Distribution of Aquaporin-4 channels in hippocampus and prefrontal cortex in mk-801-treated balb/c mice.

Functional disorders of the glymphatic system and Aquaporin-4 (AQP-4) channels take part in the pathophysiology of neurodegenerative disease. The aim of this study was to describe the distribution of AQP-4 channels in the prefrontal cortex and hippocampus in a mouse model of NMDA receptor blocking agent-induced schizophrenia-like behavior model. NMDA receptor antagonist MK-801 was used to produce the experimental schizophrenia model. MK-801 injections were administered for eleven days to Balb/c mice intraperitoneally. Beginning from the sixth day of injection, the spatial learning and memory of the mice were tested by the Morris water maze (MWM) task. A group of mice was injected with MK-801 for ten days without the MWM task. Hippocampus and prefrontal specimens were collected from this group. Tissue samples were stained immunohistochemically and AQP-4 channels were examined by electron microscope. Time to find the platform was significantly longer at MK-801 injected group than the control group at the MWM task. Also, time spent at the target quadrant by the MK-801 group was shorter compared to the control group. AQP-4 expression increased significantly at MK-801 group glial cells, neuronal perikaryon, perineuronal and pericapillary spaces. In the MK-801 group, there was remarkable damage in neurons and glial cells. Increased AQP-4 channel expression and neurodegeneration at the MK-801 group induced with schizophrenia-like behavior model. MK-801 induced NMDA receptor blockade causes a decline in cognitive and memory functions. Increased AQP-4 expression at the prefrontal cortex and hippocampus to elicit and transport products of synaptic neurotransmitters and end metabolites is suggested.

Effects of clozapine and risperidone antipsychotic drugs on the expression of CACNA1C and behavioral changes in rat 'Ketamine model of schizophrenia.

Calcium Voltage-Gated Channel Subunit Alpha1 C (CACNA1C) is one of the most important genes associated with schizophrenia. In this study, 45 male Wistar rats were divided into 5 groups of saline, control, ketamine, clozapine, and risperidone. Animals in ketamine, risperidone, and clozapine groups received ketamine (30 mg/kg-i.p.) for 10 days. After the last injection of ketamine, we started injecting clozapine (7.5 mg/kg-i.p.), risperidone (1 mg/kg-i.p.), up to 28 days. Twenty-four hours after the last injection, open field, social interaction, and elevated plus-maze tests and gene expression in hippocampus were performed. The results of the social interaction test revealed a significant decrease in cumulative time with ketamine, compared with the saline group, and an increase with clozapine and risperidone compared with the ketamine group. Moreover, results from the elevated plus-maze test demonstrated a critical decrease in open arm time and increase in close arm time with ketamine compared with saline, as well as increased in open arm time with risperidone compared with ketamine. Further results revealed a significant increase in rearing and grooming with ketamine compared to saline, as well as a decrease with risperidone and clozapine compared to ketamine. There were no significant differences in CACNA1C gene expression between groups in the rat hippocampus. In brief, the results of this study indicated that clozapine and risperidone could partially improve cognitive impairments in the rat. However, our findings demonstrated that this treatment is not related to CACNA1C gene expression.

Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal rats.

BACKGROUND: Multiple studies have revealed that repeated or long-term exposure to ketamine causes neurodegeneration and cognitive dysfunction. Pyroptosis is an inflammatory form of programmed cell death that has been linked to various neurological diseases. However, the role of NLRP3/caspase-1 axis-related pyroptosis in ketamine-induced neurotoxicity and cognitive dysfunction remains uncertain. METHODS: To evaluate whether ketamine caused NLRP3/caspase1-dependent pyroptosis, flow cytometry analysis, western blotting, ELISA test, histopathological analysis, Morris water maze (MWM) test, cell viability assay, and lactate dehydrogenase release (LDH) assay were carried out on PC12 cells, HAPI cells, and 7-day-old rats. In addition, the NLRP3 inhibitor MCC950 or the caspase-1 inhibitor VX-765 was used to investigate the role of the NLRP3/caspase-1 axis in ketamine-induced neurotoxicity and cognitive dysfunction. RESULTS: Our findings demonstrated that ketamine exposure caused cell damage and increased the levels of pyroptosis in PC12 cells, HAPI cells, and the hippocampus of neonatal rats. After continuous exposure to ketamine, targeting NLRP3 and caspase-1 with MCC950 or VX765 improved pyroptosis, reduced neuropathological damages, and alleviated cognitive dysfunction. CONCLUSION: NLRP3/Caspase-1 axis-dependent pyroptosis is involved in ketamine-induced neuroinflammation and cognitive dysfunction, and it provides a promising strategy to treat ketamine-related neurotoxicity.

