Inhibition of glycogen synthase kinase-3 attenuates psychotomimetic effects of ketamine.

N-methyl-D-aspartate (NMDA) glutamate receptors mediate fast neurotransmission and regulate synaptic plasticity in the brain. Disruption of NMDA receptor-mediated signaling by noncompetitive antagonists, such as PCP or ketamine, evokes psychotomimetic behaviors, although the cellular mechanisms by which hypofunctional NMDA receptor signaling drives behavioral pathology are still unclear. Activation of glycogen synthase kinase-3 (GSK-3) has been implicated in the cellular neurotoxicity of NMDA receptor antagonists. Accordingly, in the present study we examined the ability of GSK-3 inhibitors, SB216763 and 1-azakenpaullone, to reverse the behavioral aberrations induced by ketamine. Male NMRI mice received intracerebroventricular (i.c.v.) injection of the GSK-3 inhibitors, SB216763 and 1-azakenpaullone, 5 min prior to ketamine administration. Locomotor activity, rotarod performance, prepulse inhibition, novel object recognition, and duration of loss of righting reflex were monitored. GSK-3 inhibitors attenuated ketamine-induced locomotor hyperactivity, motor incoordination, sensorimotor impairment, and cognitive deficits, but did not affect ketamine anesthesia. These data support an important role of GSK-3 in the expression of behavioral aberrations associated with NMDA receptor hypofunction, and suggest that GSK-3 inhibitors may ameliorate certain behavioral and cognitive dysfunctions in patients with schizophrenia.

Behavioural and toxic interaction profile of ketamine in combination with caffeine.

Ketamine street tablets often contain several other compounds in addition to ketamine, among them is caffeine. The purpose of this study was to examine whether caffeine interacts with ketamine-induced behavioural and toxic effects. Male ICR mice were treated with ketamine alone or ketamine combined with various doses of caffeine, then the locomotor activity, rotarod test, prepulse inhibition of acoustic startle, loss of righting reflex, and mortality rate were examined. Caffeine enhanced the locomotor hyperactivity, caused disruption of the rotarod performance, and mortality rates due to ketamine, whereas prepulse inhibition deficits and anaesthesia remained unaffected. These findings demonstrate that use of ketamine in combination with caffeine enhances its stimulant responses and lethal risk, suggesting that a potentially toxic interaction exists between ketamine and caffeine.

Attenuation of ketamine-evoked behavioral responses by mGluR5 positive modulators in mice.

RATIONALE: Recent studies have shown that metabotropic glutamate receptor 5 (mGluR5) can modulate N-methyl-D-aspartate receptor function. Our previous findings demonstrated that the selective mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) and the antagonist 2-methyl-6-(phenylethynyl)-pyridine can reduce and enhance the ketamine anesthesia, respectively. OBJECTIVE: The purpose of this study was to examine whether CHPG and positive allosteric modulator 3,3'-difluorobenzaldazine (DFB) can reverse ketamine-induced behavioral responses including locomotor hyperactivity, motor incoordination, sensorimotor gating deficit, and learning impairment. METHODS: Mice were pretreated with CHPG (5-50 nmol,) or DFB (40-100 nmol) followed by ketamine administration. Locomotor activity, rotarod test, prepulse inhibition (PPI) of acoustic startle test, and novel object recognition test were examined. RESULTS: CHPG and DFB had no effect on these behaviors when administered alone. Both of them attenuated the locomotor hyperactivity, motor incoordination, and cognitive impairment induced by ketamine. However, the ketamine-induced PPI deficit was reversed by CHPG (50 nmol) but not by DFB (up to 100 nmol). CHPG and DFB have distinct potency and efficacy in attenuating ketamine-induced behavioral response. CONCLUSIONS: These behavioral data extend previous findings and further suggest that positive modulation of mGluR5 may provide a novel approach for development of antipsychotic agents.