dizocilpine-maleate and Weight-Gain

At present, the research on the prevention of schizophrenia is still in its infancy. Pyrroloquinoline quinone (PQQ) has potential to treat psychological and neurological diseases including schizophrenia. However, the preventive effect of PQQ on schizophrenia remains unclear.. In this study, we aimed to examine the preventive effect of supplementation of dietary PQQ from pregnancy or after birth on dizocilpine (MK-801)-induced schizophrenia-like behaviors in mice.. Supplementation of dietary PQQ from pregnancy could effectively prevent MK-801-induced weight gain decrease, hyperlocomotion, stereotypical behavior, ataxia, exploratory activity decrease, social interaction disorder, memory deficit, and depression in mice. Supplementation of dietary PQQ after birth could effectively prevent MK-801-induced weight gain decrease, stereotypical behavior, ataxia, and memory deficit in mice. Female mice responded to a greater degree than males in preventing MK-801-induced weight gain decrease in both forms of PQQ supplementation. For mice that began PQQ supplementation after birth, females performed better than males in preventing MK-801-induced ataxia, memory deficit, and depression. For mice that began PQQ supplementation from pregnancy, males performed better than females in preventing MK-801-induced memory deficit. In vitro experiments indicated that PQQ supplementation in the earlier stage of life contributed to the growth of neurons and the development of neurites.. Our current study suggested that PQQ supplementation from pregnancy or postpartum could prevent some schizophrenia-like behaviors induced by MK-801 in mice. Our work supported the potential usage of dietary supplement of PQQ in preventing or alleviating symptoms associated with schizophrenia.

Topics: Animals; Ataxia; Dietary Supplements; Dizocilpine Maleate; Female; Male; Memory Disorders; Mice; PQQ Cofactor; Pregnancy; Schizophrenia; Weight Gain

Olanzapine is a commonly used drug in the treatment of schizophrenia, but its clinical application has been restricted by metabolic-related side effects. In order to mitigate the weight gain side effects caused by olanzapine, other drugs with different targets were selected for combined use and evaluated in animal models of schizophrenia. SEP-363856 is a novel psychotropic agent which is under phase III clinical trials for schizophrenia treatment. The aim of the research was to evaluate whether co-administration of olanzapine and SEP-363856 exerts synergistic anti-schizophrenic effects in the apomorphine (APO)-induced climbing test, the MK-801-induced hyperactivity test, and the Morris water maze test, and therefore reduces the weight gain side effects induced by olanzapine. Through isobolographic analysis, the results showed a synergistic interaction in the climbing test; the experimental ED30 (3 mg/kg) was significantly smaller (p < 0.05) than the theoretical ED30 (5 mg/kg). Additionally, such potentiating effects appeared additive in the MK-801 challenge experiment. Co-treatment with an effective dose of olanzapine and a low dose of SEP-363856 reversed MK-801-induced cognitive impairment symptoms in mice. Moreover, combination treatment with olanzapine and SEP-363856 controls sustained weight gain in mice with chronic exposure to olanzapine. These results support further clinical trials to test the effectiveness of co-treatment of olanzapine and SEP-363856 for controlling symptoms and weight gain in patients with schizophrenia during antipsychotic treatments.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Dizocilpine Maleate; Humans; Mice; Olanzapine; Pyrans; Schizophrenia; Weight Gain

Abuse of toluene-containing inhalants is common during adolescence, with ongoing chronic misuse associated with adverse outcomes and increased risk for addictive behaviours in adulthood. However, the mechanisms mediating the adaptive processes related to these outcomes are not well defined. To model human abuse patterns we exposed male adolescent Wistar rats (postnatal day 27) to chronic intermittent inhaled toluene (CIT, 10,000 ppm) or air (control) for 1h/day, three times/week for 3 weeks. The effects of CIT on behaviour and recovery were monitored. Locomotor activity was recorded following two consecutive injections of amphetamine (1mg/kg, i.p.) 72 and 96 h after the last exposure. This was followed with injection of the NMDA receptor antagonist MK801 (0.5mg/kg, i.p.) 20 days after the last exposure. CIT resulted in a significant and persistent retardation in weight gain during the exposure period and abstinence (p<0.05). Repeated exposure resulted in tolerance to the onset of toluene-induced behaviours and recovery latency. There was a reduction in the acute stimulant effects of amphetamine in CIT-exposed animals and an increase in the magnitude of locomotor activity (p<0.0125) following a subsequent exposure when compared to the responses observed in controls; this was associated with altered locomotor responses to MK801. Repeated exposure to CIT during adolescence alters parameters of growth, as measured by body weight, and leads to tolerance, indicating that increasing concentrations of the compound may be needed to reach the same behavioural state. Toluene during this period also alters responses to a psychostimulant which may be related to long-term glutamatergic dysfunction.