Lipoxin A4 methyl ester protects PC12 cells from ketamine-induced neurotoxicity via the miR-22/BAG5 pathway.

OBJECTIVE: Ketamine is an anesthetic that induces neurotoxicity when administered at high doses. In this work, we explored the protective effects of lipoxin A4 methyl ester (LXA4 ME) against ketamine-induced neurotoxicity and the underlying protective mechanism in pheochromocytoma (PC12) cells. METHODS: PC12 cells were treated with 50 µM of ketamine and different LXA4 ME concentrations of LXA4 ME (5-50 nM) for 24 h, and their viability, apoptosis, and oxidative status were assessed. RESULTS: Quantitative real-time polymerase chain reaction experiments showed that ketamine downregulated miR-22 expression and upregulated Bcl-2-associated athanogene 5 (BAG5) in PC12 cells in a concentration-dependent manner. LXA4 ME induced the opposite effects, thus attenuating ketamine-induced neurotoxicity. Further in vitro assays showed that miR-22 directly targeted BAG5, thus promoting cell viability by suppressing cell apoptosis and oxidative stress. Under expression miR-22 or upregulation of BAG5 antagonized the effects of LXA4 ME. CONCLUSION: LXA4 ME can protect PC12 cells from ketamine-induced neurotoxicity by activating the miR-22/BAG5 signaling pathway. Thus, LXA4 ME can be used as a protective drug against ketamine-induced neural damage.

l-α-aminoadipate causes astrocyte pathology with negative impact on mouse hippocampal synaptic plasticity and memory.

Increasing evidence shows that astrocytes, by releasing and uptaking neuroactive molecules, regulate synaptic plasticity, considered the neurophysiological basis of memory. This study investigated the impact of l-α-aminoadipate (l-AA) on astrocytes which sense and respond to stimuli at the synaptic level and modulate hippocampal long-term potentiation (LTP) and memory. l-AA selectivity toward astrocytes was proposed in the early 70's and further tested in different systems. Although it has been used for impairing the astrocytic function, its effects appear to be variable in different brain regions. To test the effects of l-AA in the hippocampus of male C57Bl/6 mice we performed two different treatments (ex vivo and in vivo) and took advantage of other compounds that were reported to affect astrocytes. l-AA superfusion did not affect the basal synaptic transmission but decreased LTP magnitude. Likewise, trifluoroacetate and dihydrokainate decreased LTP magnitude and occluded the effect of l-AA on synaptic plasticity, confirming l-AA selectivity. l-AA superfusion altered astrocyte morphology, increasing the length and complexity of their processes. In vivo, l-AA intracerebroventricular injection not only reduced the astrocytic markers but also LTP magnitude and impaired hippocampal-dependent memory in mice. Interestingly, d-serine administration recovered hippocampal LTP reduction triggered by l-AA (2 h exposure in hippocampal slices), whereas in mice injected with l-AA, the superfusion of d-serine did not fully rescue LTP magnitude. Overall, these data show that both l-AA treatments affect astrocytes differently, astrocytic activation or loss, with similar negative outcomes on hippocampal LTP, implying that opposite astrocytic adaptive alterations are equally detrimental for synaptic plasticity.

Increased Nectin-4 levels in chronic ketamine abusers and the relationship with lower urinary tract symptoms.

