恩施硒茶对小鼠低氧/复氧损伤的保护作用及氯胺酮对这种保护作用的调节

目的 :探讨恩施硒茶对小鼠低氧 /复氧 (H /R)损伤的保护作用及氯胺酮对这种保护作用的调节。方法 :将小鼠用硒茶和氯胺酮处理后 ,建立小鼠H /R模型 ,观察血液中的活性氧 (ROS)、超氧化物歧化酶 (SOD)、过氧化氢酶 (CAT )等的变化。结果 :硒茶组和氯胺酮组ROS均减少 ,且氯胺酮的作用明显强于硒茶 ;硒茶组SOD及CAT活性增强 (P <0 .0 1 ) ,氯胺酮组SOD活性明显减弱(P <0 .0 1 ) ,氯胺酮、硒茶联合组ROS、MDA明显减少 (P <0 .0 1 )。结论 :硒茶有很强的抗氧化作用 ,它能清除体内的ROS ,氯胺酮能清除ROS ,降低SOD的活力 ;二者联合能更有效地清除ROS。     

氯胺酮对小鼠Ⅲ度烧伤死亡率和瘢痕形成的作用

目的观察氯胺酮对小鼠Ⅲ度烧伤死亡率和疤痕形成的作用,为临床应用提供实验依据。方法小鼠背部用95%酒精造成Ⅲ度火焰烧伤,烧伤面积7cm2,烧伤时间30s;氯胺酮用量10～20mg/kg,分别于烧伤后或烧伤前后腹腔注射,对照组注射等量生理盐水,通过烧伤小鼠早期死亡率和烧伤后期瘢痕面积观察其作用。结果 BALB/c和C57BL/6小鼠烧伤后立即、4h、24h腹腔注射氯胺酮20mg/kg,小鼠死亡率分别为42.8%和100%,与对照组无明显差别（P〉0.05）;C57BL/6小鼠烧伤前10min和烧伤后4h、24h注射氯胺酮10mg/kg,小鼠死亡率为100%,与对照组也无差别。烧伤时间减为20s,于烧伤烧伤后立即和24h注射氯胺酮20mg/kg,35d后测定瘢痕面积,治疗组明显小于对照组（P〈0.05）。结论氯胺酮无明显降低小鼠烧伤早期死亡率的效果,但有减少烧伤瘢痕面积的作用,可能与氯胺酮抗炎作用有关。     

氯胺酮诱导细胞自噬的研究进展

氯胺酮是一种N-甲基-D-天冬氨酸受体(NMDAR)拮抗剂,常作为分离性麻醉剂广泛应用于临床和外科手术中,因其具有较强的致幻效应并使人产生欣快感而在众多娱乐场所中被消遣滥用。此外,氯胺酮还是一种起效迅速的抗抑郁药,对中枢神经系统兼有兴奋和抑制作用,但是长期使用氯胺酮会对中枢神经系统产生较强的神经毒性和精神依赖性。自噬是一个溶酶体依赖性降解蛋白质和细胞器以维持内环境稳态的过程。在氯胺酮诱导神经毒性的过程中,自噬具有双向调控的作用,可加重或减轻机体的神经毒性,但其具体的机制尚不清楚。该文主要从氯胺酮诱导细胞自噬的机制、氯胺酮诱导的自噬与神经毒性的关系以及药物对氯胺酮神经毒性的干预作用等方面进行综述,旨在为进一步研究氯胺酮诱导细胞自噬的机制以及自噬在氯胺酮神经毒性中的调控机制提供参考。     

