Acetyl L-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos.

Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) type glutamate receptors is commonly used as a pediatric anesthetic. Multiple studies have shown ketamine to be neurotoxic, particularly when administered during the brain growth spurt. Previously, we have shown that ketamine is detrimental to motor neuron development in the zebrafish embryos. Here, using both wild type (WT) and transgenic (hb9:GFP) zebrafish embryos, we demonstrate that ketamine is neurotoxic to both motor and sensory neurons. Drug absorption studies showed that in the WT embryos, ketamine accumulation was approximately 0.4% of the original dose added to the exposure medium. The transgenic embryos express green fluorescent protein (GFP) localized in the motor neurons making them ideal for evaluating motor neuron development and toxicities in vivo. The hb9:GFP zebrafish embryos (28 h post fertilization) treated with 2 mM ketamine for 20 h demonstrated significant reductions in spinal motor neuron numbers, while co-treatment with acetyl L-carnitine proved to be neuroprotective. In whole mount immunohistochemical studies using WT embryos, a similar effect was observed for the primary sensory neurons. In the ketamine-treated WT embryos, the number of primary sensory Rohon-Beard (RB) neurons was significantly reduced compared to that in controls. However, acetyl L-carnitine co-treatment prevented ketamine-induced adverse effects on the RB neurons. These results suggest that acetyl L-carnitine protects both motor and sensory neurons from ketamine-induced neurotoxicity.

Evaluation of medetomidine-ketamine and atipamezole for reversible anesthesia of free-ranging gray wolves (Canis lupus).

Twenty-eight anesthetic events were carried out on 24 free-ranging Scandinavian gray wolves (Canis lupus) by darting from a helicopter with 5 mg medetomidine and 250 mg ketamine during winter in 2002 and 2003. Mean±SD doses were 0.162±0.008 mg medetomidine/kg and 8.1±0.4 mg ketamine/kg in juveniles (7-10 mo old) and 0.110±0.014 mg medetomidine/kg and 5.7±0.5 mg ketamine/kg in adults (>19 mo old). Mean±SD induction time was shorter (P<0.01) in juveniles (2.3±0.8 min) than in adults (4.1±0.6 min). In 26 cases, the animals were completely immobilized after one dart. Muscle relaxation was good, palpebral reflexes were present, and there were no reactions to handling or minor painful stimuli. Mild to severe hyperthermia was detected in 14/28 anesthetic events. Atipamezole (5 mg per mg medetomidine) was injected intramuscularly for reversal 98±28 and 94±40 min after darting in juveniles and adults, respectively. Mean±SD time from administration of atipamezole to coordinated walking was 38±20 min in juveniles and 41±21 min in adults. Recovery was uneventful in 25 anesthetic events, although vomiting was observed in five animals. One adult that did not respond to atipamezole was given intravenous fluids and was fully recovered 8 hr after darting. Two animals died 7-9 hr after capture, despite intensive care. Both mortalities were attributed to shock and circulatory collapse following stress-induced hyperthermia. Although effective, this combination cannot be recommended for darting free-ranging wolves from helicopter at the doses presented here because of the severe hyperthermia seen in several wolves, two deaths, and prolonged recovery in one individual.

Role of glycogen synthase kinase-3ß in ketamine-induced developmental neuroapoptosis in rats.

BACKGROUND: Ketamine-induced neuroapoptosis has been attributed to diverse stress-related mechanisms. Glycogen synthase kinase-3ß (GSK-3ß) is a multifunctional kinase that is active in neuronal development and linked to neurodegenerative disorders. We hypothesized that ketamine would enhance GSK-3ß-induced neuroapopotosis, and that lithium, an inhibitor of GSK-3ß, would attenuate this response in vivo. METHODS: Protein levels of cleaved caspase-3, protein kinase B (AKT), GSK-3ß, and cyclin D1 were measured in post-natal day 7 rat pups after 1.5, 3, 4.5, and 6 h exposure to ketamine. A cohort of rat pups was randomized to a 6 h exposure to ketamine with and without lithium. Neuroapoptosis was measured by cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling staining by immunohistochemistry. Protein levels of cleaved caspase-3 and -9 and the total and phosphorylated forms of AKT, GSK-3ß, and cyclin D1 (cell cycle protein) were also measured. RESULTS: Ketamine produced a duration-dependent increase in cleaved caspase-3 and cyclin D1, which corresponded to decreases in phosphorylated AKT and GSK-3ß. Co-administration of lithium with ketamine attenuated this response. CONCLUSIONS: Ketamine-induced neuroapoptosis is associated with a temporal decrease in GSK-3ß phosphorylation, and simultaneous administration of lithium mitigated this response. These findings suggest that GSK-3ß is activated during this ketamine-induced neuroapoptosis.

