Chronic Ketamine Administration Research Articles

Ketamine administration during adolescence impairs synaptic integration and inhibitory synaptic transmission in the adult dentate gyrus.

Ketamine administration during adolescence affects cognitive performance; however, its long-term impact on synaptic function and neuronal integration in the hippocampus a brain region critical for cognition remains unclear. Using functional and molecular analyses, we found that chronic ketamine administration during adolescence exerts long-term effects on synaptic integration, expanding the temporal window in an input-specific manner affecting the inner molecular layer but not the medial perforant path inputs in the adult mouse dorsal hippocampal dentate gyrus. Ketamine also alters the excitatory/inhibitory balance by reducing the efficacy of inhibitory inputs likely due to a reduction in parvalbumin-positive interneurons number and function. These findings indicate that during adolescence, ketamine exerts a strong effect on inhibitory synaptic function mediated by parvalbumin-positive neurons that ultimately impact synaptic integration in the dorsal adult dentate gyrus, which could help to understand the neurobiological and functional bases that confer greater vulnerability to the adolescent brain.

Inulin alleviates chronic ketamine-induced impairments in memory and prepulse inhibition by regulating the gut microbiota, inflammation, and kynurenine pathway.

Chronic ketamine administration causes cognitive impairments similar to those observed in schizophrenia. Growing evidence suggests that patients with schizophrenia show alterations in gut microbiota, which is associated with cognitive impairments. Inulin could regulate gut microbiota. However, it is unclear whether chronic ketamine exposure causes cognitive impairments by mediating gut microbiota and whether inulin ameliorates these impairments. In this study, we found that chronic ketamine exposure for 14days induced gut dysbiosis, thereby increasing gut permeability, upregulating LPS-activated TLR4-NF-κB-NLRP3 inflammatory pathway, causing hippocampal neuroinflammation and neuronal damage, activating tryptophan (TRP)-kynurenine (KYN)-kynurenic acid (KYNA) pathway in the hippocampus, peripheral serum, and feces, and thus leading to deficits in recognition memory and prepulse inhibition (PPI). In addition, inulin treatment restored gut dysbiosis by increasing the abundance of Turicibacter and Ileibacterium and decreasing the abundance of Alistipes, Alloprevotella, Desulfovibrio, and Parasutterella, which may improve gut barrier damage by upregulating tight junction protein expression, suppress LPS-mediated TLR4-NF-κB-NLRP3 inflammatory pathway to reduce neuroinflammation and neuronal damage, inhibit TRP-KYN-KYNA metabolism pathway, and thus alleviate chronic ketamine-associated impairments in PPI and memory. Our findings provide additional evidence that inulin treatment is a potential intervention strategy for treating chronic ketamine-associated cognitive impairments and cognitive deficits in schizophrenia.

Effects of acute and chronic ketamine administration on spontaneous and evoked brain activity

Schizophrenia is believed to be, at least in part, a dysfunction of the glutamatergic system. In line with anatomical evidence, suppressing N-methyl-D-aspartate (NMDA) neurotransmission leads to symptoms that are characteristic of schizophrenia. Rodent models of schizophrenia often involve the acute application of NMDA antagonists, which produce both behavioural and brain activity changes that closely resemble symptoms observed in schizophrenia. It is, however, important to note that the full spectrum of schizophrenia symptoms may not be manifested following the acute suppression of NMDA receptors. This has led to the proposal of a chronic model where NMDA receptors are suppressed for prolonged periods. Although the chronic model has shown promising results from a behavioural perspective and alterations in metabolic processes in the brain, its impact on brain oscillations remains largely unknown. The aim of this study is to examine the impact of acute and chronic NMDA neurotransmission suppression on brains’ oscillatory activity. To achieve this, chronic brain activity recordings in mice of both sexes were used to assess both spontaneous and evoked brain oscillations. The study demonstrates that an acute suppression of NMDA receptors alters brain oscillations across a wide frequency spectrum and diminishes the oscillatory potency in evoked responses, paralleling changes observed in schizophrenia. However, the chronic suppression of NMDA receptors did not have the expected cumulative effect on brain activity. This research highlights the robust yet similar impacts of acute and chronic NMDA receptor suppression on brain activity, contributing to the nuanced understanding of rodent models of schizophrenia.

Evaluation of the acute oral toxicity and antipsychotic activity of a dual inhibitor of PDE1B and PDE10A in rat model of schizophrenia.