Apelin receptor(APJ)拮抗剂F13A对小鼠抑郁样行为的影响及起效时间*

目的:明确apelin receptor(APJ)拮抗剂F13A对小鼠抑郁样行为的影响及起效时间。方法:实验小鼠随机分成对照组(Control),F13A组(F13A)和氯胺酮组(ketamine),每组9只,对照组小鼠腹腔注射生理盐水(10 ml/kg,ip)+侧脑室注射生理盐水(每职1μl,i.c.v),F13A组小鼠腹腔注射生理盐水(10 ml/kg,ip)+侧脑室注射F13A(6 μg/μl,i.c.v),氯胺酮组小鼠腹腔注射氯胺酮(10 ml/kg, 2 mg/ml,ip)+侧脑室注射生理盐水(1μl,i.c.v);实验分三批进行,第一批实验在注射后30 min,进行第一次强迫游泳测试(FST1),FST1后24 h进行第二次强迫游泳测试(FST2);第二批实验在注射后30 min进行第一次自发活动测试(LMT1),LMT1前24 h进行自发活动习惯化,LMT1后24 h进行第二次自发活动测试(LMT2);第三批实验注射后30 min进行FST1,FST1前24 h进行强迫游泳应激(FSS),FST1后24 h进行第二次强迫游泳测试(FST2)。 结果:与对照组比较,在无FSS时,氯胺酮组小鼠不动时间显著性减少(P﹤0.01),而F13A组小鼠无明显变化;在FST2中,F13A组小鼠不动时间显著性增加(P﹤0.01),而氯胺酮组小鼠无显著性差异;在LMT1和LMT2中各组小鼠活动度均无显著性差异;在经历FSS后,在FST1中氯胺酮组、F13A组小鼠不动时间均显著性减少(P﹤0.01);在FST2中,F13A组小鼠的不动时间显著性减少(P﹤0.05),而氯胺酮组小鼠无显著性差异(P＞0.05)。结论:APJ受体拮抗剂F13A在强迫游泳测试中发挥快速起效(30 min)且持久作用(24 h)的抗抑郁样潜力,并且这种作用可能与应激有关。     

低剂量氯胺酮对工作记忆的影响

氯胺酮是一种N-甲基-D-天冬氨酸受体（NMDAR）阻滞剂，低剂量氯胺酮具有良好的镇痛、抗炎和抗抑郁作用，近年来受到了广泛的关注。但是低剂量氯胺酮对于高级认知功能的影响尚未全面阐明。工作记忆是涉及众多复杂认知活动的关键功能，有研究显示低剂量氯胺酮急性或慢性使用均会损伤工作记忆，其神经机制也开始受到关注。深入分析低剂量氯胺酮对于工作记忆的影响及其机制对于指导氯胺酮的临床使用具有重要意义。本文首先介绍了低剂量氯胺酮作用于神经系统的药理作用途径，以及工作记忆本身的神经环路机制，进而回顾了近年来关于低剂量氯胺酮对工作记忆的急性和慢性作用的相关研究，并重点分析了低剂量氯胺酮损伤工作记忆的可能的神经机制，希望对低剂量氯胺酮在临床中的合理使用提供科学依据。     

非人灵长类个性化麻醉方案的探讨

目的 比较氯胺酮、舒泰、速眠新Ⅱ、戊巴比妥钠等4种全身麻醉药或其组合对非人灵长类的麻醉效果,探寻能替代或者减少氯胺酮使用的个性化麻醉方案。方法 以单独使用氯胺酮麻醉的方案作为对照,另设单独使用舒泰、氯胺酮复合速眠新Ⅱ、舒泰复合速眠新Ⅱ和戊巴比妥钠复合速眠新Ⅱ等麻醉4个实验组,每组选取5只食蟹猴进行实验,记录麻醉后的心率、体温、血氧饱和度、以及麻醉诱导时间和维持时间,以比较各方案的麻醉效果。结果 与单独使用氯胺酮麻醉比较,其他四种麻醉方案在心率、体温、血氧饱和度和麻醉诱导时间上均无显著性差异,不同方案麻醉维持时间分布在30~200min之间。在非人灵长类的全身麻醉中,舒泰可以很好地替代氯胺酮;氯胺酮复合速眠新Ⅱ麻醉可取得较长的麻醉维持时间,并减少氯胺酮的使用量;舒泰与速眠新Ⅱ联用、戊巴比妥钠与速眠新Ⅱ联用的方案也可替代氯胺酮,且麻醉维持时间较长。结论 在一定的麻醉时间内,联合用药可以降低氯胺酮的使用量,不同麻醉方案灵活运用可满足不同实验对麻醉维持时间的需求。     

氯胺酮快速抗抑郁作用及其机制

抑郁症是一种常见精神疾病,极大影响人类健康。传统抗抑郁药治疗起效慢、缓解率低。氯胺酮作为一种全身麻醉剂广泛应用于临床,近年来发现其具有快速、高效的抗抑郁作用。其抗抑郁作用可能与NMDA受体、AMPA受体、BDNF、m TOR、GSK-3、突触可塑性等密切相关,但具体机制仍不清楚。深入研究氯胺酮快速抗抑郁的作用机制对新型快速抗抑郁药物的研究具有重要意义。     