Topics: Aging; Amphetamine; Animals; Central Nervous System Stimulants; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Motor Activity; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Solvents; Substance-Related Disorders; Time Factors; Toluene; Weight Gain

Prenatal maternal immune activation has been used to test the neurodevelopmental hypothesis of schizophrenia. Most of the data are in mouse models; far less is available for rats. We previously showed that maternal weight change in response to the immune activator polyinosinic-polycytidylic acid (Poly IC) in rats differentially affects offspring. Therefore, we treated gravid Harlan Sprague-Dawley rats i.p. on embryonic day 14 with 8 mg/kg of Poly IC or Saline. The Poly IC group was divided into those that lost or gained the least weight, Poly IC (L), versus those that gained the most weight, Poly IC (H), following treatment. The study design controlled for litter size, litter sampling, sex distribution, and test experience. We found no effects of Poly IC on elevated zero maze, open-field activity, object burying, light-dark test, straight channel swimming, Morris water maze spatial acquisition, reversal, or shift navigation or spatial working or reference memory, or conditioned contextual or cued fear or latent inhibition. The Poly IC (H) group showed a significant decrease in the rate of route-based learning when visible cues were unavailable in the Cincinnati water maze and reduced prepulse inhibition of acoustic startle in females, but not males. The Poly IC (L) group exhibited altered responses to acute pharmacological challenges: exaggerated hyperactivity in response to (+)-amphetamine and an attenuated hyperactivity in response to MK-801. This model did not exhibit the cognitive, or latent inhibition deficits reported in Poly IC-treated rats but showed changes in response to drugs acting on neurotransmitter systems implicated in the pathophysiology of schizophrenia (dopaminergic hyperfunction and glutamatergic hypofunction).

Topics: Amphetamine; Animals; Dizocilpine Maleate; Dopamine Agents; Excitatory Amino Acid Antagonists; Female; Learning; Male; Maternal Exposure; Maze Learning; Motor Activity; Neuropsychological Tests; Poly I-C; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Reflex, Startle; Weight Gain

Maternal infection during pregnancy elevates risk for schizophrenia and related disorders in offspring. Converging evidence suggests the maternal inflammatory response mediates the interaction between maternal infection, altered brain development, and behavioral outcome. The extent to which individual differences in the maternal response to immune challenge influence the development of these abnormalities is unknown. The present study investigated the impact of individual differences in maternal response to the viral mimic polyinosinic:polycytidylic acid (poly I:C) on offspring behavior. We observed significant variability in body weight alterations of pregnant rats induced by administration of poly I:C on gestational day 14. Furthermore, the presence or absence of maternal weight loss predicted MK-801 and amphetamine stimulated locomotor abnormalities in offspring. MK-801 stimulated locomotion was altered in offspring of all poly I:C treated dams; however, the presence or absence of maternal weight loss resulted in decreased and modestly increased locomotion, respectively. Adult offspring of poly I:C treated dams that lost weight exhibited significantly decreased amphetamine stimulated locomotion, while offspring of poly I:C treated dams without weight loss performed similarly to vehicle controls. Social isolation and increased maternal age predicted weight loss in response to poly I:C but not vehicle injection. In combination, these data identify environmental factors associated with the maternal response to immune challenge and functional outcome of offspring exposed to maternal immune activation.

