Caloric restriction increases the sensitivity to the hyperphagic effect of nociceptin/orphanin FQ limiting its ability to reduce binge eating in female rats

Rationale

Several studies have documented impairments in memory processes as a result of ketamine administration; however, few studies have compared the profile of cognitive effects of ketamine to other drugs.

Objectives

The aim of this study was to compare the cognitive effects of ketamine with those of triazolam in healthy volunteers.

Methods

Doses of ketamine (0.2, 0.4 mg/kg intramuscular (i.m.)), triazolam (0.2, 0.4 mg/70 kg p.o.), and double-dummy placebos were administered to 20 volunteers under repeated measures, counterbalanced, double-blind conditions. Peak physiological, psychomotor, subjective, and cognitive effects were examined.

Results

Ketamine impaired balance when balance was assessed early in the task order, whereas triazolam impaired psychomotor coordination and divided attention irrespective of task order. Triazolam also tended to produce greater effects on working memory and episodic memory tasks than ketamine at doses that produced lower subjective effects and higher estimates of performance.

Conclusions

Ketamine produces less cognitive impairment than triazolam at doses that produced greater subjective effects. Thus ketamine does not produce the underestimation of cognitive impairment typically seen with triazolam.     

Effects of ketamine on the peripheral autonomic nervous system of the rat.

The effects of ketamine (2-(o-chlorophenyl) 2-methylaminocyclohexanone) (2-50 mg/kg) on the responses of the pithed rat arterial pressure, anococcygeus muscle and colon to selective stimulation of the spinal autonomic outflows were examined. Ketamine depressed the vasopressor response produced by stimulation of the lumbar sympathetic outflow in a dose-dependent manner but did not significantly affect the pressor response to intravenous noradrenaline (NA) administration. Ketamine depressed the motor responses of the anococcygeus to stimulation of the pre-ganglionic lumbar sympathetic outflow or to stimulation of post-ganglionic fibres in the sacral region in a dose-dependent manner, the response to preganglionic stimulation being relatively more sensitive to such depression. The anococcygeus response to NA was significantly potentiated with doses of ketamine of 20 mg/kg and 50 mg/kg. Ketamine depressed the motor response of the smooth muscle of the colon to stimulation of the sacral parasympathetic outflow in a dose-dependent manner and at lower doses than were required to produce an equivalent depression of the sympathetic responses in the other tissues. A comparison was made of the effects of ketamine and cocaine on the motor responses of the anococcygeus muscle in vitro to NA, carbachol and field stimulation. Both ketamine and cocaine produced a non-specific depression of all responses at high doses whereas cocaine but not ketamine produced a large potentiation of NA and motor nerve responses at lower doses. The results are discussed in relation to the hypothesis that ketamine might elevate blood pressure in conscious animals and man by potentiating vascular adrenergic responses.     

Effect of a subanesthetic dose of ketamine on memory and conscious awareness in healthy volunteers

RATIONALE: Ketamine is an NMDA receptor antagonist with psychotogenic and cognitive effects in healthy volunteers and schizophrenic patients which has been proposed to be a useful tool to investigate neurobiological basis of schizophrenia. OBJECTIVE: The present study characterized the effects of a subanesthetic dose of ketamine on memory and related subjective states of awareness in healthy volunteers. METHODS: Twenty-six subjects were given either a 60-min ketamine (0.5 mg/kg per hour) or a placebo infusion. To obtain constant plasma ketamine throughout the experiment, ketamine was administered using a computer-controlled infusion system. Subjects carried out episodic memory tasks involving words presented before and during infusion. Memory performance was assessed with recognition and free recall tasks. Subjective states of awareness were assessed using an experiential approach. Levels of psychopathology were evaluated with BPRS. RESULTS: Ketamine impaired performance in free recall and recognition of words presented during, but not before, infusion. There were no differences between groups concerning states of awareness associated with recognition memory. Subjects under ketamine had higher BPRS total scores as well as BPRS negative and positive cluster scores than control subjects. CONCLUSIONS: Ketamine decreases episodic memory performance by impairing encoding, but not retrieval processes. It does not selectively impair subjective states of awareness associated with recognition memory as it has been seen in patients with schizophrenia. Ketamine might mimic the memory impairment associated with acute, but not chronic, forms of schizophrenia.     