Persistent ketamine use causes susceptibility to addiction and bladder toxicity. We examined the association of lower urinary tract symptoms and levels of Nectin-4, a member of the cell adhesion molecules that is essential for maintaining the urothelium barrier in chronic ketamine abusers. We measured the plasma levels of Nectin-4 in 88 patients with ketamine dependence and 69 controls. Patients with ketamine dependence were assessed for ketamine use variables, psychological symptoms, and lower urinary tract symptoms. We found Nectin-4 levels were increased in ketamine-dependent patients compared to the controls (p < 0.0001). Patients with urinary tract symptoms exhibited lower Nectin-4 levels than those without (p = 0.021). Our results suggest an up-regulation of Nectin-4 following chronic and heavy ketamine use. Patients with ketamine dependence with a compromised upregulation of Nectin-4 are likely to have more severe urinary tract symptoms. The mechanisms underlying the involvement of Nectin-4 in ketamine addiction and bladder toxicity warrant future investigation.

Ketamine disrupts gaze patterns during face viewing in the common marmoset.

Faces are stimuli of critical importance for primates. The common marmoset (Callithrix jacchus) is a promising model for investigations of face processing, as this species possesses oculomotor and face-processing networks resembling those of macaques and humans. Face processing is often disrupted in neuropsychiatric conditions such as schizophrenia (SZ), and thus, it is important to recapitulate underlying circuitry dysfunction preclinically. The N-methyl-d-aspartate (NMDA) noncompetitive antagonist ketamine has been used extensively to model the cognitive symptoms of SZ. Here, we investigated the effects of a subanesthetic dose of ketamine on oculomotor behavior in marmosets during face viewing. Four marmosets received systemic ketamine or saline injections while viewing phase-scrambled or intact videos of conspecifics' faces. To evaluate effects of ketamine on scan paths during face viewing, we identified regions of interest in each face video and classified locations of saccade onsets and landing positions within these areas. A preference for the snout over eye regions was observed following ketamine administration. In addition, regions in which saccades landed could be significantly predicted by saccade onset region in the saline but not the ketamine condition. Effects on saccade control were limited to an increase in saccade peak velocity in all conditions and a reduction in saccade amplitudes during viewing of scrambled videos. Thus, ketamine induced a significant disruption of scan paths during viewing of conspecific faces but limited effects on saccade motor control. These findings support the use of ketamine in marmosets for investigating changes in neural circuits underlying social cognition in neuropsychiatric disorders.NEW & NOTEWORTHY Face processing, an important social cognitive ability, is impaired in neuropsychiatric conditions such as schizophrenia. The highly social common marmoset model presents an opportunity to investigate these impairments. We administered subanesthetic doses of ketamine to marmosets to model the cognitive symptoms of schizophrenia. We observed a disruption of scan paths during viewing of conspecifics' faces. These findings support the use of ketamine in marmosets as a model for investigating social cognition in neuropsychiatric disorders.

Synergistic efficacy and diminished adverse effect profile of composite treatment of several ADHD medications.

Although attention-deficit/hyperactivity disorder (ADHD) is widely studied, problems regarding the adverse effect risks and non-responder problems still need to be addressed. Combination pharmacotherapy using standard dose regimens of existing medication is currently being practiced mainly to augment the therapeutic efficacy of each drug. The idea of combining different pharmacotherapies with different molecular targets to alleviate the symptoms of ADHD and its comorbidities requires scientific evidence, necessitating the investigation of their therapeutic efficacy and the mechanisms underlying the professed synergistic effects. Here, we injected male ICR mice with MK-801 to induce ADHD behavioral condition. We then modeled a "combined drug" using sub-optimal doses of methylphenidate, atomoxetine, and fluoxetine and investigated the combined treatment effects in MK-801-treated mice. No sub-optimal dose monotherapy alleviated ADHD behavioral condition in MK-801-treated mice. However, treatment with the combined drug attenuated the impaired behavior of MK-801-treated animals. Growth impediment, sleep disturbances, or risk of substance abuse were not observed in mice treated subchronically with the combined drugs. Finally, we observed that the combined ADHD drug rescued alterations in p-AKT and p-ERK1/2 levels in the prefrontal cortex and hippocampus, respectively, of MK-801-treated mice. Our results provide experimental evidence of a possible new pharmacotherapy option in ameliorating the ADHD behavioral condition without the expected adverse effects. The detailed mechanism of action underlying the synergistic therapeutic efficacy and reduced adverse reaction by combinatorial drug treatment should be investigated further in future studies.