Topics: Age Factors; Amphetamine; Analysis of Variance; Animals; Animals, Newborn; Antiviral Agents; Behavior, Animal; Body Weight; Central Nervous System Stimulants; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Individuality; Locomotion; Male; Poly I-C; Predictive Value of Tests; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Weight Gain; Weight Loss

Several studies involving postnatal administration of the N-methyl-D-aspartate (NMDA) antagonists, dizocilpine (MK-801; 3 x 0.5 mg/kg, at 08.00, 16.00 and 24.00 h) on Postnatal day 11, or Ketamine (1 x 50 mg/kg) or Ethanol (1 x 2.5 g/kg, Ethanol-Low, or 2 x 2.5 g/kg, 2-h interval, Ethanol-High) on Postnatal day 10, are described. Some mice from each treatment/vehicle group were sacrificed 24 h after NMDA antagonist treatment and brain regions were taken for fluoro-jade staining analysis. Functional analysis was initiated at 60 days of age. All three treatments inducing an antagonistic action at NMDA receptors, MK-801, Ketamine and Ethanol-High induced a similar pattern of initial hypoactivity followed by marked and lasting hyperactivity in the motor activity test chambers. In each case, the basal hyperactivity level was abolished by acute treatment with a low dose of D-amphetamine (0.25 mg/kg). All three treatments, MK-801, Ketamine and Ethanol-High, induced a deficit in acquisitive performance in the radial arm maze test of instrumental learning. The deficit induced by postnatal MK-801 was abolished by acute treatment with the low dose of D-amphetamine. All three treatments, MK-801, Ketamine and Ethanol-High, resulted in normal acquisitive performance during the first three test days in the circular swim with the submerged platform maintained in a constant position, but on the fourth test day, with the platform position shifted to a different "quadrant", induced marked deficits. Fluoro-jade staining analyses indicated a devastating cell degeneration in several brain regions of mice administered NMDA antagonists postnatally, including the hippocampus, frontal cortex, parietal cortex, and cerebellum. Severe cell degeneration in the laterodorsal thalamus due to Ethanol or diazepam (5 mg/kg) appeared not to affect the different aspects of function. The pattern of dysfunctional outcome and apoptotic cell loss following postnatal NMDA antagonist treatment offers a plausible similarity to the major aspects of 'syndromatic continuity' in ADHD, hyperactivity, inattention and impulsivity, thereby providing an interesting animal model of the disorder.

Topics: Animals; Animals, Newborn; Apoptosis; Attention Deficit Disorder with Hyperactivity; Central Nervous System Depressants; Central Nervous System Stimulants; Dextroamphetamine; Diazepam; Dizocilpine Maleate; Ethanol; Excitatory Amino Acid Antagonists; Female; Fluoresceins; Fluorescent Dyes; Hypnotics and Sedatives; Ketamine; Maze Learning; Mental Disorders; Mice; Motor Activity; Nerve Degeneration; Nervous System Diseases; Organic Chemicals; Pregnancy; Receptors, N-Methyl-D-Aspartate; Swimming; Weight Gain

Three experiments were performed to study the effects of neonatal administration of glutamate receptor antagonists, on either Day 11 (dizocilpine = MK-801, 3 x 0.5 mg/kg, s.c., injected at 0800, 1600 and 2400 h) or Day 10 (Ketamine, 1 x 50 mg/kg, s.c., or Ethanol-Low, 1 x 2.5 mg/kg, or, Ethanol-High, 2 x 2.5 mg/kg, s.c., with 2-h interval) to male mice pups, on spontaneous motor behavior, habituation to a novel situation and D-amphetamine-induced activity in the adult animals. Mice administered MK-801 showed initial hypoactivity followed by hyperactivity over the later (20-40 and 40-60 min) periods of testing. Mice administered Ketamine and Ethanol-High similarly displayed an initial hypoactivity followed by hyperactivity over the later time (20-60 min) of testing. Habituation to the novel activity test chambers was reduced drastically in the MK-801 mice compared with vehicle-treated mice. Similarly, mice administered Ketamine and Ethanol-High displayed too drastically reduced habituation behavior. The low dose of D-amphetamine (0.25 mg/kg) reduced the hyperactivity of neonatal MK-801-treated mice, particularly from 30-60 min onwards, and elevated the activity level of the vehicle-treated mice. Similarly, the low dose of D-amphetamine (0.25 mg/kg) reduced the hyperactivity of neonatally Ketamine-treated and Ethanol-High-treated mice, particularly from 30-60 min onwards, and elevated the activity level of the respective vehicle-treated mice. Fluoro-jade staining per mm(2) regional brain tissue of MK-801 mice pups expressed as percent of vehicle mice pups showed also that the extensiveness of staining was markedly greater in the parietal cortex, hippocampus, frontal cortex, and lesser so in the laterodorsal thalamus. Ketamine-treated mice showed cell degeneration mainly in the parietal cortex, whereas the Ethanol-High mice showed marked cell degeneration in both the parietal and laterodorsal cortex. The present findings that encompass a pattern of regional neuronal degeneration, disruptions of spontaneous motor activity, habituation deficits and reversal of hyperactivity by a low dose of D-amphetamine suggest a model of Attention Deficit Hyperactivity Disorder that underlines the intimate role of N-methyl-D-aspartate (NMDA) receptors in the developing brain.