Clonidine abolishes the adverse effects on apoptosis and behaviour after neonatal ketamine exposure in mice.

BACKGROUND: An increasing amount of both experimental and epidemiological data indicates that neonatal anaesthesia causes disruption of normal brain development in rodents and primates, as manifested by acute increased apoptosis and long-lasting altered behaviour and learning. It is necessary to seek strategies that avoid the possible adverse effects after anaesthesia. Our purpose is to show that increased apoptosis and behavioural alterations after ketamine exposure during this period may be prevented by clonidine, a compound already used by paediatric anaesthetists for sedation. METHODS: To investigate the protective properties of clonidine pre-treatment, five groups of 10-day-old mice were injected with either ketamine 50 mg/kg, clonidine 40 µg/kg, ketamine 50 mg/kg 30 min after 10 µg/kg clonidine, ketamine 50 mg/kg 30 min after 40 µg/kg clonidine or saline (control). Apoptosis was measured 24 h after treatment using Flouro-Jade staining. Spontaneous activity in a novel environment was tested at an age of 55 days. RESULTS: Pre-treatment with 40 µg/kg clonidine, but not 10 µg/kg clonidine, 30 min before ketamine exposure abolished ketamine-induced apoptosis and the behavioural changes observed in the young adult mice. The mice exposed to clonidine alone showed no differences from the saline-treated (control) mice. CONCLUSION: The administration of clonidine eliminated the adverse effects of ketamine in this mouse model, suggesting a possible strategy for protection. Alone, clonidine did not cause any adverse effects in these tests.

Glycine transporter inhibitor attenuates the psychotomimetic effects of ketamine in healthy males: preliminary evidence.

Enhancing glutamate function by stimulating the glycine site of the NMDA receptor with glycine, D-serine, or with drugs that inhibit glycine reuptake may have therapeutic potential in schizophrenia. The effects of a single oral dose of cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) amino-methylcarboxylic acid hydrochloride (Org 25935), a glycine transporter-1 (GlyT1) inhibitor, and placebo pretreatment on ketamine-induced schizophrenia-like psychotic symptoms, perceptual alterations, and subjective effects were evaluated in 12 healthy male subjects in a randomized, counter-balanced, within-subjects, crossover design. At 2.5 h after administration of the Org 25935 or placebo, subjects received a ketamine bolus and constant infusion lasting 100 min. Psychotic symptoms, perceptual, and a number of subjective effects were assessed repeatedly before, several times during, and after completion of ketamine administration. A cognitive battery was administered once per test day. Ketamine produced behavioral, subjective, and cognitive effects consistent with its known effects. Org 25935 reduced the ketamine-induced increases in measures of psychosis (Positive and Negative Syndrome Scale (PANSS)) and perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)). The magnitude of the effect of Org 25935 on ketamine-induced increases in Total PANSS and CADSS Clinician-rated scores was 0.71 and 0.98 (SD units), respectively. None of the behavioral effects of ketamine were increased by Org 25935 pretreatment. Org 25935 worsened some aspects of learning and delayed recall, and trended to improve choice reaction time. This study demonstrates for the first time in humans that a GlyT1 inhibitor reduces the effects induced by NMDA receptor antagonism. These findings provide preliminary support for further study of the antipsychotic potential of GlyT1 inhibitors.

Effective immobilizing doses of medetomidine-ketamine in free-ranging, wild Norwegian reindeer (Rangifer tarandus tarandus).

Combinations of medetomidine and ketamine were evaluated in free-ranging, wild Norwegian reindeer (Rangifer tarandus tarandus) as part of a reintroduction program in southwestern Norway in November 1995 and November 1996. The drugs were administered by dart from a helicopter. The mean (SD) effective immobilizing doses for 29 adults (8 males, 21 females) were 0.21 (0.04) mg medetomidine/kg and 1.0 (0.2) mg ketamine/ kg based on estimated body mass. There was no significant difference in mean induction times between males and females. However, animals with optimal hits (shoulder or thigh muscles; n=16) had a significantly shorter (P<0.05) mean induction time than did animals with suboptimal hits (abdomen or flank; n=13), 5.6 (2.2) min and 11.1 (4.7) min, respectively. Inductions were calm, and immobilized animals were maintained in sternal recumbency. Clinical side effects included hypoxemia and hyperthermia in most animals. For reversal, all animals received 5 mg atipamezole per mg medetomidine, half intravenously and half intramuscularly, and the mean (SD) time to standing was 3.7 (3.6) min.