A Conantokin Peptide Con-T[M8Q] Inhibits Morphine Dependence with High Potency and Low Side Effects.

N-methyl-D-aspartate receptor (NMDAR) antagonists have been found to be effective to inhibit morphine dependence. However, the discovery of the selective antagonist for NMDAR GluN2B with low side-effects still remains challenging. In the present study, we report a selective NMDAR GluN2B antagonist con-T[M8Q](a conantokin-T variant) that potently inhibits the naloxone-induced jumping and conditioned place preference of morphine-dependent mice at nmol/kg level, 100-fold higher than ifenprodil, a classical NMDAR NR2B antagonist. Con-T[M8Q] displays no significant impacts on coordinated locomotion function, spontaneous locomotor activity, and spatial memory mice motor function at the dose used. Further molecular mechanism experiments demonstrate that con-T[M8Q] effectively inhibited the transcription and expression levels of signaling molecules related to NMDAR NR2B subunit in hippocampus, including NR2B, p-NR2B, CaMKII-α, CaMKII-ß, CaMKIV, pERK, and c-fos. The high efficacy and low side effects of con-T[M8Q] make it a good lead compound for the treatment of opiate dependence and for the reduction of morphine usage.

Genistein attenuates cognitive deficits and neuroapoptosis in hippocampus induced by ketamine exposure in neonatal rats.

Ketamine is a frequently used anesthetic in pediatric patients that can cause cognitive impairment. Genistein, a bioactive component of soy products, has been shown to suppress neuronal death through regulating the expression of apoptosis related genes. In this study, we hypothesized that genistein could alleviate ketamine-induced cognitive impairment by ameliorating hippocampal neuronal loss and tested this hypothesis in rats. Neonatal rats were treated with ketamine and genistein. Hippocampal tissue was harvested for histological and biochemical analysis to determine neuronal apoptosis and proteins involved in the apoptotic pathways. Behavioral assays including contextual fear conditioning test and Morris water maze test were performed to assess cognitive functions, including learning and memory. We found that in fear conditioning test, genistein restored freezing time in ketamine treated rats in a dose dependent manner. Similarly, genistein attenuated impaired learning and memory in Morris water maze test in rats treated with ketamine. Additionally, ketamine-induced neuronal apoptosis in rat hippocampus was attenuated by genistein treatment. Finally, we found that genistein partially restored proteins associated with apoptosis, including Bax, Bcl-2, cleaved caspase 3, and phosphorylated GSK-3ß and Akt. Genistein suppresses hippocampal neuronal loss and cognitive disruption induced by ketamine in rats.

Preventive role of regular low-intensity exercise during adolescence in schizophrenia model mice with abnormal behaviors.

Schizophrenia is probably ascribed to perinatal neurodevelopmental deficits, and its onset might be affected by environmental factors. Hypofrontality with glutamatergic and dopaminergic neuronal dysfunction are known factors, but a way to mitigate abnormalities remains unfound. An early enriched environment such as a wheel running in rodents may contribute to the prevention, but its clinical applicability is very limited. From our studies, low-intensity exercise training (LET) based on physiological indices, such as lactate threshold, easily translates to humans and positively affects the brains. Hence, LET during adolescence may ameliorate abnormalities in neurodevelopment and prevent the development of schizophrenia. In the current study, LET prevented sensitization to phencyclidine (PCP) treatment, impairment of cognition, and affective behavioral abnormalities in an animal model of schizophrenia induced by prenatal PCP treatment. Further, LET increased dopamine turnover and attenuated the impairment of phosphorylation of ERK1/2 after exposure to a novel object in the prenatal PCP-treated mice. These results suggest that LET during adolescence completely improves schizophrenia-like abnormal behaviors associated with improved glutamate uptake and the dopamine-induced ERK1/2 signaling pathway in the PFC.