Phosphodiesterase 1B (PDE1B) and PDE10A are dual-specificity PDEs that hydrolyse both cyclic adenosine monophosphate and cyclic guanosine monophosphate, and are highly expressed in the striatum. Several reports have suggested that PDE10A inhibitors may present a promising approach for the treatment of positive symptoms of schizophrenia, whereas PDE1B inhibitors may present a novel mechanism to modulate cognitive deficits. Previously, we have reported a novel dual inhibitor of PDE1B and PDE10A, compound 2 [(3-fluorophenyl)(2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone] which has shown inhibitory activity for human recombinant PDE1B and PDE10A in vitro. In the present study, the safety profile of compound 2 has been evaluated in rats in the acute oral toxicity study, as well as; the antipsychotic-like effects in the rat model of schizophrenia. Compound 2 was tolerated up to 1 g/kg when administered at a single oral dose. Additionally, compound 2 has strongly suppressed ketamine-induced hyperlocomotion, which presented a model for the positive symptoms of schizophrenia. It has also shown an ability to attenuate social isolation induced by chronic administration of ketamine and enhanced recognition memory of rats ​in the novel object recognition test. Altogether, our results suggest that compound 2 represents a promising therapy for the treatment of the three symptomatic domains of schizophrenia.

CBD Effects on Motor Profile and Neurobiological Indices Related to Glutamatergic Function Induced by Repeated Ketamine Pre-Administration.

Clinical evidence and experimental studies have shown the psychotomimetic properties induced by ketamine. Moreover, acute or chronic ketamine (KET) administration has been widely used for modeling schizophrenia-like symptomatology and pathophysiology. Several studies have reported the antipsychotic potential of cannabidiol (CBD), while there is limited information on the cannabidiol effect on KET-induced schizophrenia-like impairments. Therefore, the goal of the present study was to evaluate neuroplastic changes induced by repeated KET administration, which is used as an experimental model of schizophrenia—with a behavioral focus on positive-like symptomatology– and to assess the modulatory role of CBD treatment. The present findings have shown a robust increase in motor activity in KET-treated rats, following a 10-day period of chronic administration at the sub-anesthetic dose of 30 mg/kg (i.p), that was reversed to normal by subsequent chronic CBD treatment. Concerning the expression of glutamate receptors, the current findings have shown region-dependent KET-induced constitutional alterations in NMDA and AMPA receptors that were modified by subsequent CBD treatment. Additionally, repeated KET administration increased ERK1/2 phosphorylation state in all regions examined, apart from the ventral hippocampus that was modulated by subsequent CBD treatment. The present results show, for the first time, a stimulated motor output coupled with a specific glutamatergic-related status and ERK1/2 activation following chronic KET administration that were attenuated by CBD treatment, in a region-dependent manner. These findings provide novel information concerning the antipsychotic potential of CBD using a specific design of chronic KET administration, thus contributing to experimental approaches that mirror the symptomatology and pathophysiology of schizophrenia.

A comparison of the pharmacokinetics and NMDAR antagonism-associated neurotoxicity of ketamine, (2R,6R)-hydroxynorketamine and MK-801

With the increasing use of ketamine as an off-label treatment for depression and the recent FDA approval of (S)-ketamine for treatment-resistant depression, there is an increased need to understand the long-term safety profile of chronic ketamine administration. Of particular concern is the neurotoxicity previously observed in rat models following acute exposure to high doses of ketamine, broadly referred to as ‘Olney's lesions’. This type of toxicity presents as abnormal neuronal cellular vacuolization, followed by neuronal death and has been associated with ketamine's inhibition of the N-methyl-d-aspartate receptor (NMDAR). In this study, a pharmacological and neuropathological analysis of ketamine, the potent NMDAR antagonist MK-801, and the ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK)] in rats is described following both single dose and repeat dose drug exposures. Ketamine dosing was studied up to 20 mg/kg intravenously for the single-dose neuropathology study and up to 60 mg/kg intraperitoneally for the multiple-dose neuropathology study. MK-801 dosing was studied up to 0.8 mg/kg subcutaneously for both the single and multiple-dose neuropathology studies, while (2R,6R)-HNK dosing was studied up to 160 mg/kg intravenously in both studies. These studies confirm dose-dependent induction of ‘Olney's lesions’ following both single dose and repeat dosing of MK-801. Ketamine exposure, while showing common behavioral effects, did not induce wide-spread Olney's lesions. Treatment with (2R,6R)-HNK did not produce behavioral effects, toxicity or any evidence of Olney's lesion formation. Based on these results, future NMDAR-antagonist neurotoxicity studies should strongly consider taking pharmacokinetics more thoroughly into account.