Interactions of verapamil and diltiazem with ketamine: effects on memory and sleeping time in mice

The effects of ketamine (3, 10 and 30 mg/kg) alone and in combination with verapamil (10 mg/kg) or diltiazem (30 mg/kg) on the acquisition, consolidation and retrieval of memory using a passive avoidance task in mice were studied. Ketamine significantly inhibited the acquisition and consolidation of memory at 10 and 30 mg/kg dose levels and these effects were antagonized by diltiazem 30 mg/kg but not by verapamil 10 mg/kg. Studies of sleeping time demonstrated that pretreatment with verapamil 10 mg/kg increased the duration of sleeping time. Diltiazem, however, did not potentiate the effects of ketamine on sleeping time. The present findings indicate that diltiazem can counter the effects of ketamine on memory. The data also indicates that pretreatment of surgical patients with verapamil may reduce the dose of ketamine required for anesthesia.     

Effects of morphine sulfate on operant behavior in rhesus monkeys

The acute effects of morphine sulfate were assessed using a battery of complex food-reinforced operant tasks that included temporal response differentiation (TRD, n = 5), delayed matching-to-sample (DMTS, n = 6), progressive ratio (PR, n = 9), incremental repeated acquisition (IRA, n = 9), and conditioned position responding (CPR, n = 7) tasks. Performance in these tasks is thought to depend upon specific brain functions such as time perception (TRD), learning (IRA), short-term memory and attention (DMTS), color and position discrimination (CPR), and motivation to work for food (PR). Morphine sulfate (0.1-5.6 mg/kg IV), given 15 min presession, produced significant dose-dependent decreases in the number of reinforcers obtained in each task. Response accuracy was significantly decreased at doses greater than or equal to 1.0 mg/kg for TRD when compared to saline injections. Accuracy was not consistently affected in any other task in the test battery. Response rates decreased or response latencies increased significantly at doses of 1.0 mg/kg and above for the PR task, at 3.0 mg/kg and above for the IRA and TRD tasks, and only at the highest dose 5.6 mg/kg in the CPR and DMTS tasks. Percent task completed was decreased following doses of 1.0 mg/kg and higher for the IRA, PR and TRD tasks, at doses of 3.0 mg/kg and higher for the DMTS task, and at the high dose of 5.6 mg/kg for the CPR task. These results indicate that in monkeys, the performance of operant tasks designed to model learning ability (IRA), time perception (TRD) and motivation (PR) are more sensitive to the disruptive effects of morphine than is performance in tasks designed to model short-term memory and attention (DMTS). The task which models color and position discrimination (CPR) was the least sensitive to disruption by morphine.     

Acute effects of ketamine on memory systems and psychotic symptoms in healthy volunteers.

N-methyl-D-aspartate (NMDA) receptor antagonists have been demonstrated to induce schizophrenia-like symptoms and cognitive impairment in humans. The NMDA receptor has been strongly implicated in memory, but research to date on the effects of NMDA antagonists has examined only some aspects of human memory functions. This study used a double-blind, placebo-controlled, independent groups design with 54 healthy volunteers to examine the effects of infusions of two doses (0.4, 0.8 mg/kg) of the NMDA antagonist ketamine upon the five human memory systems, aspects of executive functioning and schizophrenia-like and dissociative symptoms. Ketamine produced a dose-dependent impairment to episodic and working memory and a slowing of semantic processing. Ketamine also impaired recognition memory and procedural learning. Attention, perceptual priming and executive functioning were not affected following the drug. In addition, ketamine induced schizophrenia-like and dissociative symptoms, which were not correlated with the cognitive measures. These data suggest that, in humans, ketamine produces a selective pattern of impairments to working, episodic, and procedural memory but not to perceptual priming, attention or aspects of executive functioning.     