Anesthetic ketamine impairs rats' recall of previous information: the nitric oxide synthase inhibitor N-nitro-L-arginine methylester antagonizes this ketamine-induced recognition memory deficit.

BACKGROUND: There is poor experimental evidence concerning the effects of anesthetic doses of the noncompetitive N-methyl-D-aspartate receptor antagonist ketamine on rodents' memory abilities. The current study was designed (1) to investigate the consequences of posttraining administration of anesthetic ketamine (100 mg/kg intraperitoneally) on rats' recognition memory and (2) to evaluate the ability of the nitric oxide synthase inhibitor N-nitro-L-arginine methylester (L-NAME; 1, 3, and 10 mg/kg intraperitoneally) to counteract the expected behavioral deficits produced by anesthetic ketamine. Finally, in an attempt to clarify if the expected memory impairments produced by anesthetic ketamine were related to the anesthesia, we also tested the effects of a subanesthetic dose of it (3 mg/kg intraperitoneally) on rats' recognition memory. METHODS: The novel object recognition test, a procedure assessing recognition memory in rats, was selected. RESULTS: Posttraining administration of anesthetic (but not of subanesthetic) ketamine disrupted rats' performance in the novel object recognition paradigm. The discrimination index (D) was decreased by ketamine from 0.415 (using saline) to 0.128, thus indicating that the anesthetic dose of ketamine impaired recognition memory. L-NAME (1-3, but not 10, mg/kg) reversed this memory deficit produced by ketamine; the D index of 0.128 using ketamine treatment was increased by 1 and 3 mg/kg L-NAME to 0.427 and 0.478, respectively. CONCLUSIONS: The current results indicate that anesthetic ketamine impaired rats' posttraining memory components (storage and/or retrieval of information) and that a nitric oxide component modulates its behavioral effects.

Reversal of ketamine/xylazine combination anesthesia by atipamezole in olive baboons (Papio anubis).

BACKGROUND: The potential of Atipamezole (ATI) to reverse Ketamine/Xylazine (KET/XYL) anesthesia in the Olive baboon (Papio anubis) was studied. METHODS: Anesthesia was induced with 10 mg/kg KET and 0.5 mg/kg XYL intramuscularly. Mean arousal time (MAT), heart rate (HR), systolic arterial blood pressure (SAP), rectal temperature, respiratory rate (RR), and hemoglobin oxygen saturation (SpO(2)) were monitored. Baboons were treated with: KET/XYL only, KET/XYL followed by 100 microg/kg ATI or by 200 microg/kg ATI administered 25 minutes after KET/XYL. RESULTS: Atipamezole rapidly reversed depressed HR and SAP (10 +/- 5.2 minutes), RR (5 +/- 2 minutes) and SpO(2) (3 +/- 6 minutes) and significantly decreased MAT (13 +/- 2.2 minutes) vs. KET/XYL alone (35 +/- 5 minutes). Emesis was absent and salivation was observed after administration of 200 microg/kg ATI only. CONCLUSIONS: Atipamezole at 100 microg/kg is sufficient for rapid and smooth reversal of KET/XYL anesthesia in the Olive baboon with minimal side effects.

Orexin A decreases ketamine-induced anesthesia time in the rat: the relevance to brain noradrenergic neuronal activity.