Efficacy of ketamine in relieving neuropathic pain: a systematic review and meta-analysis of animal studies.

In humans, proof of long-term efficacy of ketamine treatment in neuropathic pain is lacking. To improve our understanding of ketamine behavior under various administration conditions, we performed a systematic review and meta-analyses of controlled studies on the efficacy of ketamine in mice and rats with a disease model of nerve injury on relief of allodynia. Searches in PubMed and EMBASE identified 31 unique studies. Four meta-analyses were conducted. The first analysis included 19 comparisons on a single ketamine dose and measurement of effect within 3 hours of dosing and showed an appreciable effect (standardized mean difference 1.6, 95% confidence interval 1.1-2.1). Subgroup analyses showed no effect of species, administration route, or dose. A single administration was insufficient to sustain relief of allodynia at 24 or 72 hours after dosing, as observed in our second analysis (7 comparisons) with similar effects in ketamine-treated and control animals. Chronic ketamine administration (9 comparisons) caused profound relief of allodynia when tested during ketamine exposure (effect size 5.1, 3.7-6.5). The final analysis (6 comparisons) showed that chronic administration caused a slow loss of relief of allodynia with 70% loss of effect 24 days after end of treatment. No subgroups analyses were possible in the last 3 meta-analyses due to small group sizes. These results indicate long-term ketamine anti-allodynic effects after chronic exposure (>3 days) but not after a single administration. Given several limitations, extrapolation of the animal data to the human condition is tenuous.

Ketamine Administration Leads to Learning-Memory Dysfunction and Decreases Serum Brain-Derived Neurotrophic Factor in Rats.

ObjectiveThis study investigated the effects of acute or chronic ketamine administration on learning and memory function as well as levels of brain-derived neurotrophic factor (BDNF) in the hippocampus and blood in order to explore the potential correlation between learning-memory dysfunction and ketamine.MethodsRats were treated with 25 mg/kg ketamine for 3 d (n = 20) or 14 d (n = 20). Saline-treated rats were used as controls. The Morris water maze test was used to evaluate spatial learning and memory after 10 d of withdrawal. The level of BDNF in serum and the hippocampus were measured by ELISA.ResultsThe number of platform crossings and residence time in the target platform quadrant were significantly reduced in ketamine 3 d and 14 d groups than in the saline controls (both p < 0.05). In addition, the average escape latency of ketamine 3 d and 14 d groups were significantly longer than that of the saline 3 d and 14 d groups (p < 0.0001), respectively. Further examination found that only serum samples from ketamine 14 d group showed significantly decreased BDNF level compared to that from saline 14 d groups (p < 0.05). However, no differences were detected in hippocampus samples.ConclusionChronic ketamine exposure (25 mg/kg) causes spatial learning and memory deficits in SD rats, which may be associated with decreased serum BDNF levels.

Neurobehavioral, testicular and erectile impairments of chronic ketamine administration: Pathogenesis and ameliorating effect of N-acetyl cysteine

Ketamine, a dissociative anesthetic, recently has spread as a recreational drug. Its abuse lead to neurobehavioral disturbance in addition to toxic effects on other body organs. To evaluate the toxic effects of chronic administration of low ketamine doses on the memory, testicles, and erection, explore its pathophysiology through oxidative stress mechanism and examine the ameliorating effect of N-acetyl cysteine (NAC). A total of 40 male albino rats were assigned to control, vehicle, ketamine only I.P. (10 mg/kg), and ketamine (10 mg/kg) + NAC (150 mg/kg) groups. Assessment of memory affection and erectile function by Passive Avoidance, Novel Object Recognition, and copulatory tests were performed. Estimation of malondialdehyde (MDA), catalase (CAT), and total antioxidant capacity (TAC) in serum and prefrontal & hippocampal homogenate, and luteinizing hormone (LH), testosterone in serum were done. Prefrontal cortex, hippocampus, and testes were collected for histopathology. Chronic ketamine administration induced significant memory deficits (P < 0.05), reduced erectile function (P < 0.05), severe hypospermatogenesis, increased MDA, reduced CAT, TAC levels in serum, and tissue homogenate (P < 0.05) and reduction of LH, and testosterone (P < 0.05). Treatment with NAC resulted in significant improvement of memory function, improved erectile function, and decrease in oxidative injury in both serum and tissue homogenates. Testosterone and LH levels exhibited significant difference between treatment groups and controls (P < 0.05). NAC reduced the deleterious histopathological changes. These data suggest that long-term ketamine affects short and long memory, induces erectile and testicular dysfunction through oxidative stress. Co-administration with NAC ameliorates these toxic effects.