Impaired spatial memory after ketamine administration in chronic low doses

Ketamine is a noncompetitive antagonist of the NMDA-receptors, used as a dissociative anesthetic, presently included in the category of the psychoactive substances known as "club drugs". Ketamine administration was associated with impaired working memory and increased psychopathological symptoms, but there is a lack of information regarding the effects of chronic sub-anesthetic doses. Adult Wistar rats were administered ketamine, 5 and 10 mg/kg twice daily, subcutaneously for 14 days. One week later, rats were tested in an object recognition/object location task and in the open field arena. There was altered performance in both the object recognition/location and in the open field tests by the group chronically exposed to the lower dose of ketamine. These animals displayed a decreased discrimination index (p<0.05) in the object recognition task, were unable to recognize the displacement of a familiar object and displayed decreased activity across open filed sessions. Importantly, these alterations were not observed in animals administered a higher dose of ketamine. Collectively, these results consistently show that chronic administration of ketamine in sub-anesthetic doses may lead to decreased habituation and inability to update spatial representations.     

Ketamine impairs response inhibition and is positively reinforcing in healthy volunteers: a dose–response study

Rationale Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist that has medical indications but is also used as a recreational drug. Previous research has found persisting cognitive and psychotogenic effects of ketamine in chronic abusers of this drug 3 days after an acute dose.Objective The present study aimed to investigate the effects of ketamine on two processes related to drug abuse, response inhibition and reinforcement, and to examine whether an acute dose of ketamine produced residual cognitive effects in healthy volunteers.Methods Fifty-four healthy volunteers were given an 80-min infusion of one of two doses (0.4, 0.8 mg kg^–1) of ketamine or placebo. Subjects completed a battery of tests at three time points: pre-infusion, during the infusion and 3 days later at follow-up. The battery consisted of tests of episodic and semantic memory, schizophrenic-like and dissociative symptoms, response inhibition and measures of subjective effects, including mood, bodily symptoms and enjoyment of and desire for the drug.Results Ketamine acutely impaired response inhibition and had related biphasic effects on the subjective reinforcing effects of the drug. Ketamine also acutely impaired episodic but not semantic memory and increased schizophrenic-like and dissociative symptoms. No residual cognitive effects were observed 3 days following an acute dose.Conclusions The lack of residual effects in healthy volunteers on day 3 indicates that impairments found on day 3 in ketamine abusers are chronic effects. The abuse of ketamine may be related to its capacity both to reinforce and to decrease response inhibition.     

Effects of etomidate,ketamine or propofol,and their combinations with conventional antiepileptic drugs on amygdala-kindled convulsions in rats

Ketamine, etomidate and propofol modified behavioral and electrographic correlates of kindled seizures in rats. In detail, ketamine (5 mg/kg) and propofol (15 mg/kg) significantly increased afterdischarge threshold, reduced seizure severity and shortened seizure and afterdischarge durations. Etomidate (7.5 mg/kg) was effective in terms of seizure and afterdischarge durations. Moreover, the combinations of ketamine (2.5 mg/kg) with carbamazepine (15 mg/kg) or valproate (50 mg/kg; all drugs at their subeffective doses), reduced the severity and duration of kindled seizures. The antiseizure potency of the ketamine/carbamazepine combination was comparable to that of carbamazepine alone administered at 20 mg/kg, while the effect of ketamine/valproate was comparable to the efficacy of valproate alone at 100 mg/kg. However, the combinations of ketamine with phenobarbital or diphenylhydantoin did not exert any protective action. Propofol and etomidate entirely failed to interact with conventional antiepileptics. The combinations of ketamine with carbamazepine or valproate did not induce any significant motor impairment in the chimney test or memory deficit in the passive avoidance task. A pharmacokinetic interaction, at least in plasma, can be excluded, because ketamine (2.5 mg/kg) did not affect the free plasma concentrations of carbamazepine or valproate. Results of the present study may suggest that there may be no risk of negative interactions between injectable anesthetics and antiepileptics in cases of partial epilepsy.     