Normal Tone-In-Noise Sensitivity in Trained Budgerigars despite Substantial Auditory-Nerve Injury: No Evidence of Hidden Hearing Loss.

Loss of auditory-nerve (AN) afferent cochlear innervation is a prevalent human condition that does not affect audiometric thresholds and therefore remains largely undetectable with standard clinical tests. AN loss is widely expected to cause hearing difficulties in noise, known as "hidden hearing loss," but support for this hypothesis is controversial. Here, we used operant conditioning procedures to examine the perceptual impact of AN loss on behavioral tone-in-noise (TIN) sensitivity in the budgerigar (Melopsittacus undulatus; of either sex), an avian animal model with complex hearing abilities similar to humans. Bilateral kainic acid (KA) infusions depressed compound AN responses by 40-70% without impacting otoacoustic emissions or behavioral tone sensitivity in quiet. Surprisingly, animals with AN damage showed normal thresholds for tone detection in noise (0.1 ± 1.0 dB compared to control animals; mean difference ± SE), even under a challenging roving-level condition with random stimulus variation across trials. Furthermore, decision-variable correlations (DVCs) showed no difference for AN-damaged animals in their use of energy and envelope cues to perform the task. These results show that AN damage has less impact on TIN detection than generally expected, even under a difficult roving-level condition known to impact TIN detection in individuals with sensorineural hearing loss (SNHL). Perceptual deficits could emerge for different perceptual tasks or with greater AN loss but are potentially minor compared with those caused by SNHL.SIGNIFICANCE STATEMENT Loss of auditory-nerve (AN) cochlear innervation is a common problem in humans that does not affect audiometric thresholds on a clinical hearing test. AN loss is widely expected to cause hearing problems in noise, known as "hidden hearing loss," but existing studies are controversial. Here, using an avian animal model with complex hearing abilities similar to humans, we examined for the first time the impact of an experimentally induced AN lesion on behavioral tone sensitivity in noise. Surprisingly, AN-lesioned animals showed no difference in hearing performance in noise or detection strategy compared with controls. These results show that perceptual deficits from AN damage are smaller than generally expected, and potentially minor compared with those caused by sensorineural hearing loss (SNHL).

Fluoxetine attenuates prepulse inhibition deficit induced by neonatal administration of MK-801 in mice.

Increasing evidence supports schizophrenia may be a neurodevelopmental and neurodegenerative disorder. Fluoxetine, a selective serotonin reuptake inhibitor, has been reported to have neuroprotective effects and be effective in treating neurodegenerative disorders including schizophrenia. The objective of the present study was to evaluate the effect and underlying neuroprotective mechanism of fluoxetine on the sensorimotor gating deficit, a schizophrenia-like behavior in a neurodevelopmental schizophrenic mouse model induced by MK-801, an N-methyl-D-aspartate glutamate receptor antagonist. On postnatal day 7, mouse pups were treated with a total seven subcutaneous daily injections of MK-801 (1 mg/kg/day), followed by intraperitoneal injection of fluoxetine (5 or 10 mg/kg/day) starting on postnatal day 14 in the MK-801-injected mice for 4 weeks. The sensorimotor gating deficit in mice was measured by prepulse inhibition (PPI) behavioral test on postnatal day 43. After the behavioral test, the protein expression of brain-derived neurotrophic factor (BDNF) was measured by western blot or ELISA in the frontal cortex of mice. Our results showed fluoxetine attenuated PPI deficit and the decrease of cerebral BDNF expression in the MK-801-injected mice. These results suggest that fluoxetine can be used to treat sensorimotor gating deficit in a neurodevelopmental mouse model of schizophrenia, and the attenuating effect of fluoxetine on sensorimotor gating deficit may be related to fluoxetine's neuroprotective effect targeting on the modulation of cerebral BDNF.

Repeated phencyclidine disrupts nicotinic acetylcholine regulation of dopamine release in nucleus accumbens: Implications for models of schizophrenia.

