GluN2A-selective positive allosteric modulator-nalmefene-flumazenil reverses ketamine-fentanyl-dexmedetomidine-induced anesthesia and analgesia in rats.

Anesthetics are used to produce hypnosis and analgesic effects during surgery, but anesthesia for a long time after the operation is not conducive to the recovery of animals or patients. Therefore, finding appropriate treatments to counter the effects of anesthetics could enhance postoperative recovery. In the current study, we discovered the novel role of a GluN2A-selective positive allosteric modulator (PAM) in ketamine-induced anesthesia and investigated the effects of the PAM combined with nalmefene and flumazenil (PNF) in reversing the actions of an anesthetic combination (ketamine-fentanyl-dexmedetomidine, KFD). PAM treatment dose-dependently decreased the duration of the ketamine-induced loss of righting reflex (LORR). Compared with those in the KFD group, the duration of LORR and the analgesic effect of the KFD + PNF group were obviously decreased. Meanwhile, successive administration of PNF and KFD had no adverse effects on the cardiovascular and respiratory systems. Both the KFD group and the KFD + PNF group showed no changes in hepatic and renal function or cognitive function in rats. Moreover, the recovery of motor coordination of the KFD + PNF group was faster than that of the KFD group. In summary, our results suggest the potential application of the PNF combination as an antagonistic treatment strategy for anesthesia.

Omega-3 fatty acids prevent the ketamine-induced increase in acetylcholinesterase activity in an animal model of schizophrenia.

AIMS: Schizophrenia is a debilitating neurodevelopmental disorder that is associated with dysfunction in the cholinergic system. Early prevention is a target of treatment to improve long-term outcomes. Therefore, we evaluated the preventive effects of omega-3 fatty acids on AChE activity in the prefrontal cortex, hippocampus and striatum in an animal model of schizophrenia. MAIN METHODS: Young Wistar rats (30 days old) were initially treated with omega-3 fatty acids or vehicle alone. Animals received ketamine to induce an animal model of schizophrenia or saline plus omega-3 fatty acids or vehicle alone for 7 consecutive days beginning on day 15. A total of 22 days elapsed between the treatment and intervention. Animals were sacrificed, and brain structures were dissected to evaluate AChE activity and gene expression. KEY FINDINGS: Our results demonstrate that ketamine increased AChE activity in these three structures, and omega-3 fatty acids plus ketamine showed lower values for the studied parameters, which indicate a partial preventive mechanism of omega-3 fatty acid supplementation. We observed no effect on AChE expression. Together, these results indicate that omega-3 fatty acid supplementation effectively reduced AChE activity in an animal model of schizophrenia in all studied structures. In conclusion, the present study provides evidence that ketamine and omega-3 fatty acids affect the cholinergic system, and this effect may be associated with the physiopathology of schizophrenia. Further studies are required to investigate the mechanisms that are associated with this effect.

CRF1 receptor antagonists do not reverse pharmacological disruption of prepulse inhibition in rodents.

RATIONALE: As enhanced corticotropin-releasing factor (CRF) transmission is associated with induction of sensorimotor gating deficits, CRF1 receptor antagonists may reverse disrupted prepulse inhibition (PPI), an operational measure of sensorimotor gating. OBJECTIVES: To determine the effects of CRF1 receptor antagonists in pharmacological models of disrupted PPI and to determine if long-term elevated central CRF levels alter sensitivity towards PPI disrupting drugs. METHODS: CP154,526 (10-40 mg/kg), SSR125543 (3-30 mg/kg) and DMP695 (40 mg/kg) were tested on PPI disruption provoked by D-amphetamine (2.5, 3 mg/kg), ketamine (5, 30 mg/kg) and MK801 (0.2, 0.5 mg/kg) in Wistar rats, C57Bl/6J and CD1 mice, and on spontaneously low PPI in Iffa Credo rats and DBA/2J mice. PPI-disrupting effects of D-amphetamine (2.5-5 mg/kg) and MK801 (0.3-1 mg/kg) were examined in CRF-overexpressing (CRFtg) mice, which display PPI deficits. Finally, we determined the influence of CP154,526 on D-amphetamine-induced dopamine outflow in nucleus accumbens and prefrontal cortex of CRFtg mice using in vivo microdialysis. RESULTS: No CRF1-antagonists improved PPI deficits in any test. CRFtg mice showed blunted PPI disruption in response to MK801, but not D-amphetamine. Further, D-amphetamine-induced dopamine release was less pronounced in CRFtg versus wild-type mice, a response normalized by pretreatment with CP154,526. CONCLUSION: The inability of CRF1 receptor antagonists to block pharmacological disruption of sensorimotor gating suggests that the involvement of CRF1 receptors in the modulation of dopaminergic and glutamatergic neurotransmission relevant for sensory gating is limited. Furthermore, the alterations observed in CRFtg mice support the notion that long-term elevated central CRF levels induce changes in these neurotransmitter systems.