柚皮苷及其与吴茱萸碱联合用药对APPswe/PS△E9转基因痴呆模型小鼠学习记忆能力的影响

目的 探讨柚皮苷及柚皮苷与吴茱萸碱联合用药对APPswe/PS△E9转基因痴呆模型小鼠学习记忆能力的影响,研究柚皮苷与吴茱萸碱联合使用是否具有协同或叠加作用.方法 APPswe/PS△E9转基因痴呆模型小鼠随机分组,每组12只,雌雄各半,分别选择在3月龄和5月龄两个时间段开始进行治疗,各给药组按设定剂量分别单独或联合加入鼠粮中.3月龄给药16周、5月龄给药4周后进行水迷宫实验,以安理申作为阳性药对照,并与安慰剂组小鼠进行比较.Thioflavin-S荧光染色检测单独使用柚皮苷治疗转基因小鼠脑组织老年斑的形成.结果 单独使用柚皮苷4周和16周,缩短寻找平台的潜伏期分别为22％、32％;单独使用吴茱萸碱4周和16周,缩短寻找平台的潜伏期分别为33％、10％.柚皮苷治疗16周减少海马老年斑26％.柚皮苷与吴茱萸碱联合应用能够显著缩短寻找平台的潜伏期47％.结论 单独使用柚皮苷或吴茱萸碱均能改善痴呆模型小鼠的学习记忆能力,柚皮苷长期的使用优于短期的治疗效果,但是吴茱萸碱短期有效,长期作用反而下降;柚皮苷与吴茱萸碱联合应用能够显著改善APPswe/PS△E9痴呆模型小鼠的学习记忆能力,但联合用药组并未表现出强于单独给药组的协同保护效应.     

慢性槲皮素增强小鼠空间学习记忆

利用小鼠D-半乳糖衰老模型, 通过Morris水迷宫(MWM)等动物行为实验和小鼠皮层与海马组织还原型谷胱甘肽和羟自由基含量测定等生化指标实验, 对槲皮素延缓脑衰老作用和机制进行了研究. 实验结果表明, 槲皮素能提高D-半乳糖衰老模型小鼠的空间搜索学习和记忆能力, 这些作用与槲皮素改善衰老小鼠皮层和海马的功能、抑制氧化应激反应有关, 与增加还原型谷胱甘肽含量以减少羟自由基含量有关. 为充分利用槲皮素作为一种天然的抗衰老药物奠定了良好的实验基础.     

多肽免疫抑制牙龈卟啉单胞菌引起的小鼠感染及牙槽骨吸收作用的研究

目的探讨牙龈卟啉单胞菌(Porphyromonasgingivalis,P.g)血凝素2(hemagglutinin-2,HA-2)的氯化血红素结合位点多肽作为抗原免疫小鼠,对降低P.g感染后毒性和抑制牙周炎牙槽骨吸收的作用。方法将多肽与牛血清白蛋白(Bovine serum albumin,BSA)偶联作为抗原免疫BALB/c小鼠。P.g国际标准菌株ATCC33277厌氧培养,皮下注射菌液,监测小鼠脓肿的大小及转归,评价多肽对P.g皮下感染的保护作用;口腔接种细菌感染小鼠,检测小鼠牙周炎牙槽骨吸收量,评价其对于P.g引起的牙周炎牙槽骨吸收的保护作用。结果多肽DGFPGDHYAVMISK作为抗原免疫小鼠可减小小鼠皮下接种P.g处形成脓肿的大小,并加快皮下脓肿的愈合;可抑制口腔感染P.g后小鼠牙周炎模型牙槽骨的吸收。结论多肽DGFPGDHYAVMISK免疫小鼠对P.g感染小鼠具有一定的保护作用;可减少小鼠牙周炎模型牙槽骨的吸收。为开发新的牙周病防治方法奠定基础。     

Mice Lacking NMDA Receptors in Parvalbumin Neurons Display Normal Depression-Related Behavior and Response to Antidepressant Action of NMDAR Antagonists