Dopaminergic dysregulation in nucleus accumbens has been implicated in the origin of schizophrenia. Accumbal cholinergic interneurons exert powerful modulatory control of local dopamine function, through nicotinic receptors located on dopamine terminals. Fast-scan cyclic voltammetry in rat brain slices in vitro was used to measure dopamine release evoked by high-frequency electrical stimulation, mimicking phasic dopamine activity. We investigated whether cholinergic regulation of stimulated dopamine release was disrupted by pretreatment with phencyclidine, a non-competitive NMDA receptor antagonist, which provides a well validated animal model of schizophrenia. Dihydro-ß-erythroidine, an antagonist at ß2-subuit containing nicotinic receptors, caused a concentration-dependent enhancement of stimulated dopamine release, indicating cholinergic inhibitory control over dopamine release. The agonist, nicotine, also caused concentration-dependent increases in release, consistent with rapid desensitisation of the receptors previously described. In slices taken from animals pretreated with phencyclidine, the augmentation of electrically-stimulated dopamine release elicited by both drugs was attenuated, particularly when each drug was applied at high concentration. In addition, the concentration-dependence of each drug effect was lost. Taken together these findings indicate that pretreatment with phencyclidine causes changes in acetylcholine systems modulating dopamine release in accumbens. Since phencyclidine treatment was terminated at least a week before the slices were taken, the effects are due to long-term changes in function resulting from the treatment, rather than from transient changes due to the presence of the drug at test. Such enduring dysregulation of cholinergic control of phasic dopamine release could account for deficits in behaviours mediated by accumbal dopamine seen in schizophrenia, and may provide a route for novel therapeutic strategies to treat the disease.

Deletion of the Mitochondrial Matrix Protein CyclophilinD Prevents Parvalbumin Interneuron Dysfunctionand Cognitive Deficits in a Mouse Model of NMDA Hypofunction.

Redox dysregulation and oxidative stress are final common pathways in the pathophysiology of a variety of psychiatric disorders, including schizophrenia. Oxidative stress causes dysfunction of GABAergic parvalbumin (PV)-positive interneurons (PVI), which are crucial for the coordination of neuronal synchrony during sensory and cognitive processing. Mitochondria are the main source of reactive oxygen species (ROS) in neurons and they control synaptic activity through their roles in energy production and intracellular calcium homeostasis. We have previously shown that in male mice transient blockade of NMDA receptors (NMDARs) during development [subcutaneous injections of 30 mg/kg ketamine (KET) on postnatal days 7, 9, and 11] results in long-lasting alterations in synaptic transmission and reduced PV expression in the adult prefrontal cortex (PFC), contributing to a behavioral phenotype that mimics multiple symptoms associated with schizophrenia. These changes correlate with oxidative stress and impaired mitochondrial function in both PVI and pyramidal cells. Here, we show that genetic deletion (Ppif-/-) of the mitochondrial matrix protein cyclophilin D (CypD) prevents perinatal KET-induced increases in ROS and the resulting deficits in PVI function, and changes in excitatory and inhibitory synaptic transmission in the PFC. Deletion of CypD also prevented KET-induced behavioral deficits in cognitive flexibility, social interaction, and novel object recognition (NOR). Taken together, these data highlight how mitochondrial activity may play an integral role in modulating PVI-mediated cognitive processes.SIGNIFICANCE STATEMENT Mitochondria are important modulators of oxidative stress and cell function, yet how mitochondrial dysfunction affects cell activity and synaptic transmission in psychiatric illnesses is not well understood. NMDA receptor (NMDAR) blockade with ketamine (KET) during development causes oxidative stress, dysfunction of parvalbumin (PV)-positive interneurons (PVI), and long-lasting physiological and behavioral changes. Here we show that mice deficient for the mitochondrial matrix protein cyclophilin D (CypD) show robust protection from PVI dysfunction following perinatal NMDAR blockade. Mitochondria serve as an essential node for a number of stress-induced signaling pathways and our experiments suggest that failure of mitochondrial redox regulation can contribute to PVI dysfunction.