Ketamine inhibits serotonin synthesis and metabolism in vivo

Ketamine (160 mg/kg, i.p.) was found to reduce the accumulation of 5-hydroxytryptophan (5-HTP) in whole brain following inhibition of L-aromatic amino acid decarboxylase with 50 mg/kg of 3-hydroxybenzylhydrazine (NSD-1015). Smaller doses of ketamine did not affect whole brain 5-HTP accumulation. However in regional studies, 80 mg/kg of ketamine significantly reduced 5-HTP accumulation in the spinal cord and the midbrain-thalamus. A dose of 160 mg/kg ketamine also reduced 5-HTP accumulation in the spinal cord and midbrain-thalamus and in the medulla-pons, striatum and cortex as well. No significant changes in 5-HTP accumulation were observed in the hypothalamus or hippocampus. Ketamine (160 mg/kg) also reduced whole brain 5-hydroxyindoleacetic acid (5-HIAA) levels and slightly elevated whole brain 5-hydroxytryptamine (5-HT) levels. Smaller doses did not affect either 5-HIAA or 5-HT levels. Ketamine did not affect whole brain tryptophan levels nor did it inhibit [3H]tryptophan uptake or conversion to [3H]5-HT in vitro. These data demonstrate that ketamine reduced both 5-HT synthesis and metabolism in vivo. Since ketamine did not affect brain tryptophan levels nor did it inhibit 5-HT in vitro, the reduction of 5-HT turnover following ketamine administration appears to be a neuronal, adaptive phenomenon possibly occurring in response to a blockade of 5-HT uptake by ketamine.     

Differential muscarinic and NMDA contributions to visuo-spatial paired-associate learning in rhesus monkeys

RATIONALE: Early, accurate detection of degenerative neurological disorders such as Alzheimer's disease (AD) is essential for therapies designed to slow disease progression. Performance of a touch-screen mediated visuo-spatial paired-associates learning (vsPAL) task predicts neurocognitive decline in elderly populations presenting with mild cognitive impairment and distinguishes AD patients from elderly depressed individuals. Translation of this cognitive task to a non-human model may therefore provide an improved tool for study of the etiology and treatment of dementia. OBJECTIVE: The goal of the current study was to contrast cholinergic and glutamatergic contributions to performance of this AD-sensitive task by challenging rhesus monkeys performing vsPAL with muscarinic antagonist and non-competitive NMDA antagonist drugs. METHODS: Seven monkeys were trained to perform vsPAL and then serially challenged with acute doses of scopolamine (3, 10, 17 microg/kg, IM) and ketamine (0.3, 1.0, 1.78 mg/kg, IM). RESULTS: Scopolamine produced a dosexdifficulty related impairment of both recognition memory and incremental acquisition aspects of task performance. In contrast, ketamine administration resulted in a dose-dependent impairment of recognition memory but not incremental acquisition. CONCLUSIONS: Monkeys' performance of a task sensitive to AD in humans was impaired by two classic pharmacological models of cognitive impairment, therefore supporting the use of this nonhuman model to explore mechanisms of AD-associated cognitive decline. The differential pattern of impairment observed is consistent with a hypothesis that muscarinic mechanisms are required for linking external events with an existing internal representation, whereas NMDA mechanisms are required for the formation/strengthening of such an internal representation.     

The effects of sub-anaesthetic doses of ketamine on memory, cognitive performance and subjective experience in healthy volunteers

The cognitive and subjective effects of sub-anaesthetic doses of ketamine on healthy volunteers were examined. Twelve healthy volunteers received 25 mg ketamine, 10 mg ketamine and saline placebo, i.m. in a double-blind, Latin square design. A cognitive, perceptual and self-report test battery was administered over 45 min. The order of tests was rotated to control for timing effects. Ketamine (25 mg) significantly affected verbal learning and memory, parallel visual search, some measures of psychomotor performance, measures of arousal, subjective mood ratings and visual perception. Measures of attention and frontal lobe functioning were relatively unaffected. Thus, low doses of ketamine had selective, dose-related effects on memory, perceptual and psychomotor functions. The disruption of memory and perceptual processes may help to explain the unique subjective state induced by ketamine.     