The underlying circuit imbalance in major depression remains unknown and current therapies remain inadequate for a large group of patients. Discovery of the rapid antidepressant effects of ketamine - an NMDA receptor (NMDAR) antagonist – has linked the glutamatergic system to depression. Interestingly, dysfunction in the inhibitory GABAergic system has also been proposed to underlie depression and deficits linked to GABAergic neurons have been found with human imaging and in post-mortem material from depressed patients. Parvalbumin-expressing (PV) GABAergic interneurons regulate local circuit function through perisomatic inhibition and their activity is NMDAR-dependent, providing a possible link between NMDAR and the inhibitory system in the antidepressant effect of ketamine. We have therefore investigated the role of the NMDAR-dependent activity of PV interneurons for the development of depression-like behavior as well as for the response to rapid antidepressant effects of NMDAR antagonists. We used mutant mice lacking NMDA neurotransmission specifically in PV neurons (PV-Cre+/NR1f/f) and analyzed depression-like behavior and anhedonia. To study the acute and sustained effects of a single NMDAR antagonist administration, we established a behavioral paradigm of repeated exposure to forced swimming test (FST). We did not observe altered behavioral responses in the repeated FST or in a sucrose preference test in mutant mice. In addition, the behavioral response to administration of NMDAR antagonists was not significantly altered in mutant PV-Cre+/NR1f/f mice. Our results show that NMDA-dependent neurotransmission in PV neurons is not necessary to regulate depression-like behaviors, and in addition that NMDARs on PV neurons are not a direct target for the NMDAR-induced antidepressant effects of ketamine and MK801.     

Physiological,pharmacokinetic and liver metabolism comparisons between 3-, 6-, 12- and 18-month-old male Sprague Dawley rats under ketamine-xylazine anesthesia

The main objective of this study was to compare the physiological changes (withdrawal and corneal reflexes, respiratory and cardiac frequency, blood oxygen saturation, and rectal temperature) following intraperitoneal administration of ketamine (80 mg/kg) and xylazine (10 mg/kg) to 3-, 6-, 12- and 18-month-old male Sprague Dawley rats (n=6/age group). Plasma pharmacokinetics, liver metabolism, and blood biochemistry were examined for a limited number of animals to better explain anesthetic drug effects. Selected organs were collected for histopathology. The results for the withdrawal and corneal reflexes suggest a shorter duration and decreased depth of anesthesia with aging. Significant cardiac and respiratory depression, as well as decreased blood oxygen saturation, occurred in all age groups however, cardiac frequency was the most affected parameter with aging, since the 6-, 12-, and 18-month-old animals did not recuperate to normal values during recovery from anesthesia. Pharmacokinetic parameters (T_1/2 and AUC) increased and drug clearance decreased with aging, which strongly suggests that drug exposure is associated with the physiological results. The findings for liver S9 fractions of 18-month-old rats compared with the other age groups suggest that following a normal ketamine anesthetic dose (80 mg/kg), drug metabolism is impaired, leading to a significant increase of drug exposure. In conclusion, age and related factors have a substantial effect on ketamine and xylazine availability, which is reflected by significant changes in pharmacokinetics and liver metabolism of these drugs, and this translates into shorter and less effective anesthesia with increasing age.     

Effects of phencyclidine and ketamine on cardiovascular activity and temperature in the squirrel monkey

Heart rate (HR), mean arterial blood pressure (BP) and core temperature (TEMP) were recorded from chair-restrained squirrel monkeys surgically prepared with chronically indwelling arterial and venous catheters to determine the effects of acute intravenous (i.v.) injections of phencyclidine and ketamine and intramuscular (i.m.) injections of ketamine. Phencyclidine (0.03-3.0 mg/kg) and ketamine (0.3-30.0 mg/kg) i.v. increased BP and decreased TEMP, and the changes in BP and in TEMP were greater in magnitude and duration after phencyclidine. Heart rate also increased monotonically after 0.03-0.3 mg/kg phencyclidine or 0.3-10.0 mg/kg ketamine, but the effects of higher doses of either drug were biphasic with decreases followed by increases in HR. When either of two doses of ketamine (10.0 and 30.0 mg/kg) was injected i.m., the effects were qualitatively similar to those observed after i.v. administration although of much less magnitude, and there was no evidence of a biphasic change in HR. The data show that these two dissociative anesthetics differ in duration of action and in magnitude of effect on cardiovascular activity and core temperature in the squirrel monkey, and that phencyclidine is approximately ten times as potent as ketamine.     

Combined Effects of a Metabolic Inhibitor (Gabaculine) and an Uptake Inhibitor (Ketamine) on the γ-Aminobutyrate System in Mouse Brain

Abstract: The intramuscular administration of a γ-aminobutyrate-α-oxoglutarate aminotransferase (GABA-T) inhibitor, gabaculine, to mice resulted in significant increases in GABA content and decreases in the content of aspartate, glutamate, and glutamine in the nerve endings (synaptosomes). These effects were ameliorated by the concurrent administration of the GABA uptake inhibitor ketamine. A major cause of these effects was the gabaculine-induced inhibition of GABA-T activity and the lessening of this inhibition by ketamine. The latter phenomenon was not due to a direct action of ketamine on the enzyme, nor to an interaction between gabaculine and ketamine. Rather, it appeared that ketamine might be interfering with the transport of gabaculine into the cellular structures. The anticonvulsant action of the GABA-T inhibitor and the GABA uptake inhibitor together was little different from that of the GABA-T inhibitor alone.     