Chronic administration of ketamine induces cognitive deterioration by restraining synaptic signaling

The discovery of the rapid antidepressant effects of ketamine has arguably been the most important advance in depression treatment. Recently, it was reported that repeated long-term ketamine administration is effective in preventing relapse of depression, which may broaden the clinical use of ketamine. However, long-term treatment with ketamine produces cognitive impairments, and the underlying molecular mechanisms for these impairments are largely unknown. Here, we found that chronic in vivo exposure to ketamine for 28 days led to decreased expression of the glutamate receptor subunits GluA1, GluA2, GluN2A, and GluN2B; decreased expression of the synaptic proteins Syn and PSD-95; decreased dendrite spine density; impairments in long-term potentiation (LTP) and synaptic transmission in the hippocampal CA1 area; and deterioration of learning and memory in mice. Furthermore, the reduced glutamate receptor subunit and synaptic protein expression and the LTP deficits were still observed on day 28 after the last injection of ketamine. We found that the expression and phosphorylation of CaMKIIβ, ERK1/2, CREB, and NF-κB were inhibited by ketamine. The reductions in glutamate receptor subunit expression and dendritic spine density and the deficits in LTP, synaptic transmission, and cognition were alleviated by overexpression of CaMKIIβ. Our study indicates that inhibition of CaMKIIβ-ERK1/2-CREB/NF-κB signaling may mediate chronic ketamine use-associated cognitive impairments by restraining synaptic signaling. Hypofunction of the glutamatergic system might be the underlying mechanism accounting for chronic ketamine use-associated cognitive impairments. Our findings may suggest possible strategies to alleviate ketamine use-associated cognitive deficits and broaden the clinical use of ketamine in depression treatment.

MTOR Expression in Hippocampus and Prefrontal Cortex Is Downregulated in a Rat Model of Schizophrenia Induced by Chronic Administration of Ketamine.

Schizophrenia is a severe chronic neuropsychiatric disorder, and it negatively affects individuals' quality of life, but the pathogenesis of schizophrenia remains unclear. This study aimed to explore whether the administration of ketamine in rats causes changes in mTOR (mechanistic/mammalian target of rapamycin) expression in the hippocampus and prefrontal cortex. Ketamine was used to establish an animal model of schizophrenia. Rats were randomly divided into four groups: control group (normal saline), low-dose group (15mg/kg ketamine), middle-dose group (30mg/kg ketamine), and high-dose group (60mg/kg ketamine). The rats were intraperitoneally injected with ketamine or normal saline twice a day (9 AM and 9 PM) for 7 consecutive days. Immunohistochemistry was used to detect mTOR protein expression in the hippocampus and prefrontal cortex from rats at 13h after the last treatment. Using immunohistochemistry, the expression of the mTOR protein was localized exclusively in the CA3 region of the hippocampus and in the Cg1 region of the prefrontal cortexes. Ketamine at 60mg/kg decreased the expression of mTOR protein in the brain of rats. Ketamine successfully established a rat model of schizophrenia. This study helps elucidate the mechanisms of ketamine-induced schizophrenia and provides novel insights for drug discovery and development.