Dizocilpine prevents the development of tolerance to ethanol-induced error on a circular maze test

Dizocilpine [(+)MK-801] and ketamine, in doses that disrupt learning and memory, also prevent the development of tolerance to the motor impairing effects of ethanol (EtOH). However, dizocilpine itself affects motor behavior. In order to separate the possible influence of these two effects on the development of tolerance to EtOH, food-reinforced performance on a circular maze test was used in two different experiments. EtOH alone (1.2 g/kg) tended to increase the error score and reduce number of runs per trial, running speed, and total distance run, but on chronic administration of EtOH, tolerance developed progressively to all these effects. Dizocilpine also increased the error score, but had a biphasic effect on measures of running: low and intermediate doses (0.009 and 0.075 mg/kg, IP) increased running distance, whereas a high dose (0.15 mg/kg) decreased running speed and distance. When combined with EtOH, dizocilpine tended to overcome the effect of EtOH on running activity, but not on error score. Chronically, dizocilpine (0.075 and 0.15 mg/kg) prevented the development of tolerance to the effect of EtOH on error score, even though the lower dose of dizocilpine permitted tolerance to the effects of EtOH on running. These results suggest that NMDA receptor antagonists selectively inhibit tolerance to cognitive effects of ethanol even when the antagonists do not affect motor performance.     

Cognitive and subjective acute dose effects of intramuscular ketamine in healthy adults

Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) antagonist. Given the purported role of the NMDA receptor in long-term potentiation, the primary purpose of the present study was to further understand the dose-related effects of ketamine on memory. The study was also designed to provide information about the relative effects of ketamine on memory versus nonmemory effects and to more fully characterize ketamine's overall pattern and time course of effects. Single intramuscular injections of ketamine (0.2 mg/kg, 0.4 mg/kg) were administered to 18 healthy adult volunteers using a double-blind, placebo-controlled, crossover design. Word lists were used to evaluate episodic memory (free recall, recognition memory, source memory) and metamemory. Working memory, time estimation, psychomotor performance, and subjective effects were assessed repeatedly for 5 hours after drug administration. Ketamine selectively impaired encoding (as measured by free recall) while sparing retrieval, working memory while sparing attention, and digit symbol substitution task speed while sparing accuracy. Ketamine did not significantly impair recognition or source memory, metamemory, or time estimation. There were no hallucinations or increases in mystical experiences with ketamine. Memory measures were less sensitive to ketamine effects than subjective or psychomotor measures. Subjective effects lasted longer than memory and most psychomotor impairments. Ketamine produces selective, transient, dose- and time-related effects. In conjunction with previous studies of drugs with different mechanisms of actions, the observed selectivity of effects enhances the understanding of the pharmacological mechanisms underlying memory, attention, psychomotor performance, and subjective experience.     

Potentiation of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism.

The interplay of opiate and NMDA glutamate receptors may contribute to psychosis, cognitive function, alcoholism, and substance dependence. Ketamine and ethanol block the NMDA glutamate receptor. The purpose of this randomized double-blind, placebo-controlled human laboratory study was to evaluate whether the interactive effects of drugs acting at opiate and NMDA glutamate receptors might partially explain the efficacy of naltrexone for the treatment of alcoholism, that is, whether naltrexone 25 mg pretreatment would modulate ketamine effects in healthy human subjects. Two groups of healthy subjects were studied. An initial group (n=31) received a perception-altering subanesthetic dose of ketamine (bolus of 0.23 mg/kg over 1 min followed by a 60-min infusion of 0.58 mg/kg or saline bolus and infusion). A second group (n=24) completed the same testing procedures, but received a subperceptual ketamine dose (bolus 0.081 mg/kg over 10 min followed by an infusion of 0.4 mg/kg/h). Ketamine produced positive symptoms, negative symptoms, emotional discomfort, and cognitive effects as measured by the Positive and Negative Syndrome Scale (PANSS) in a dose-related fashion. The lower ketamine dose produced subjective effects similar to two standard ethanol drinks, whereas the higher ketamine dose produced effects similar to five standard drinks. Although naltrexone produced no significant behavioral effects, it significantly magnified the increase in the total PANSS score produced by the lower subperceptual dose of ketamine, but not the higher perception-altering dose of ketamine. These data suggest that the interplay of opiate receptor antagonism and NMDA receptor antagonism may be relevant to the protective effects of naltrexone on alcohol consumption via potentiation of dysphoric effects associated with the NMDA receptor antagonist effects of ethanol. However, these data suggest that at levels of NMDA receptor antagonism associated with heavy drinking, this protective effect of naltrexone on drinking is no longer present.     