Long-Lasting Antidepressant Action of Ketamine,but Not Glycogen Synthase Kinase-3 Inhibitor SB216763, in the Chronic Mild Stress Model of Mice

Background

Clinical studies demonstrate that the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, induces rapid antidepressant effects in patients with refractive major depressive disorder and bipolar depression. This rapid onset of action makes ketamine a highly attractive drug for patients, particularly those who do not typically respond to therapy. A recent study suggested that glycogen synthase kinase (GSK)-3 may underlie the rapid antidepressant action of ketamine, although the precise mechanisms are unclear. In this study, we examined the effects of ketamine and GSK-3 inhibitor SB216763 in the unpredictable, chronic mild stress (CMS) mouse model of mice.

Methodology/Principal Findings

Adult C57/B6 male mice were divided into 2 groups, a non-stressed control group and the unpredictable CMS (35 days) group. Then, either vehicle, ketamine (10 mg/kg), or the established GSK-3 inhibitor, SB216763 (10 mg/kg), were administered into mice in the CMS group, while vehicle was administered to controls. In the open field test, there was no difference between the four groups (control+vehicle, CMS+vehicle, CMS+ketamine, CMS+SB216763). In the sucrose intake test, a 1% sucrose intake drop, seen in CMS mice, was significantly attenuated after a single dose of ketamine, but not SB216763. In the tail suspension test (TST) and forced swimming test (FST), the increased immobility time seen in CMS mice was significantly attenuated by a single dose of ketamine, but not SB216763. Interestingly, the ketamine-induced increase in the sucrose intake test persisted for 8 days after a single dose of ketamine. Furthermore, a single administration of ketamine, but not SB216763, significantly attenuated the immobility time of the TST and FST in the control (non-stressed) mice.

Conclusions/Significance

These findings suggest that a single administration of ketamine, but not GSK-3 inhibitor SB216763, produces a long-lasting antidepressant action in CMS model mice.     

Comparison of psychic emergence reactions after (+/-)-ketamine and (+)-ketamine in mice

Ketamine is a racemic mixture containing equal parts of (+)-ketamine and (-)-ketamine. The ketamine enantiomorphs are different in anesthesia and psychic emergence reactions after anesthesia. Therefore, (+)-ketamine was compared with racemic ketamine in a number of randomized studies in volunteers and patients. However, their relations remain controversial. In the present studies, the psychic emergence reactions after injection of (+/-)-ketamine and (+)-ketamine were compared in mice. At equimolar doses, the (+)-isomers elicited episodes of hypnosis nearly 1.4-fold more potent than those of the racemic ketamine. After the administration of equihypnotic doses of (+)-ketamine and (+/-)-ketamine, the posthypnotic stimulation of locomotor activity, stereotype behavior and 5-HT-induced head-twitch response by the (+)-enantiomorph was significantly less intense than that of racemic ketamine. In receptor binding test, (+)-ketamine showed a higher affinity for NMDA receptor than that of (+/-)-ketamine, while (+)-ketamine and (+/-)-ketamine showed no affinity for dopamine D2 and serotonin 5-HT2 receptor. These results suggest that the (+)-ketamine has fewer posthypnotic side effects than (+/-)-ketamine when (+)-ketamine and (+/-)-ketamine were administered at equihypnotic dosages and that dopamine D2 and serotonin 5-HT2 receptor were not involved in the effects of (+)-ketamine and (+/-)-ketamine.     