Sarcophine and (7S, 8R)-dihydroxydeepoxysarcophine from the Red Sea soft coral Sarcophyton glaucum as in vitro and in vivo modulators of glycine receptors.

The inhibitory glycine receptor (GlyR) is a key mediator of synaptic signalling in spinal cord, brain stem, and higher centres of the central nervous system. We examined the glycinergic activity of sarcophine (SN), a marine terpenoid known for its various biological activities, and its trans-diol derivative (7S, 8R)-dihydroxy-deepoxysarcophine (DSN). SN was isolated from the Red Sea soft coral Sacrophyton glaucum, DSN was semisynthesized by hydrolysis of the epoxide ring. In cytotoxicity tests against HEK293 cells, SN and DSN had LD50 values of 29.3 ± 3.0 mM and 123.5 ± 13.0 mM, respectively. Both compounds were tested against recombinant human α1 glycine receptors in HEK293 cells using whole-cell recording techniques. Both, SN and DSN were shown for the first time to be inhibitors of recombinant glycine receptors, with KIvalues of 2.1 ± 0.3 µM for SN, and 109 ± 9 µM for DSN. Receptor inhibition was also studied in vivo in a mouse model of strychnine toxicity. Surprisingly, in mouse experiments strychnine inhibition was not augmented by either terpenoid. While DSN had no significant effect on strychnine toxicity, SN even delayed strychnine effects. This could be accounted for by assuming that strychnine and sarcophine derivatives compete for the same binding site on the receptor, so the less toxic sarcophine can prevent strychnine from binding. The combination of modulatory activity and low level of toxicity makes sarcophines attractive structures for novel glycinergic drugs.

Metformin attenuates antipsychotic-induced metabolic dysfunctions in MK801-induced schizophrenia-like rats.

RATIONALE: Second-generation antipsychotics are the first-line medications prescribed for schizophrenic patients; however, some of them, such as olanzapine and risperidone, may induce metabolic dysfunctions during short-term treatment. Metformin is an effective adjuvant that attenuates antipsychotic-induced metabolic dysfunctions (AIMD) in clinical practice. Whether metformin can reverse AIMD and whether metformin affects the therapeutic effects of antipsychotics in animal models of schizophrenia are questions that still need to be investigated. METHODS: In this study, an animal model of schizophrenia was established by consecutive injections of MK801 during the neurodevelopmental period. In adulthood, different dosages of olanzapine or risperidone treatment were administered to the schizophrenia model animals for 14 days. Both therapeutic effects and metabolic adverse effects were measured by behavioral tests, histopathological tests, and biochemical tests. The coadministration of different doses of metformin with olanzapine or risperidone was used to evaluate the effects of metformin on both AIMD and the therapeutic effect of those antipsychotics. RESULTS: The MK801-treated rats showed schizophrenia-like behavior and variations in the shape and volume of the hippocampus. Both olanzapine and risperidone reversed the MK801-induced behavioral abnormalities as the dosage increased; however, they degenerated the hepatocytes in the liver and influenced the blood lipid levels and blood glucose levels. The coadministration of metformin did not affect the therapeutic effects of olanzapine or risperidone on behavioral abnormalities but attenuated the metabolic dysfunctions induced by those antipsychotics. CONCLUSION: Metformin attenuated the olanzapine- and risperidone-induced metabolic dysfunctions in MK801-induced schizophrenia-like rats without reducing the therapeutic effects of the antipsychotics.

Clozapine Improves Behavioral and Biochemical Outcomes in a MK-801-Induced Mouse Model of Schizophrenia.

