瘾的关系，对认识阿片类物质成瘾的机理和发现药物作用的靶标的重要意义。应用蛋白质组学方法，我们观察到慢性吗啡处理能引起小鼠海马中与能量代谢密切相关的呼吸链中的NADH脱氢酶的辅基Fe-s蛋白，三羧酸循环中丙酮酸脱氢酶复合物中二氢硫辛酰转乙酰基酶和糖酵解关键酶乳酸脱氢酶表达显著地降低。荧光实时定量PCR（RT-PCR）分析表明编码这三个蛋白质表达的mRNA含量相应地降低。吗啡慢性处理小鼠海马组织中的ATP水平显著地低于正常小鼠海马组织中ATP水平，进一步证实慢性吗啡依赖小鼠海马中三个与能量代谢相关的酶表达降低。     

吗啡依赖性小鼠的海马蛋白质组学分析

海马是一个与学习记忆功能有密切关系的脑区，研究资料表明它是参与阿片类物质依赖作用的形成的重要脑区之一。阿片类物质引起的海马神经元突触可塑性改变可能是这些物质引起依赖作用的神经生物学基础。神经元突触可塑性变化是一个复杂的生物学过程，涉及到蛋白质表达的变化及由此引起生物化学反应和信号传导     

荞麦多酚对谷氨酸和红藻氨酸诱导的海马神经元死亡的抑制作用[英]／Pu F L…∥和汉医药学杂志.

荞麦Fagopyrum esculentum Moench多酚(BWP)具有改善大鼠空间记忆损害和反复脑缺血造成的细胞凋亡等作用，但作用机理不明。作者研究了BWP对谷氨酸和红藻氨酸致原代培养海马神经元死亡的作用。     

小檗碱对局灶性脑缺血大鼠原癌基因c—fos表达的影响

目的：研究大鼠局灶性脑缺血过程中c-fos mRNA表达的动态变化，并观察小檗碱（Ber）对其作用。方法：运用斑点杂交技术，观察Ber对局灶性脑缺血再灌注大鼠大脑皮质及海马组织c-fos mRNA表达的影响。结果：大鼠局灶性脑缺血2h再灌注0．5－4h，脑皮质及海马组织c-fos mRNA出现一过性高表达，2h达高峰，分别为对照组的4．5和4．7倍。Ber 20mg/(kg·d)ip显抑制大鼠脑缺血诱导的c-fos高表达，降低病灶侧海马和皮层组织水、钙含量。结论：脑缺血过程中c-fos原癌基因呈现一过性高表达，Ber可降低c-fos mRNA水平，该作用可能是其抗脑缺血机理之一。     

基于突触可塑性探讨针刺防治认知障碍的机制

认知是中枢神经的高级智能活动之一，神经元之间通过相互识别和相互作用实现信息交流并产生反馈。突触可塑性对于大脑海马区学习和认知功能的发展有着不可替代作用，针刺防治认知障碍的作用机制可能与调节突触可塑性有关，但其机制还不明确，值得进一步深入研究。本文主要从突触可塑性相关的蛋白变化、神经胶质细胞的激活、相关自噬及临床相关疾病等方面阐述针刺疗法对认知功能的影响及其研究现状，为今后针刺防治认知障碍性疾病的临床应用和实验研究提供参考。     

海马细胞凋亡的钙通路与创伤后应激障碍发生机制的相关性

创伤后应激障碍(PTSD)是应激相关的精神疾病。海马是学习记忆的重要部位,在条件性惊恐反射的消退过程中起重要作用。最近研究发现,在PTSD患者中海马的体积相对减小。然而,神经元萎缩和凋亡引起的海马体积减小的机制仍未清。本文主要研究海马细胞凋亡的钙通路与创伤后应激障碍发生机制的相关性。     

天泰Ⅰ号对老年痴呆模型的益智作用及机理探讨

对老年小鼠以ＡｌＣｌ３复制老年痴呆模型，以特异性Ｍ１和Ｍ２受体亚型抗体检测模型小鼠海马Ｍ１和Ｍ２受体含量，观察天泰１号对模型小鼠的作用效果，结果表明，模型小鼠海马Ｍ１和Ｍ２含量显著降低，天泰Ⅰ号可显著提高模型小鼠的学习记忆能力，并显著增加其海马Ｍ１受体亚型的含量，但对Ｍ２无明显影响。     