Optimizing dosage of ketamine and xylazine in murine echocardiography

1. Ketamine and xylazine (KX) mixture is the most commonly used anaesthetic drug during echocardiography in mice to induce sedation and immobility. Nevertheless, the doses of KX reported in the literature vary substantially with associated significant difference in cardiac function. To explore the optimal KX dosage and observation time for murine echocardiography, we compared the effects of various KX combinations on echocardiographic measurement. 2. Mice were anaesthetized with ketamine (50 or 100 mg/kg) and xylazine (0-10 mg/kg). Echocardiography was performed 5, 10, 20 and 40 min after induction of anaesthesia. Also, cardiac function was assessed in mice with and without pressure-overload induced left ventricle (LV) hypertrophy and dysfunction, either under anaesthesia with KX or whilst conscious. 3. Ketamine at 100 mg/kg alone or together with xylazine at 0.1 mg/kg was associated with a high and stable heart rate (HR), a high fractional shortening (FS) and produced the least effect on LV inner dimension at end of diastole (LVIDd). Ketamine and xylazine at 100 and 10 mg/kg, respectively, produced a lower and stable FS, but with a low and unstable HR. All other combinations resulted in depressed and unstable cardiac function during this period. 4. The dose-dependent suppression of FS by xylazine was counteracted partly by ketamine. 5. Although in the chronic pressure-overload model LV hypertrophy can be detected accurately in both the anaesthetized or conscious state, systolic dysfunction was masked partially by higher doses of xylazine (2.5 or 10 mg/kg) combined with ketamine at 100 mg/kg. 6. With KX anaesthesia, both the dose of xylazine and the anaesthetic duration are critical in achieving an ideal condition for murine echocardiography. Ketamine at 100 mg/kg alone produces acceptable anaesthesia, stable cardiac function with a minimal depressant effect and is therefore recommended if single-dose anaesthetic is to be used.     

Effects of ketamine on different types of anxiety/fear and related memory in rats with lesions of the median raphe nucleus.

The aim of the present study was to determine the involvement of the median raphe serotonergic system in the effects of ketamine on anxiety behaviours and related memory. The effects of ketamine pretreatment (3 and 10 mg/kg, i.p.) on three types of fear-motivated behaviours, unconditioned one-way escape, conditioned avoidance and freezing were tested. Experiments were performed with the inhibitory avoidance apparatus in rats with ibotenic acid lesions of the median raphe nucleus. It was found that 10 mg/kg ketamine had an anxiogenic-like effect on one-way escape type of fear and anxiolytic-like effect on conditioned freezing-related fear; these effects were unaffected by median raphe lesions. Both ketamine doses impaired freezing-related fear memory. Ketamine (10 mg/kg) also produced an anxiolytic-like effect on avoidance type of fear and impaired avoidance memory. The median raphe lesions attenuated the anxiolytic action of the drug on the avoidance type of fear and prevented ketamine-induced avoidance memory impairment. These results suggest that the anxiolytic-like effect of ketamine on avoidance-type fear is mediated through the median raphe serotonergic system.     