The effects of sub-anesthetic ketamine plus ethanol on behaviors and apoptosis in the prefrontal cortex and hippocampus of adolescent rats

Ketamine has become increasingly popular in adolescent drug abusers worldwide. Meanwhile, alcohol is usually used by ketamine users. However, little work has been conducted to examine the chronic combined effects of ketamine and ethanol on adolescent brain. Here we probed into the effects of chronic administration of ketamine at recreational doses alone or combined with ethanol on behaviors and neuron damage in an adolescent rat model. 28-day old rats were treated with either 20 or 30 mg/kg ketamine plus or not plus 10% ethanol daily for 21 days. Depressive like behaviors, anxiety like behavior and memory impairment were tested using open field test, forced swimming test, elevated plus maze and Morris water maze. Apoptosis in prefrontal cortex (PFC) and hippocampus (HIP) were determined by the TdT-mediated dUTP Nick-End Labeling (TUNEL) and protein and mRNA levels of caspase-3, Bax and Bcl-2. Results show that co-application of ketamine and ethanol significantly increased immobility time in the forced swimming test, up-regulated TUNEL positive cells and both protein and mRNA expressions of caspase-3 and Bax, compared with the control group and ketamine and ethanol use alone groups in the PFC, but not in the HIP. Our study suggests that chronic co-administration of ketamine and ethanol results in depressive-like behavior and the caspase-dependent apoptosis in the PFC of adolescent rats' brains.

Ketamine Tolerance in Sprague-Dawley Rats after Chronic Administration of Ketamine, Morphine, or Cocaine.

Ketamine is one of the most commonly used anesthetics in human and veterinary medicine, but its clinical effectiveness is often compromised due to tolerance to its anesthetic effects. Although ketamine tolerance has been demonstrated in a number of behavioral measures, no published work has investigated tolerance to ketamine's anesthetic effects other than duration of anesthesia. In addition, a reported practice in anesthesiology is to alter anesthetic doses for procedures when the patient has a history of drug abuse. Empirically investigating the effects of administration of a drug of abuse on ketamine's potency and efficacy to produce anesthesia could help in the creation of anesthetic plans that maximize safety for both clinicians and patients. The goal of the current study was to test the effects of repeated administration of ketamine, morphine, or cocaine on ketamine's ability to produce anesthesia. In 2 studies, male Sprague-Dawley rats received daily injections of ketamine (32 or 100 mg/kg IP), morphine (3.2 or 5.6 mg/kg IP), or cocaine (3.2 or 10 mg/kg IP) for 14 consecutive days and then were tested on day 15 for ketamine-induced anesthesia by using a cumulative-dosing procedure (32 to 320 mg/kg IP). Chronic treatment with either ketamine or morphine-but not cocaine-produced tolerance to ketamine's anesthetic effects in a dose-dependent manner. These results suggest that ketamine's clinical effectiveness as an anesthetic will vary as a function of its history of use. Furthermore, given that chronic morphine administration produced tolerance to ketamine's anesthetic effects, various pain medications may reduce ketamine's effectiveness for anesthesia.

Chronic administration of ketamine ameliorates the anxiety- and aggressive-like behavior in adolescent mice induced by neonatal maternal separation.

Ketamine has long been used as an anesthetic agent. However, ketamine use is associated with numerous side effects, including flashbacks, amnesia, delirium, and aggressive or violent behavior. Ketamine has also been abused as a cocktail with ecstasy, cocaine, and methamphetamine. Several studies have investigated therapeutic applications of ketamine, demonstrating its antidepressant and anxiolytic effects in both humans and rodents. We recently reported that neonatal maternal separation causes enhanced anxiety- and aggressive-like behaviors in adolescent. In the present study, we evaluated how acute and chronic ketamine administration affected the behavioral consequences of neonatal maternal separation in adolescent mice. Litters were separated from dams for 4 hours per day for 19 days beginning after weaning. Upon reaching adolescence (post-natal day 35–49), mice were acutely (single injection) or chronically (7 daily injections) treated with a sub-anesthetic dose (15 mg/kg) of ketamine. At least 1 h after administration of ketamine, mice were subjected to open-field, elevated-plus maze, and resident-intruder tests. We found that acute ketamine treatment reduced locomotor activity. In contrast, chronic ketamine treatment decreased anxiety, as evidenced by increased time spent on open arms in the elevated-plus maze, and remarkably reduced the number and duration of attacks. In conclusion, the present study suggests that ketamine has potential for the treatment of anxiety and aggressive or violent behaviors.