斑海马提取物抗大鼠血栓形成的作用及成份分析

对斑海马甲醇提取物抗血栓作用的研究结果表明，ＥＨＴ能明显抑制大鼠生颈动脉血栓和大鼠脑血栓的形成，提示ＥＨＴ具有明显血栓作用，其有效成份为多种不饱和脂肪酸。     

Toxicity of the venom of the sea-snake, Laticauda colubrina, with observations on a Malay "folk cure"

Venom from the sea-snake, Laticauda colubrina, was subjected to toxicity testing in mice. The ₅₀ was 0·45 mg per kg with 95 per cent confidence limits of 0·34 to 0·60 mg per kg. Aqueous extracts of Clinacanthus nutans, a Southeast Asian plant esteemed in Asian folk medicine as a snake venom antidote, were found to be ineffective in prolonging survival time of mice injected with lethal doses of sea-snake venom. Intravenous administration of 0·40 mg venom per kg body weight to a pentobarbital-anesthetized dog produced respiratory arrest, cardiovascular collapse, and death in 12 min. At a lower venom dosage (0·09 mg per kg), death occurred in 2·5 hr. The symptoms of envenomation were suggestive of medullary paralysis, although such a diagnosis was inconclusive.     

Histamine is an antagonist of the acetylcholine receptor at the frog endplate.

The effects of histamine on the acetylcholine (ACh) receptor-channel complex were examined by means of voltage-clamp at the frog endplate. ACh was ionophoretically applied to the endplate. Histamine was added to the perfusate. Histamine (100 nM - 1 mM) reversibly depressed the peak amplitude of the ACh-induced inward current in a dose-dependent manner. The double reciprocal plot of the dose-response relationship between the peak ACh current and the amount of ACh applied suggested that histamine (100 microM) depressed the ACh-induced current in a competitive manner. Histamine prevented the specific ACh binding site within the receptor-channel complex from binding erabutoxin, a sea-snake venom, which binds irreversibly to the specific ACh binding site. Histamine had no detectable effects on the equilibrium potential of the endplate current but shortened the half-decay time of the endplate current in a voltage-dependent manner. It was therefore concluded that histamine blocks not only the specific ACh binding site but also interacts with the ACh-channel site. The present experiments strongly suggest that histamine can act as an antagonist to modulate nicotinic cholinergic transmission.     

BTCP is a potent reinforcer in rats: comparison of behavior maintained on fixed- and progressive-ratio schedules

N-[1-(2-benzo[b]thiophenyl)cyclohexyl]piperidine (BTCP) is a phencyclidine (PCP) derivative that acts as a potent dopamine (DA) reuptake inhibitor. Earlier studies have shown that BTCP can substitute for the reinforcing effects of cocaine. Therefore, the aim of the study was to further characterize the reinforcing effects of BTCP. The reinforcing actions of BTCP were compared to those of cocaine at equimolar concentrations in drug-na?ve rats. Two groups of animals were implanted with jugular catheters and trained to intravenously self-administer BTCP or cocaine (0.25 mg/infusion) on a fixed-ratio five schedule (FR 5) of reinforcement. Both BTCP and cocaine produced comparable inverted U-shaped dose-effect curves on this schedule over doses of 0.03, 0.06, 0.125, and 0.25 mg/infusion. Two doses (0.125 and 0.25 mg/infusion) that produced reliable self-administration in all the animals for cocaine and BTCP were then tested on a progressive-ratio schedule. At each dose, BTCP supported higher breaking points (BPs) than cocaine. The results demonstrate that rats readily acquire responding maintained by BTCP and suggest that BTCP may have greater reinforcing effects than cocaine at equimolar concentrations.     