Action of a Novel PDE4 inhibitor ZL-n-91 on lipopolysaccharide-induced acute lung injury.

In the present study, we investigated the effect of classic PDE4 inhibitor rolipram and novel PDE4 inhibitor ZL-n-91 on LPS-induced acute lung injury (ALI) in mice and its mechanism. ALI was induced in ICR mice by instilling intratracheally with LPS, and mice were divided into seven groups: control (Saline), LPS group, ZL-n-91 (3 microg, 10 microg, and 30 microg kg(-1), ip), Rolipram (1.0 mg kg(-1), ip) and dexamethasone (0.5 mg kg(-1), ip). After the 6h of instilling intratracheally with LPS in mice, total leukocyte number, neutrophil number and protein content in BALF increased rapidly, a large number of neutrophil infiltration around the pulmonary vessel and airway, the lung wet weight/dry weight (w/d)ratio raised significantly. MPO activity, TNF-alpha level and cAMP-PDE, PDE4 activity in lung homogenate raised significantly. P(a)O(2), P(a)CO(2) and PH value in peripheral arterial blood also changed obviously, P(a)O(2) and PH value dropped slightly and P(a)CO(2) increased significantly in LPS group. ZL-n-91 (3 microg, 10 microg, 30 microg kg(-1)) dose-dependently reduced the total leukocyte number, neutrophil number and total protein content in BALF, MPO activity, TNF-alpha level and cAMP-PDE, PDE4 activity in lung homogenate, but the effect of ZL-n-91 in pathological changes and lung wet w/d ratio is slight; Rol and Dex significantly reduced lung wet w/d ratio and improved pathological changes, neutrophil around the pulmonary vessel and airway significantly reduced, symptoms of lung edema relieved; The PH value, P(a)O(2) and P(a)CO(2) in ZL-n-91 high dosage group and Rol group had changes, but there was no significant difference compared with LPS group or saline group; After the administration, the righting reflex recovery time significantly shorten in every group of ZL-n-91. the righting reflex recovery time of Rol group was similar with ZL-n-91 30 microg kg(-1) group, while Dex group was similar with saline group. The present study confirms that the inhibitory effect of ZL-n-91(30 microg kg(-1)) on the inflammatory reactivity, including inhibition of inflammatory cell and protein exudation, MPO and PDE4 activity, improvement of the blood gas, those effects were equivalent with rolipram 1 mg kg(-1), and suggested that ZL-n-91 was stronger than rolipram in PDE4 inhibition. So we speculated that ZL-n-91 may have stronger therapeutic potential for treatment of inflammatory disease than rolipram, meantime have stronger nervous system effect than rolipram.

Hypericum extract reverses S-ketamine-induced changes in auditory evoked potentials in humans - possible implications for the treatment of schizophrenia.

BACKGROUND: Auditory evoked potentials (AEP) provide a correlate of cognitive dysfunction in schizophrenia. Both cognitive dysfunction and AEP-characteristics might be related to reduced glutamatergic neurotransmission as induced by glutamate-antagonist like ketamine. Hypericum extract LI160 has demonstrated a ketamine-antagonising effect. We examined whether LI160 reverses changes of a low dose ketamine on AEP in healthy subjects. METHODS: We performed a double-blind randomized treatment with either 2 x 750 mg LI 160 or placebo given one week, using a crossover design, in 16 health subjects. A test-battery including AEPs, the oculodynamic test (ODT) and a cognitive test were performed before and after an infusion with 4 mg of S-ketamine over a period of 1 hour. RESULTS: S-ketamine lead to a significant decrease in the N100-P200 peak to peak (ptp) amplitude after the placebo treatment, whereas ptp was significantly increased by S-ketamine infusion in the LI160 treated subjects. The ODT and the cognitive testing revealed no significant effect of ketamine-infusion and therefore no interaction between treatment groups. CONCLUSIONS: AEP measures are sensitive means to assess the effect of low dose ketamine. Provided that ketamine mimics cognitive deficits in schizophrenia, LI160 might be effective to treat these symptoms.

Lamotrigine prevents ketamine but not amphetamine-induced deficits in prepulse inhibition in mice.