BACKGROUND: Orexins (OXs) regulate wakefulness, and a lack of OX Type-I receptors cause narcolepsy. OX selectively increases norepinephrine (NE) release from rat cerebral cortical slices, and brain noradrenergic neurons are involved in the sleep-wakefulness cycle. Ketamine increases NE release from the rat cerebral cortex. We hypothesized that OX would affect ketamine anesthesia's interactions with brain noradrenergic neuronal activity. METHODS: We used Sprague Dawley rats. We studied 1) in vivo effects of orexin A (OXA) and SB-334867-A (Orexin-1 receptor antagonist) on ketamine-induced anesthesia time, 2) in vivo effects of OXA on ketamine-induced increase in NE release from the frontal cortex assessed using microdialysis, and 3) in vitro effects of ketamine on OXA-evoked NE release from rat cerebrocortical slices. RESULTS: 1) Intracerebroventricular OXA 1 nmol significantly decreased ketamine anesthesia time by 20%-30% at 50, 100, and 125 mg/kg intraperitoneal (IP) ketamine. SB-334867-A fully reversed the decrease produced by OXA. 2) OXA also decreased the release of NE induced by ketamine even though OXA increased the release of NE in rat prefrontal cortex. Maximum NE release in Group OX + K (intracerebroventricular OXA 1 nmol + IP ketamine 100 mg/kg) was 271% and was significantly smaller than that in Group K (ketamine 100 mg/kg IP, 390% of baseline, P = 0.029). 3) Ketamine inhibited OX-evoked NE release with clinically relevant IC(50) values. CONCLUSION: Orexinergic neurons may be an important target for ketamine. OXA antagonized ketamine anesthesia via Orexin-1 receptor with noradrenergic neurons.

A comparison of two combinations of xylazine-ketamine administered intramuscularly to alpacas and of reversal with tolazoline.

OBJECTIVE: To evaluate the anesthetic and cardiorespiratory effects of two doses of intramuscular (IM) xylazine/ketamine in alpacas, and to determine if tolazoline would reduce the anesthetic recovery time. STUDY DESIGN: Prospective randomized crossover study. ANIMALS: Six castrated male alpacas. METHODS: Each alpaca received a low dose (LD) (0.8 mg kg(-1) xylazine and 8 mg kg(-1) ketamine IM) and high dose (HD) (1.2 mg kg(-1) xylazine and 12 mg kg(-1) ketamine IM) with a minimum of one week between trials. Time to sedation, duration of lateral recumbency and analgesia, pulse rate, respiratory rate, hemoglobin oxygen saturation, arterial blood pressure, blood-gases, and the electrocardiogram were monitored and recorded during anesthesia. With each treatment three alpacas were randomly selected to receive tolazoline (2 mg kg(-1) IM) after 30 minutes of lateral recumbency. RESULTS: Onset of sedation, lateral recumbency and analgesia was rapid with both treatments. The HD was able to provide > or =30 minutes of anesthesia in five of six alpacas. The LD provided > or =30 minutes of anesthesia in three of six alpacas. Respiratory depression and hypoxemia occurred with the HD treatment during the first 10 minutes of lateral recumbency: two animals were severely hypoxemic and received nasal oxygen for 5 minutes. Heart rate decreased, but there were no significant changes in arterial blood pressure. Tolazoline significantly shortened the duration of recumbency with the HD. CONCLUSIONS: The HD provided more consistent clinical effects in alpacas than the LD. Intramuscular tolazoline shortened the duration of lateral recumbency in alpacas anesthetized with the HD combination. CLINICAL RELEVANCE: Both doses of the combination were effective in providing restraint in alpacas and the duration of restraint was dose dependent. Supplemental oxygen should be available if using the HD and IM administration of tolazoline will shorten the recovery time.

Mutual enhancement of central neurotoxicity induced by ketamine followed by methamphetamine.

We hereby report that repeated administration of ketamine (350 mg/kg in total) and methamphetamine (30 mg/kg in total) causes specific glutamatergic and dopaminergic neuron deficits, respectively, in adult mouse brain. Acute ketamine did not affect basal body temperature or the later methamphetamine-induced hyperthermia. However, pretreatment with repeated doses of ketamine aggravated methamphetamine-induced dopaminergic terminal loss as evidenced by a drastic decrease in the levels of dopamine, 3,4-dihydroxyphenylacetic acid, and dopamine transporter density as well as poor gait balance performance. In contrast, methamphetamine-induced serotonergic depletion was not altered by ketamine pretreatment. Likewise, the subsequent treatment with methamphetamine exacerbated the ketamine-induced glutamatergic damage as indicated by reduced levels of the vesicular glutamate transporter in hippocampus and striatum and poor memory performance in the Morris water maze. Finally, since activation of the D1 and AMPA/kainate receptors has been known to be involved in the release of glutamate and dopamine, we examined the effects of co-administration of SCH23390, a D1 antagonist, and CNQX, an AMPA/kainate antagonist. Intraventricular CNQX infusion abolished ketamine's potentiation of methamphetamine-induced dopamine neurotoxicity, while systemic SCH23390 mitigated methamphetamine's potentiation of ketamine-induced glutamatergic toxicity. We conclude that repeated doses of ketamine potentiate methamphetamine-induced dopamine neurotoxicity via AMPA/kainate activation and that conjunctive use of methamphetamine aggravates ketamine-induced glutamatergic neurotoxicity possibly via D1 receptor activation.