Effect of time-out duration on the reinforcing strength of cocaine assessed under a progressive-ratio schedule in rhesus monkeys

Progressive-ratio (PR) schedules of reinforcement have provided valuable information regarding the reinforcing strength of cocaine and the underlying neurobiological mechanisms. Parametric manipulations, such as altering time-out (TO) values, can affect the shape of the cocaine dose-response curve. Earlier studies have used PR schedules with widely varying parameters, thus complicating comparisons across experiments. This study evaluated the reinforcing strength of cocaine (0.005-0.9 mg/kg) as a function of post-reinforcement TO duration (5, 10, 30, or 60 min) under a PR schedule in rhesus monkeys. Daily sessions ended when 2 h elapsed without an injection; the breakpoint value was defined as the total number of injections. When the TO was 10 min, the relationship between cocaine dose and the number of injections received (i.e. BP) was characterized by an inverted U-shaped curve in all monkeys. Increasing the TO to 30 min resulted in a rightward shift of the ascending limb of the dose-response curve, but did not affect self-administration of higher doses. The number of injections received of a low cocaine dose was not further increased when the TO was shortened to 5 min, nor did increasing the TO to 60 min alter self-administration of the highest tested dose. These results suggest that drug accumulation plays a role in determining the reinforcing strength of low and intermediate cocaine doses under PR schedules. However, the reinforcing strength of higher cocaine doses was unaffected by manipulating TO, suggesting that the BP value is a useful measure of reinforcing strength.     

Sequence-specific effects of neurokinin substance P on memory,reinforcement, and brain dopamine activity

There is ample evidence that the neurokinin substance P (SP) can have neurotrophic as well as memory-promoting effects. This paper outlines a recent series of experiments dealing with the effects of SP and its N- and C-terminal fragments on memory, reinforcement, and brain monoamine metabolism. It was shown that SP, when applied peripherally (IP), promotes memory (inhibitory avoidance learning) and is reinforcing (place preference task) at the same dose of 37 nmol/kg. Most important, however, is the finding that these effects seemed to be encoded by different SP sequences, since the N-terminal SP1-7 (185 nmol/kg) enhanced memory, whereas C-terminal hepta- and hexapeptide sequences of SP proved to be reinforcing in a dose equimolar to SP. These differential behavioral effects were paralleled by selective and site-specific changes in dopamine (DA) activity, as both SP and its C-, but not N-terminus, increased extracellular DA in the nucleus accumbens (NAc), but not in the neostriatum. The neurochemical changes lasted at least 2 h after injection. These results show that the reinforcing action of peripheral administered SP may be mediated by its C-terminal sequence, and that this effect could be related to DA activity in the NAc. Direct application of SP (0.74 pmol) into the region of the nucleus basalis magnocellularis (NBM) was also memory-promoting and reinforcing, and again, these effects were differentially produced by the N-terminus and C-terminus, supporting the proposed structure-activity relationship for SP's effects on memory and reinforcement. These results may provide a hypothetical link between the memory-modulating and reinforcing effects of SP and the impairment in associative functioning accompanying certain neurodegenerative processes.     

Attenuation of cocaine self-administration in squirrel monkeys following repeated administration of the mGluR5 antagonist MPEP: comparison with dizocilpine

RATIONALE: The mGluR5 antagonist MPEP has effects that suggest potential as a pharmacotherapy for cocaine addiction. MPEP can attenuate self-administration of cocaine in animals; however, studies usually involved only acute treatment with MPEP and a single dose of self-administered cocaine. Cocaine addicts use varied amounts of cocaine over long periods of time, and an effective pharmacotherapy would almost certainly require more chronic treatment. OBJECTIVES: The present study (1) compared the effects of repeated treatment with MPEP or the NMDA receptor antagonist dizocilpine on the reinforcing effects of a range of doses of cocaine and (2) determined the pharmacological specificity of the effects of the drugs in attenuating cocaine self-administration compared to food-reinforced behavior. An effective pharmacotherapy should selectively reduce cocaine self-administration. MATERIALS AND METHODS: Groups of monkeys responded under a fixed-ratio schedule of i.v. cocaine self-administration or food-pellet delivery. The effects of daily treatment with MPEP and dizocilpine were determined under both the schedule of i.v. cocaine injection and food delivery. RESULTS: Treatment with MPEP and dizocilpine significantly reduced cocaine self-administration, producing rightward and downward shifts in the ascending limb of the cocaine dose-response function. MPEP and dizocilpine selectively and significantly attenuated self-administration of a low reinforcing dose of cocaine compared to food without evidence of tolerance. CONCLUSIONS: Both MPEP and dizocilpine functioned as partially surmountable antagonists of the reinforcing effects of cocaine. The similar effects of the two drugs raises the possibility that MPEP attenuated the reinforcing effects of cocaine, at least in part, via mGluR5-mediated inhibition of NMDA receptor activity.     