Behavioral effects associated with chronic ketamine or remacemide exposure in rats

The effects of chronic exposure to ketamine or remacemide on the acquisition and performance of food-reinforced operant behaviors was assessed in female Sprague-Dawley rats. Ketamine is an anesthetic N-methyl-D-aspartate (NMDA) receptor antagonist, whereas remacemide is an active central nervous system compound with both NMDA receptor antagonist and sodium channel blocking properties. Learning, audio/visual discrimination and motivation were modeled using incremental repeated acquisition (IRA), audio/visual discrimination (AVD) and progressive ratio (PR) tasks, respectively. Ketamine (10 or 100 mg/kg/day), remacemide (100 or 150 mg/kg/day) or water was administered daily (7 days/week) via orogastric gavage beginning on postnatal day (PND) 23 and continuing until PND 257. Monday through Friday behavioral assessments began on PND 27 and continued until PND 383. Chronic treatment with the high dose of ketamine decreased response rate in all tasks suggesting decreased motivation or motoric capabilities. Chronic treatment with ketamine or remacemide had no effect on the acquisition of IRA task performance at any dose tested. While chronic treatment with either high-dose ketamine or low-dose remacemide only delayed the acquisition of AVD task performance for a brief period midway through treatment, chronic treatment with high-dose remacemide delayed the acquisition of AVD task performance until late in treatment. The findings for ketamine are quite different from those of MK-801 (the prototypic NMDA receptor antagonist) in a previous rat study in which MK-801 severely disrupted the acquisition of both IRA and AVD task performances. These observations suggest important differences in the mechanism of action between ketamine and MK-801. For example, ketamine has a much lower binding affinity than MK-801 for the NMDA receptor, the dopamine transporter and the dopamine D2 receptor. In addition, the findings for remacemide observed in rats are in marked contrast with those seen in monkeys where chronic remacemide had profound disruptive effects on the acquisition of both IRA and AVD task performances and suggest important species differences.     

Effects of ketamine on pulmonary inflammatory responses and survival in rats exposed to polymicrobial sepsis.

PURPOSE: Ketamine is reported to suppress production of proinflammatory cytokines and activity of nuclear factor-kappa B (NF-kappaB) after lipopolysaccharide (LPS) stimulation. Our study was designed to investigate the effects of ketamine on pulmonary inflammatory responses and survival in a clinically relevant model of polymicrobial sepsis, induced by cecal ligation and puncture (CLP). METHODS: After the induction of sepsis or sham-operation, animals were treated with ketamine (0.5, 5 or 10 mg/kg) or saline (10 ml/kg) at 3h after operation. At 6 h post-operation, the levels of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-6, activity of NF-kappaB, expression of Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) of the lungs were measured. And the mortality was recorded for 7 days. RESULTS: TNF-alpha and IL-6 production, NF-kappaB activity, TLR2 and TLR4 expression in rat lungs were increased after CLP. Ketamine at the doses of 5 mg/kg and 10 mg/kg suppressed CLP-induced elevation of TNF-alpha and IL-6 production, NF-kappaB activity and TLR2 expression. Ketamine 0.5, 5 and 10 mg/kg inhibited TLR4 expression in sepsis. Ketamine 5mg/kg and 10 mg/kg after CLP improved the survival of rats. CONCLUSIONS: Ketamine at sub-anesthetic doses could suppress the production of inflammatory cytokines such as TNF-alpha and IL-6, attenuate NF-kappaB activity, and inhibit TLR2 and TLR4 expression in polymicrobial sepsis. These anti-inflammatory effects of ketamine may correlate with improved survival in sepsis.     

Opioid mechanisms of some behavioral effects of ketamine

The effect of naloxone on the duration of sleep and on analgesia produced by ketamine, and on the development of tolerance and cross-tolerance with morphine to ketamine analgesic effects were investigated in mice. Ketamine produced a dose-dependent analgesia. Naloxone (4 mg/kg) significantly inhibited the analgesic effects of ketamine (40 mg/kg), but (given in a dose of 2 mg/kg) did not affect the duration of ketamine sleep. Chronic administration of ketamine (160 mg/kg twice daily for 7 days) resulted in a gradual shortening of ketamine sleep and in the development of tolerance to the analgesic action of ketamine. There also developed cross-tolerance between analgesic effects of morphine and ketamine. Ketamine (20 mg/kg) significantly inhibited symptoms of morphine abstinence produced in morphine-pelleted mice by naloxone administration or by pellet removal. The results suggest that at least some elements of the mechanism of action of ketamine and morphine may be common and related to the endogenous opioid system.