Antagonistic effects of atipamezole, flumazenil and 4-aminopyridine against anaesthesia with medetomidine, midazolam and ketamine combination in cats.

Antagonistic effects of atipamezole (ATI), flumazenil (FLU) and 4-aminopyridine (4AP) alone and in various combinations after administration of medetomidine-midazolam-ketamine (MED-MID-KET) were evaluated in cats. Animals were anaesthetised with MED (50 microg/kg), MID (0.5 mg/kg) and KET (10 mg/kg) given intramuscularly. Twenty minutes later, physiological saline, ATI (200 microg/kg), FLU (0.1 mg/kg), 4AP (0.5 mg/kg), ATI-FLU, FLU-4AP, ATI-4AP or ATI-FLU-4AP was administered intravenously. FLU, 4AP alone, or FLU-4AP did not effectively antagonise the anaesthesia, hypothermia, bradycardia, and bradypnoea induced by MED-MID-KET. ATI alone was effective. ATI-FLU, ATI-4AP and ATI-FLU-4AP combinations produced an immediate and effective recovery from anaesthesia. The combination of ATI-FLU-4AP was the most effective in antagonising the anaesthetic effects, but was associated with tachycardia, tachypnoea, excitement, and muscle tremors. Combinations with ATI are more effective for antagonising anaesthesia, but ATI-FLU-4AP is not suitable.

Reversal of medetomidine-ketamine combination anesthesia in rabbits by atipamezole.

This study was performed to determine the optimal reversal dosage of atipamezole on medetomidine-ketamine combination anesthesia. The subject rabbits were divided into five groups (n=5/group), and all were anesthetized with intravenous medetomidine (0.35 mg/kg) and ketamine (5 mg/kg). Atipamezole was administered intravenously 35 min after administration of the medetomidine-ketamine mixture, at doses of a quarter, a half, equal, or two times higher than the preceding medetomidine -ketamine dose according to experimental group. Heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR) and rectal temperature (RT) were measured every five minutes and the mean arousal time (MAT) was also recorded. This study revealed that the optimal atipamezole dosage to achieve reversal effects is equal to or double the dose of medetomidine. At these dosages, HR and MAP significantly recovered and MAT was significantly shortened with no side effects being observed (p<0.05).

Intramuscular anesthesia of bonito and Pacific mackerel with ketamine and medetomidine and reversal of anesthesia with atipamezole.

OBJECTIVE: To determine anesthetic effects of ketamine and medetomidine in bonitos and mackerels and whether anesthesia could be reversed with atipamezole. DESIGN: Clinical trial. ANIMALS: 43 bonitos (Sarda chiliensis) and 47 Pacific mackerels (Scomber japonica). PROCEDURE: 28 bonitos were given doses of ketamine ranging from 1 to 8 mg/kg (0.5 to 3.6 mg/lb), i.m., and doses of medetomidine ranging from 0.2 to 1.6 mg/kg (0.1 to 0.7 mg/lb), i.m. (ratio of ketamine to medetomidine, 2.5:1 to 20:1). Doses of atipamezole equal to 1 or 5 times the dose of medetomidine were used. The remaining 15 bonitos were used to determine the anesthetic effects of ketamine at a dose of 4 mg/kg (1.8 mg/lb) and medetomidine at a dose of 0.4 mg/kg (0.2 mg/lb). The mackerels were given ketamine at doses ranging from 11 to 533 mg/kg (5 to 242 mg/lb) and medetomidine at doses ranging from 0.3 to 9.1 mg/kg (0.1 to 4.1 mg/lb; ratio of ketamine to medetomidine, 3:1 to 800:1). Doses of atipamezole equal to 5 times the dose of medetomidine were used. RESULTS: I.m. administration of ketamine at a dose of 4 mg/kg and medetomidine at a dose of 0.4 mg/kg in bonitos and ketamine at a dose of 53 to 228 mg/kg (24 to 104 mg/lb) and medetomidine at a dose of 0.6 to 4.2 mg/kg (0.3 to 1.9 mg/lb) in mackerels was safe and effective. For both species, administration of atipamezole at a dose 5 times the dose of medetomidine reversed the anesthetic effects. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that a combination of ketamine and medetomidine can safely be used for anesthesia of bonitos and mackerels and that anesthetic effects can be reversed with atipamezole.