Stress and Ketamine, Bimodal Influence on Cognitive Functions

The glutamate N-methyl-D-aspartate receptor (NMDAR) non-selective antagonist, ketamine, has been recently repurposed as a rapidly acting antidepressant, catalyzing the vigorous investigation of glutamate-signaling modulators as novel therapeutic agents for depressive disorders. Beneficial effects of this drug in the quick-acting treatment of depression are recognized. The long-term effects of ketamine have not been known, including the cognitive sphere. It is well acknowledged that prolonged exposure to stress induces depression and cognitive impairment.It seemed reasonable to ask how the long-term ketamine administration would affect stressed animals in the aspect of cognitive functions. In the current study we tested whether it is possible for ketamine, used in prolonged-regimen in rats, to alleviate stress-evoked memory deficits?Stressed (restraint 2 h daily for 21 days) and non-stressed rats (6-weeks-old) were treated with ketamine for 21 days and next subjected to a battery of behavioral tests: for the assessment of working and reference spatial memory (Morris water maze (MWM) and Barnes maze (BM)), stereotypy (stereotypy test - ST), locomotor functions (Open field - OF) and anxiety behavior (Elevated plus maze - EPM).Ketamine administration resulted in a significant stereotype behaviour in rats tested in ST.Stressed rats displayed a significant decline in the spatial working and reference memory. The effect of chronic ketamine administration depended on the type of test and differed between control rats and animals simultaneously exposed to chronic stress. However, in the MWM the impact was quite unequivocal, as we observed an improvement in spatial memory in stressed animals and a deterioration in non-stressed animals after ketamine administration. In the BM, the effect of ketamine changed in successive attempts, from favorable in the initial period to negative at the end of the test in the group of stressed animals and without a significant impact on control animals. We found no significant effects of ketamine on locomotor performance and on the level of anxiety.Taken together, these findings demonstrate that ketamine potently abolishes or prevents some kinds of stress-induced memory impairments and cognitive decline in rats, although in some circumstances, it could even increase damage to memory, especially in unstressed animals.It seems that the prolonged use of ketamine in the prevention of stress-induced memory declines can fulfill its role.

Effects of chronic ketamine on hippocampal cross-frequency coupling: implications for schizophrenia pathophysiology.

Disrupted neuronal oscillations have been identified as a potentially important biomarker for the perceptual and cognitive symptoms of schizophrenia. Emerging evidences suggest that interactions between different frequency bands, cross-frequency coupling (CFC), serve an important role in integrating sensory and cognitive information and may contribute to disease pathophysiology. In this study, we investigated the effects of 14-day consecutive administration of ketamine (30mg/kg i.p.) vs. saline on alterations in amplitude and changes in the coupling of low-frequency (0-30Hz) phase and high-frequency (30-115Hz) amplitude in the CA1 hippocampus of Long Evans rats. Intracranial electrode recordings were conducted pre- and post-injection while the animals performed a foraging task on a four-arm rectangular maze. Permutation analysis of frequency band-specific change in amplitudes revealed between-group differences in theta (6-12Hz) and slow gamma (25-50Hz) but not fast gamma (65-100Hz) bands at both slow and fast speeds. Chronic ketamine challenge resulted in decreased coupling (pre to post) at slow speeds but increased coupling at faster speeds, compared to either no or modest increased coupling in the saline group. These results demonstrate that chronic ketamine administration alters the interaction of low-frequency phase and high-frequency oscillations chronically and that such coupling varies as a function of locomotive speed. These findings provide evidence for the potential relevance of CFC to the pathophysiology of schizophrenia.

Ketamine: differential neurophysiological dynamics in functional networks in the rat brain

Recently, the N-methyl-d-aspartate-receptor (NMDAR) antagonist ketamine has emerged as a fast-onset mechanism to achieve antidepressant activity, whereas its psychomimetic, dissociative and amnestic effects have been well documented to pharmacologically model schizophrenia features in rodents. Sleep–wake architecture, neuronal oscillations and network connectivity are key mechanisms supporting brain plasticity and cognition, which are disrupted in mood disorders such as depression and schizophrenia. In rats, we investigated the dynamic effects of acute and chronic subcutaneous administration of ketamine (2.5, 5 and 10 mg kg−1) on sleep–wake cycle, multichannels network interactions assessed by coherence and phase–amplitude cross-frequency coupling, locomotor activity (LMA), cognitive information processing as reflected by the mismatch negativity-like (MMN) component of event-related brain potentials (ERPs). Acute ketamine elicited a short, lasting inhibition of rapid eye movement (REM) sleep, increased coherence in higher gamma frequency oscillations independent of LMA, altered theta-gamma phase–amplitude coupling, increased MMN peak-amplitude response and evoked higher gamma oscillations. In contrast, chronic ketamine reduced large-scale communication among cortical regions by decreasing oscillations and coherent activity in the gamma frequency range, shifted networks activity towards slow alpha rhythm, decreased MMN peak response and enhanced aberrant higher gamma neuronal network oscillations. Altogether, our data show that acute and chronic ketamine elicited differential changes in network connectivity, ERPs and event-related oscillations (EROs), supporting possible underlying alterations in NMDAR–GABAergic signaling. The findings underscore the relevance of intermittent dosing of ketamine to accurately maintain the functional integrity of neuronal networks for long-term plastic changes and therapeutic effect.