RATIONALE: Lamotrigine, a broad-spectrum anticonvulsant known to block brain sodium channels, is effective in the treatment of persons with bipolar disorder, perhaps by virtue of its ability to reduce glutamate release. Furthermore, lamotrigine decreases the perceptual abnormalities produced by the N-methyl- d-aspartate (NMDA) antagonist ketamine in humans, similar to the effects of the atypical antipsychotic clozapine. Acutely manic bipolar patients, like persons with schizophrenia, Tourette's, and obsessive compulsive disorder, exhibit decreases in sensorimotor gating, as measured by prepulse inhibition of the startle response (PPI). OBJECTIVE: We assessed the ability of lamotrigine to reduce the PPI-disruptive effects of ketamine and the dopaminergic agent amphetamine in two inbred mouse strains, C57BL/6J and 129SvPasIco. METHODS: Mice were tested in a standard PPI paradigm after administration of lamotrigine (0, 6.7, 13, or 27 mg/kg) or a combination of lamotrigine (27 mg/kg) and either d-amphetamine (10 mg/kg) or ketamine (100 mg/kg). RESULTS: In the 129SvPasIco mice, lamotrigine reversed the ketamine-induced PPI deficit, without altering PPI in control mice. In C57BL/6J mice, however, 27 mg/kg lamotrigine generally increased PPI in both control and ketamine-treated mice. Lamotrigine did not ameliorate the amphetamine-induced PPI deficit in either strain. CONCLUSIONS: In conclusion, lamotrigine can increase PPI on its own and prevent ketamine-induced, but not amphetamine-induced, disruptions of PPI. These results suggest that lamotrigine may exert its effects on PPI through the glutamatergic system.

Ketamine-induced anesthesia involves the N-methyl-D-aspartate receptor-channel complex in mice.

The role of the N-methyl-D-aspartate (NMDA) receptor-channel complex in ketamine-induced anesthesia was examined in mice. General anesthetic potencies were evaluated on a rating scale, which provided the data for anesthetic scores, loss of righting reflex, sleeping time and recovery time. All drugs were administered intraperitoneally. NMDA (60-300 mg/kg), an NMDA receptor agonist, dose-dependently antagonized the general anesthetic potencies of ketamine at a dose of 100 mg/kg which produced loss of righting reflex in more than 90% of the mice. On the other hand, a high dose of N-methyl-L-aspartate (400 mg/kg), a stereoisomer of NMDA, did not. A dose of 300 mg/kg of NMDA significantly shifted the dose-response curve of ketamine for loss of righting reflex to the right. A high dose of D-cycloserine (200 mg/kg), an agonist at the glycine site on the NMDA receptor complex, slightly but significantly shortened the sleeping time caused by ketamine (100 mg/kg). However, neither a critical subconvulsive dose of kainate (15 mg/kg), a kainate receptor agonist, nor a subconvulsive dose of quisqualate (120 mg/kg), an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor agonist, reversed general anesthesia induced by 100 mg/kg of ketamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of yohimbine as a reversing agent for ketamine-xylazine anesthesia in budgerigars.

Fourteen adult budgerigars (Melopsittacus undulatus) were anesthetized with a combination of ketamine hydrochloride (40 mg/kg) and xylazine hydrochloride (10 mg/kg) intramuscularly. Forty-five minutes after ketamine-xylazine injection, one of four yohimbine hydrochloride doses (0.0, 0.11, 0.275, or 0.44 mg/kg, IM) was administered in a 0.7% saline vehicle. Latencies were recorded in minutes from yohimbine injection until subjects' behavior indicated three different points of recovery: 1) lifting the head, 2) standing unaided without ataxia, and 3) perching. Means for all three recovery point latencies were significantly reduced by 0.275 mg/kg of yohimbine compared with saline vehicle alone. Mean latencies among treatment groups for each of the three recovery points were not significantly different, other than control versus treated groups. Based on these results, we recommend a yohimbine dose of 0.275 mg/kg as an effective reversing agent for ketamine-xylazine anesthesia in budgerigars.

Role of 5-hydroxytryptamine in ketamine-induced hypothermia in the rat.

1. Intraperitoneal injection of graded doses of ketamine produced a dose-dependent fall in body temperature of rats. Similarly, intracerebral injection of much smaller doses produced hypothermia.2. Pretreatment of the rats with p-chlorophenylalanine (PCPA) greatly attenuated the hypothermic response to ketamine whereas the intraperitoneal injection of 5-hydroxytryptophan in PCPA-treated rats restored the hypothermic effect of ketamine.3. Depletion of the brain monoamines by reserpine completely prevented the ketamine-induced hypothermia. Treatment with sodium diethyldithiocarbamate (DEDTC), however, did not modify the hypothermic effect of ketamine.4. Pretreatment of the rats with pargyline potentiated the ketamine-induced hypothermia.5. Depletion of brain monoamines by reserpine in combination with inhibition of noradrenaline biosynthesis (DEDTC) resulted in a long lasting fall in temperature which was not modified by ketamine.6. When the ambient temperature was raised from 26 degrees C to 32 degrees C, ketamine-induced hypothermia was much reduced and superimposed on a hyperthermia which occurred in all animals.7. It is concluded that ketamine produces hypothermia in rats possibly through the release of 5-hydroxytryptamine in the hypothalamus and that this effect is similar in some respects to that produced by morphine in non-tolerant rats.