Topics: Animals; Behavior, Animal; Brain; Central Nervous System Depressants; Central Nervous System Stimulants; Dextroamphetamine; Dizocilpine Maleate; Ethanol; Excitatory Amino Acid Antagonists; Female; Fluoresceins; Fluorescent Dyes; Habituation, Psychophysiologic; Hyperkinesis; Ketamine; Male; Mice; Motor Activity; N-Methylaspartate; Organic Chemicals; Pregnancy; Weight Gain

The N-methyl-D-aspartate glutamate receptor (NMDAR) is found in hypothalamic nuclei involved in the regulation of reproduction in several species of mammals and fishes. NMDAR is believed to affect reproductive development and function by regulating gonadotropin releasing hormone (GnRH)-producing cells. These pathways are likely to be sexually dimorphic, as are several other neurotransmitter systems involved in reproductive function. In this report, male and female platyfish received intraperitoneal injections of 0, 5, 10, 20, 40 or 60 microg/g body wt. of the non-competitive NMDAR antagonist MK-801. Injections began at 6 weeks of age and continued thrice weekly until control animals reached puberty, as evidenced by anal fin maturation. The percent of pubescent animals was significantly affected by sex and treatment, with fewer MK-801-injected females in puberty than control females at each dose (P<0.001), and fewer pubescent females than males at 10, 20 and 40 microg/g (P<0.05). There were no MK-801-related effects in males. Histological analyses revealed typical immature gonads and pituitary glands in treated females, and typical mature morphology in control females and all males. Immunocytochemical distribution of the R1 subunit of the NMDAR within the brain-pituitary-gonad (BPG) axis was limited to GnRH-containing brain cells in all animals; however, NMDAR1 distribution was in an immature pattern in treated females and a mature pattern in all others. Neural concentrations of GnRH were unaffected by MK-801 treatment in both sexes. These data suggest that in the platyfish, NMDAR influence on reproductive development is sexually dimorphic and occurs at, or above, the level of GnRH-containing cells of the BPG axis.

Topics: Animals; Cyprinodontiformes; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Gonads; Immunohistochemistry; Male; Pituitary Gland; Receptors, N-Methyl-D-Aspartate; Sex Characteristics; Sexual Maturation; Tissue Distribution; Weight Gain

The physiological role of activated hypothalamic N-methyl-D-aspartate (NMDA) receptors during the final phase of female sexual maturation was explored in the rat. The effects of administration of the specific non-competitive receptor antagonist MK-801 on the occurrence of first ovulation and on LH secretion were studied. Injections of MK-801 (0.1-0.2 mg/kg body wt, s.c.) were given once or twice daily, starting at 28 or 35 days of age and continuing up to the day of first ovulation, resulted in a significant delay of this ovulation. Rats that were treated daily with 0.2 mg MK-801/kg, starting on days 30 or 34 and continuing up to day 38, but not including the day of first pro-oestrus, also showed retarded first ovulation. No decrease in serum LH concentration, compared with control rats, could be detected in these rats. Acute treatment with MK-801 (one or two injections of 0.2, or one injection of 0.5 mg/kg) given at 11.30 h (and 16.00 h) on the day of first pro-oestrus produced partial (1 x 0.2 mg/kg) or complete (2 x 0.2 and 1 x 0.5 mg/kg) blockade of first ovulation; blocked rats ovulated 1 day later. Serum LH concentrations at 16.00 h on the day of pro-oestrus were significantly decreased in all MK-801-treated groups compared with saline-injected control rats. At 19.00 and 22.00 h LH concentrations remained low in all non-ovulating MK-801-treated rats, but increased in the MK-801-treated rats and ovulated.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Dizocilpine Maleate; Female; Luteinizing Hormone; Ovulation; Proestrus; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Sexual Maturation; Weight Gain