The involvement of nitric oxide in the analgesic effects of ketamine

We investigated the contribution of NO-cyclic GMP (cGMP) pathway to the antinociceptive effects of ketamine in mice by using the nitric oxide synthase inhibitor, nitro(g)- L-arginine methyl ester (L-NAME). Intraperitoneal (i.p.) (1, 5 or 10 mg/kg) or intrathecal (i.th.) (10, 30 or 60 microg/mouse) administration of ketamine produced dose-dependent antinociceptive effects in the acetic acid-induced writhing and formalin tests but not in the tail-flick nor in hot-plate tests. Pretreatment of mice with L-NAME (10 mg/kg, i.p.) which produced no antinociception on its own, significantly inhibited the antinociceptive effect of ketamine (1, 5 or 10 mg/kg, i.p.). However, L-NAME (30 microg/mouse) was given intrathecally, it neither modified the antinociceptive effect of i.th. ketamine (10, 30 or 60 microg/mouse) nor did it produce an antinociceptive effect alone. These data suggest that the activation of the NO-cGMP pathway probably at the supraspinal level, but not spinal level, contributes to the antinociceptive effects of ketamine.     

Instant and Lasting Down-Regulation of NR1 Expression in the Hippocampus is Associated Temporally with Antidepressant Activity After Acute Yueju

Accumulating evidence indicated that N-methyl-d-aspartate (NMDA) receptors are involved in the pathophysiology of depression and implicated in therapeutic targets. NMDA antagonists, such as ketamine, displayed fast-onset and long-lasting antidepressant activity in preclinical and clinical studies. Previous studies showed that Yueju pill exerts antidepressant effects similar to ketamine. Here, we focused on investigating the association of acute and lasting antidepressant responses of Yueju with time course changes of NMDA receptor subunits NR1, NR2A, and NR2B expressions in the hippocampus, a key region regulating depression response. As a result, Yueju reduced immobility time in the forced swimming test from 30 min to 5 days post a single administration. Yueju acutely decreased NR1 and NR2B protein expression in the hippocampus, with NR2A expression unaltered. NR1 expression remained down-regulated 5 days post Yueju administration, whereas NR2B returned to normal level in 24 h. Yueju and ketamine similarly ameliorated the depression-like symptoms at least for 72 h in learned helplessness test. They both reversed the up-regulated expression of NR1 in the learned helpless mice 1 or 3 days post administration. Different from ketamine, the antidepressant effects of Yueju were not influenced by blockade of amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor. These findings served as preclinical evidence that Yueju may confer acute and long-lasting antidepressant effects by favorably modulating NMDA function in the hippocampus.     

Gene expression changes in GABA(A) receptors and cognition following chronic ketamine administration in mice

Ketamine is a well-known anesthetic agent and a drug of abuse. Despite its widespread use and abuse, little is known about its long-term effects on the central nervous system. The present study was designed to evaluate the effect of long-term (1- and 3-month) ketamine administration on learning and memory and associated gene expression levels in the brain. The Morris water maze was used to assess spatial memory and gene expression changes were assayed using Affymetrix Genechips; a focus on the expression of GABA(A) receptors that mediate a tonic inhibition in the brain, was confirmed by quantitative real-time PCR and western blot. Compared with saline controls, there was a decline in learning and memory performance in the ketamine-treated mice. Genechip results showed that 110 genes were up-regulated and 136 genes were down-regulated. An ontology analysis revealed the most significant effects of ketamine were on GABA(A) receptors. In particular, there was a significant up-regulation of both mRNA and protein levels of the alpha 5 subunit (Gabra5) of the GABA(A) receptors in the prefrontal cortex. In conclusion, chronic exposure to ketamine impairs working memory in mice, which may be explained at least partly by up-regulation of Gabra5 subunits in the prefrontal cortex.     

An animal model of emotional blunting in schizophrenia

Schizophrenia is often associated with emotional blunting--the diminished ability to respond to emotionally salient stimuli--particularly those stimuli representative of negative emotional states, such as fear. This disturbance may stem from dysfunction of the amygdala, a brain region involved in fear processing. The present article describes a novel animal model of emotional blunting in schizophrenia. This model involves interfering with normal fear processing (classical conditioning) in rats by means of acute ketamine administration. We confirm, in a series of experiments comprised of cFos staining, behavioral analysis and neurochemical determinations, that ketamine interferes with the behavioral expression of fear and with normal fear processing in the amygdala and related brain regions. We further show that the atypical antipsychotic drug clozapine, but not the typical antipsychotic haloperidol nor an experimental glutamate receptor 2/3 agonist, inhibits ketamine's effects and retains normal fear processing in the amygdala at a neurochemical level, despite the observation that fear-related behavior is still inhibited due to ketamine administration. Our results suggest that the relative resistance of emotional blunting to drug treatment may be partially due to an inability of conventional therapies to target the multiple anatomical and functional brain systems involved in emotional processing. A conceptual model reconciling our findings in terms of neurochemistry and behavior is postulated and discussed.