Chlordiazepoxide directly enhances positive ingestive reactions in rats

Benzodiazepines such as chlordiazepoxide (CDP) promote feeding in a number of species. This effect has been interpreted generally to be an indirect consequence of benzodiazepine anti-anxiety action, although some have questioned whether it might not reflect instead a direct action upon the reinforcing properties of foods. The present study employed a behavioral measure that can discriminate between these possibilities: palatability-dependent consummatory actions elicited in rats by tastes. The results suggest that chlordiazepoxide enhances the positive palatability of tastes selectively while having little or no effect on aversive palatability. The net effect is to make tastes more reinforcing following CDP administration.     

Lower reinforcing strength of the phenyltropane cocaine analogs RTI-336 and RTI-177 compared to cocaine in nonhuman primates

Drugs that inhibit brain dopamine transporters (DAT) have been developed as potential agonist medications for cocaine abuse and dependence. Because the mechanism of action of such drugs is similar to cocaine, one concern regarding their use is the abuse potential of the medications themselves. The present study compared the reinforcing strength of cocaine (0.003-0.3 mg/kg) and two 3-phenyltropane analogs of cocaine, RTI-336 (3β-(4-chlorophenyl)-2β-[3-(4′-methylphenyl)isoxazol-5-yl]tropane hydrochloride; 0.003-0.1 mg/kg) and RTI-177 (3β-(4-chlorophenyl)-2β-[3-phenylisoxazol-5-yl]tropane hydrochloride; 0.003-0.1 mg/kg), using a progressive-ratio (PR) schedule in rhesus monkeys (n = 4). PR schedules of reinforcement are frequently used to measure reinforcing strength of drugs. Earlier research using limited-access conditions reported that cocaine was a stronger reinforcer than either RTI-336 or RTI-177. Because the 3-phenyltropanes have longer durations of action, one purpose of the present study was to examine reinforcing strength using longer experimental sessions. Under these conditions, cocaine functioned as a reinforcer in all monkeys, and RTI-336 and RTI-177 functioned as a reinforcer in three of four subjects. Consistent with their documented slower onset of neurochemical and pharmacological effects, RTI-336 and RTI-177 were weaker reinforcers, resulting in fewer injections than cocaine. On average, the potencies of the two RTI compounds were not different than that of cocaine. These results support the view that slow-onset DA-selective uptake inhibitors have lower abuse liability than cocaine. In addition, the present findings suggest that changes in PR session length can influence potency comparisons between drugs, but not measures of reinforcing strength.     

Pharmacological determinants of the reinforcing effects of psychostimulants: relation to agonist substitution treatment

Illicit use of psychostimulants, such as cocaine and methamphetamine, continues to pose a significant public health concern. On the basis of the relative success at treating opiate and tobacco users with agonist substitution treatments, this strategy has been pursued in the search for a pharmacotherapy for psychostimulant addiction. The reinforcing effects of drugs are central to their abuse liability; therefore, gaining a better understanding of the factors that determine the reinforcing effects of psychostimulants should inform the development of an effective treatment. Although the reinforcing effects of drugs are known to be multiply determined, the author's dissertation research focused on pharmacological factors. This review presents results from that research as well as findings reported in the extant literature, suggesting that the reinforcing effects of psychostimulant drugs are determined both by their pharmacodynamic and pharmacokinetic profiles. There is evidence to support the conclusion that affinity for dopamine transporters appears to be of critical importance, whereas serotonin transporters seem to serve a modulatory function. A more rapid rate of onset may enhance a drug's reinforcing effects, but a drug with a slow onset can still maintain self-administration. A drug's duration of action may only influence the rate but not the strength of responding that is maintained. Slow-onset, long-acting monoamine transporter ligands can be expected to have reinforcing effects and therefore abuse liability, which has implications for the use of these drugs as pharmacotherapies. Nonetheless, on the basis of promising preclinical and clinical findings, this appears to represent a viable treatment strategy.