Glutamatergic N-methyl-D-aspartate (NMDA) receptors have critical roles in several neurological and psychiatric diseases. Dizocilpine (MK-801) is a ligand at phencyclidine recognition sites that is associated with NMDA receptor-coupled cation channels, where it acts as a potent noncompetitive antagonist of central glutamate receptors. In this study, we investigate the effect of clozapine on MK-801-induced neurochemical and neurobehavioral alterations in the prefrontal cortex of mice. Acute administration of NMDA noncompetitive antagonist MK-801 impairs motor coordination, grip strength, and locomotor activity. Clozapine is the only medication that is indicated for treating refractory schizophrenia, due to its superior efficacy among all antipsychotic agents; however, its mechanism is not well understood. To understand its mechanism, we investigated the effects of clozapine on motor coordination, locomotor activity, and grip strength in mice against the NMDA receptor antagonist MK-801. MK-801 induced elevations in acetylcholinesterase (AChE) activity, monoamine oxidase (MAO) activity, and c-fos expression. The administration of clozapine inhibited the effects caused by MK-801 (0.2 mg/kg body weight). Motor coordination and grip strength paradigms that had been altered by MK-801 were restored by clozapine. Moreover, clozapine also ameliorated MK-801-induced elevation in AChE and MAO activity. Our immunostaining results demonstrated that clozapine treatment reduced overexpression of the neuronal activity marker c-fos in cortices of the brain. Results of the current study determine that clozapine ameliorated cognition in MK-801-treated mice via cholinergic and neural mechanisms. These findings show that clozapine possesses the potential to augment cognition in diseases such as schizophrenia.

Repeated ketamine administration induces recognition memory impairment together with morphological changes in neurons from ventromedial prefrontal cortex, dorsal striatum, and hippocampus.

Ketamine is an anesthetic agent that antagonizes N-methyl-d-aspartate receptors, inducing psychotic-like symptoms in healthy humans and animals. This agent has been used as a pharmacological tool for studying biochemical and physiological mechanisms underlying the clinical manifestations of schizophrenia. The main goal of this study was to evaluate the effect of repeated injections of ketamine (5 and 10 mg/kg, i.p., daily for 5 days) on recognition memory and neuronal morphology in ICR-CD1 mice. This treatment induced recognition memory impairment in the novel object recognition test and a decrease in dendritic spines density in both dorsal striatum and CA1-hippocampus. Sholl analysis showed that both ketamine doses decrease the dendritic arborization in ventromedial prefrontal cortex, dorsal striatum, and CA1-hippocampus. Finally, dendritic spines morphology was modified by both doses; that is, an increase of the filipodia-type spines (10 mg/kg) and a reduction of the mushroom-type spines (5 and 10 mg/kg) was observed in the ventromedial prefrontal cortex. In the dorsal striatum, the low dose of ketamine induced an increase in long thin spines and a decrease of mushroom spines. Interestingly, in CA1-hippocampus, there was an increase in the mushrooms type spines (5 mg/kg). Current findings suggest that the subchronic blockade of N-methyl-d-aspartate receptor changes the neuronal plasticity of several brain regions putatively related to recognition memory impairment.

ω-3PUFAs Improve Cognitive Impairments Through Ser133 Phosphorylation of CREB Upregulating BDNF/TrkB Signal in Schizophrenia.

Schizophrenia (SZ) is a serious mental condition and is associated with cognitive impairments. Brain-derived neurotrophic factor (BDNF) is one of the learning- and memory-related molecules found in the CNS and its level was reported to be reduced in SZ brain, while ω-3 polyunsaturated fatty acids (ω-3PUFAs) could improve SZ symptoms, but its mechanism of action remains unknown. Using MK801 injection-induced SZ rat model, we here found that supplementation with ω-3PUFAs improved the levels of p-CREB, BDNF, and p-TrkB in the brain of SZ rats, and restore hippocampal neuronal damage, thereby reducing cognitive impairments in SZ rats. However, overexpression of AAV9/CREB S133A (CREB inactivated mutation) downregulated BDNF/TrkB signaling pathway and remarkably abolished the preventive effect of ω-3PUFAs in MK801-induced schizophrenia. Interestingly, AAV9/CREB S133D (CREB activated mutation) improved synaptic dysfunctions and cognitive defects in MK801 rats. In conclusion, these findings indicate that MK801-induced SZ lesions dephosphorylate CREB at Ser133 site, leading to neuron damage, and ω-3PUFAs improve SZ cognitive impairments by upregulating the CREB/BDNF/TrkB pathway, which provides new clues for the mechanism of SZ cognitive impairments, and a basis for therapeutic intervention.