Immobilization of free-ranging European mink (Mustela lutreola) an polecat (Mustela putorius) with medetomidine-ketamine and reversal by atipamezole.

From March 1996 to August 1999, 24 free-ranging European mink (Mustela lutreola) and 25 free-ranging polecats (Mustela putorius) were immobilized for clinical procedures and to place radio transmitters. Data were recorded during 14 and 12 trials, respectively. Animals received intramuscularly 10 mg/kg ketamine (KET) combined with 0.20 mg/kg medetomidine (MED), antagonized by 1.00 mg/kg atipamezole (ATI). Anesthesia times were similar between species. Induction was smooth and rapid (0.7-3.9 min); the degree of anesthesia and muscle relaxation was satisfactory in most animals. Two individuals showed signs of spontaneous recovery before injection of ATI. In other individuals, ATI was injected 28.1-54.0 min after the MED-KET injection and rapidly reversed the effects of the MED. Rectal temperature and heart and respiratory rates decreased significantly 5-25 min post MED-KET injection in both species. Rectal temperature successfully remained stable by placing animals on a warmed plastic table (37 C) during anesthesia. According to these results, this anesthetic protocol produces a safe and rapid immobilization in free-ranging European mink and polecats and is recommended for surgical procedures such as radio transmitter implantation. However caution is required as hypothermia can be severe. Body temperature must be monitored and means provided to maintain stability.

Comparison of ketamine versus combination of ketamine and medetomidine in injectable anesthetic protocols: chemical immobilization in macaques and tissue reaction in rats.

This study compared balanced anesthesia between ketamine alone and ketamine with medetomidine and assessed the repeated intramuscular use of ketamine and its potential for tissue damage. The combination of ketamine and medetomidine was tested in newly arrived macaques undergoing a period of quarantine in an animal facility. Results indicated that the medetomidine and ketamine combination induced a deeper, more level plane of anesthesia of longer duration than did ketamine alone. Furthermore, use of the medetomidine-reversing agent, atipamezole, permitted more rapid recovery. In addition, a preliminary study in adult rats was undertaken to assess tissue damage induced by intramuscular injection of ketamine versus the combination of ketamine and medetomidine. Histological evaluation of tissue inflammation and muscle necrosis in rats indicated that the lower dose of ketamine afforded by combination with medetomidine caused markedly less damage to muscle tissue at injection sites.

GABA(A) receptor blockade antagonizes the immobilizing action of propofol but not ketamine or isoflurane in a dose-related manner.

UNLABELLED: The enhancing action of propofol on gamma-amino-n-butyric acid subtype A (GABA(A)) receptors purportedly underlies its anesthetic effects. However, a recent study found that a GABA(A) antagonist did not alter the capacity of propofol to depress the righting reflex. We examined whether the noncompetitive GABA(A) antagonist picrotoxin and the competitive GABA(A) antagonist gabazine affected a different anesthetic response, immobility in response to a noxious stimulus (a tail clamp in rats), produced by propofol. This effect was compared with that seen with ketamine and isoflurane. Picrotoxin increased the 50% effective dose (ED(50)) for propofol by approximately 379%; gabazine increased it by 362%, and both antagonists acted in a dose-related manner with no apparent ceiling effect (i.e., no limit). Picrotoxin maximally increased the ED(50) for ketamine by approximately 40%-50%, whereas gabazine increased it by 50%-60%. The isoflurane minimum alveolar anesthetic concentration increased by approximately 60% with the picrotoxin and 70% with the gabazine infusion. The ED(50) for propofol was also antagonized by strychnine, a non-GABAergic glycine receptor antagonist and convulsant, to determine whether excitation of the central nervous system by a non-GABAergic mechanism could account for the increases in propofol ED(50) observed. Because strychnine only increased the immobilizing ED(50) of propofol by approximately 50%, GABA(A) receptor antagonism accounted for the results seen with picrotoxin and gabazine. We conclude that GABA(A) antagonism can influence the ED(50) for immobility of propofol and the non-GABAergic anesthetic ketamine, although to a different degree, reflecting physiologic antagonism for ketamine (i.e., an indirect effect via a modulatory effect on the neural circuitry underlying immobility) versus physiologic and pharmacologic antagonism for propofol (i.e., a direct effect by antagonism of propofol's mechanism of action). This study also suggests that the immobilizing action of isoflurane probably does not involve the GABA(A) receptor because antagonism of GABA(A) receptors for animals anesthetized with isoflurane produces results quantitatively and qualitatively similar to ketamine and markedly different from propofol. IMPLICATIONS: IV picrotoxin and gabazine antagonized the immobilizing action of propofol in a dose-related manner, whereas antagonism of the immobilizing action of ketamine and isoflurane was similar, smaller than for propofol, and not dose-related. These results are consistent with a role for gamma-amino-n-butyric acid subtype A receptors in mediating propofol anesthesia but not ketamine or isoflurane anesthesia.