Altered Cortical Ensembles in Mouse Models of Schizophrenia

In schizophrenia, brain-wide alterations have been identified at the molecular and cellular levels, yet how these phenomena affect cortical circuit activity remains unclear. We studied two mouse models of schizophrenia-relevant disease processes: chronic ketamine (KET) administration and Df(16)A+/-, modeling 22q11.2 microdeletions, a genetic variant highly penetrant for schizophrenia. Local field potential recordings in visual cortex confirmed gamma-band abnormalities similar to patient studies. Two-photon calcium imaging of local cortical populations revealed in both models a deficit in the reliability of neuronal coactivity patterns (ensembles), which was not a simple consequence of altered single-neuron activity. This effect was present in ongoing and sensory-evoked activity and was not replicated by acute ketamine administration or pharmacogenetic parvalbumin-interneuron suppression. These results are consistent with the hypothesis that schizophrenia is an "attractor" disease and demonstrate that degraded neuronal ensembles are a common consequence of diverse genetic, cellular, and synaptic alterations seen in chronic schizophrenia.

Effects of Ketamine on Levels of Inflammatory Cytokines IL-6, IL-1β, and TNF-α in the Hippocampus of Mice Following Acute or Chronic Administration.

Ketamine is an injectable anesthetic and recreational drug of abuse commonly used worldwide. Many experimental studies have shown that ketamine can impair cognitive function and induce psychotic states. Neuroinflammation has been suggested to play an important role in neurodegeneration. Meanwhile, ketamine has been shown to modulate the levels of inflammatory cytokines. We hypothesized that the effects of ketamine on the central nervous system are associated with inflammatory cytokines. Therefore, we set out to establish acute and chronic ketamine administration models in C57BL/6 mice, to evaluate spatial recognition memory and emotional response, to analyze the changes in the levels of the inflammatory cytokines interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in the mouse hippocampus, employing behavioral tests, Western blot, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and immunohistochemistry. Our results showed that ketamine at the dose of 60 mg/kg induced spatial recognition memory deficit and reduced anxiety-like behaviors in mice after chronic administration. Moreover, we found that ketamine increased the hippocampal levels of IL-6 and IL-1β after single, multiple and long-term administration in a dose-dependent manner. However, the expression level of TNF-α differed in the mouse hippocampus under different conditions. Single administration of ketamine increased the level of TNF-α, whereas multiple and long-term administration decreased it significantly. We considered that TNF-α expression could be controlled by a bi-directional regulatory pathway, which was associated with the dose and duration of ketamine administration. Our results suggest that the alterations in the levels of inflammatory cytokines IL-6, IL-1β, and TNF-α may be involved in the neurotoxicity of ketamine.

Standardisation and Validation of Acute and Chronic Administration Ketamine at Different Doses to Produce Psychosis Like Behavioural Changes in Mice

Psychosis is a complex mental illness, characterised by positive, negative and cognitive symptoms. NMDA receptor antagonists have been established to induce behavioural as well as biochemical changes in rodents similar to psychotic patients. The aim of the present study was to investigate the effective dose and treatment period of ketamine to induce some behavioural changes. The results suggest that acute treatment of ketamine (50 and 100 mg/kg, i.p.) induced hyperlocomotor activity and reduced step down latency time in passive avoidance test, whereas in effective in forced swim test. Further, with the chronic administration of ketamine (50 and 100 mg/kg, i.p.) effective to produced hyperlocomotor activity, reduced the step down latency time in passive avoidance test and enhanced the immobility duration in forced swim test. Moreover, these behavioural changes persisted for 7 days after the treatment period. Thus, our findings suggest that the chronic administration of Ketamine (50 and 100 mg/kg, i.p.) potential to produce behavioural changes, would serve as an effective tool to screen antipsychotic drugs.