Pentobarbital inhibits ketamine-induced dopamine release in the rat nucleus accumbens: a microdialysis study.

UNLABELLED: Dopamine release in the nucleus accumbens (NAC) plays a crucial role in the actions of various psychotropic and addictive drugs. Ketamine and barbiturates have psychotropic effects and addictive properties, but barbiturates prevent ketamine's psychotomimetic effects. We investigated the effects of ketamine and pentobarbital on dopamine release in the NAC. A microdialysis probe was implanted in the NAC in 35 rats, which were randomly assigned to seven groups: a normal saline intraperitoneal injection (ip) group, 50 and 100 mg/kg of ketamine ip groups, 25 and 50 mg/kg of pentobarbital ip groups, and a normal saline or 25 mg/kg of pentobarbital ip followed by 50 mg/kg of ketamine ip groups. Perfusate samples were collected every 20 min, and dopamine concentration was measured by high-performance liquid chromatography. Ketamine at doses of 50 mg/kg and 100 mg/kg significantly increased dopamine release in the NAC. Conversely, pentobarbital significantly decreased dopamine release in the NAC and inhibited the ketamine-induced dopamine release. These data suggest that the dopamine release in the NAC may be involved in ketamine-induced, but not barbiturate-induced, psychotropic effects and addiction. Inhibition of ketamine-induced dopamine release by barbiturates may be a mechanism by which they prevent ketamine emergence reactions. IMPLICATIONS: Ketamine increased dopamine release in the nucleus accumbens, which was inhibited by pentobarbital. The mesolimbic dopamine system may be involved in the psychotomimetic effects of ketamine, and the suppression of ketamine emergence reactions by barbiturates may be because of the inhibition of ketamine-induced dopamine release in the nucleus accumbens.

Cardiorespiratory effects of medetomidine-butorphanol, medetomidine-butorphanol-diazepam, and medetomidine-butorphanol-ketamine in captive red wolves (Canis rufus).

Safe, effective, and reversible immobilization protocols are essential for the management of free-ranging red wolves (Canis rufus). Combinations using an alpha2-adrenoceptor agonist and ketamine have been shown to be effective for immobilization but are not reversible and can produce severe hypertension and prolonged or rough recoveries. To minimize hypertension and provide reversibility, 24 red wolves were immobilized using three medetomidine-butorphanol (MB) combinations without the use of ketamine in the initial injection. All wolves were administered medetomidine (0.04 mg/kg i.m.) and butorphanol (0.4 mg/kg i.m.). Seven wolves received no other immobilization agents (MB wolves), nine received diazepam (0.2 mg/kg i.v.) at the time they were instrumented (MBD wolves), and eight received ketamine (1 mg/kg i.v.) 30 min after instrumentation (MBK30 wolves). Physiologic parameters were monitored during immobilization. The heart rate was similar among the three groups for the first 30 min, and marked bradycardia was noted in one wolf from each group. Hypertension was observed initially in all three groups but was resolved within 10-30 min. The MBK30 wolves had significant elevations in heart rate and transient hypertension after intravenous ketamine administration. Most wolves had mild to moderate metabolic acidemia. Immobilizing drugs were antagonized in all wolves with atipamezole (0.2 mg/kg i.m.) and naloxone (0.02 mg/kg i.m.). The medetomidine-butorphanol-diazepam wolves were also given flumazenil (0.04 mg/kg i.v.). All wolves were standing within 12 min and were fully recovered within 17 min. Medetomamine-butorphanol and MBD combinations provided effective and reversible immobilization of red wolves without the sustained hypertension associated with the use of alpha2-adrenoceptor agonist-ketamine combinations. Delaying the administration of ketamine reduced its hypertensive effects.