Effect of clozapine on locomotor activity and anxiety-related behavior in the neonatal mice administered MK-801

Pınar, Neslihan; Akıllıoğlu, Kübra; Sefil, Fatih; Alp, Harun; Sağır, Mustafa; Acet, Ahmet

doi:10.17305/bjbms.2015.472

Cited by 17 publications

(8 citation statements)

References 31 publications

(36 reference statements)

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“…OLZ is an atypical antipsychotic that exhibits an affinity for different neurotransmitters receptors, including serotonin, norepinephrine, and dopamine [39]. Similar to our results, Clozapine (another atypical antipsychotic) further reduced the motor activity and exploratory behavior (rearing) of neonatal mice that had received MK-801 (0.25 mg/kg) days 7-10 after birth [40].…”

Section: Discussionsupporting

confidence: 79%

“…Regarding the response with NMDA, this would be expected to block the effects induced by MK-801 in all of the observed psychotic endotypes in the open field; however, the sole change was a decrease of stereotyped behavior and time spent grooming. It is argued that the modification of motor activity caused by NMDA receptor dysfunction is associated with changes in the signaling of neurotransmitters, such as dopamine, serotonin, acetylcholine, and norepinephrine [40, 41]. In this way, a complex interaction is established, in which the NMDA (1 mg/kg) was not able to modulate and therefore did not counteract, in our experimental design, all of the events caused by its antagonist, at least in terms of motor functions.…”

Section: Discussionmentioning

confidence: 99%

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Galphimia glauca and Natural Galphimines Block Schizophrenia-Like Symptoms Induced with Apomorphine and MK-801 in Mice

Santillán-Urquiza

Herrera-Ruíz

Zamilpa

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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Background. Galphimia glauca has been used for many years in Mexican Traditional Medicine to calm “insane people.” Triterpenes, known as galphimines, were identified in this species. One of them, Galphimine-B (G-B), acts selectively on dopaminergic neurons by antagonizing the effect of glutamate on NMDA receptors. The objective of this study was to evaluate the effect of G. glauca methanolic extract (GgMeOH), a Galphimine-Rich Fraction (GRF), as well as the galphimines G-A, G-B, and G-E, on the acute psychosis induced by Apomorphine (APO) in mice and on schizophrenia-like symptoms induced by subchronic administration of MK-801. Method. On the first day, ICR male mice were given GgMeOH, GRF, or one of the galphimines. On day two, animals were treated with APO, and on day 3, they were subjected to behavioral tests. In a second test, MK-801 was administered daily for 28 days. In this case, animals were treated daily with G. glauca products from day 9 to day 28 and then subjected to behavioral tests (passive avoidance test, open field test, forced swimming test, and social interaction test). Results. The increased number of stereotyped behaviors and grooming behaviors induced with APO were counteracted by all of the experimental treatments. MK-801 induced an increase in immobility time, which was blocked with G-B; GRF counteracted the decreased social interaction, and GgMeOH and GRF prevented the memory loss induced by MK-801. Conclusion. G. glauca and their derivatives products (GRF and galphimines) were able to interact with the dopaminergic and glutamatergic drugs and to block different behaviors associated with some of the positive, negative, and cognitive symptoms of induced schizophrenia in mice. It is necessary to continue with this research, in order to identify their mechanism of action.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Galphimia glauca and Natural Galphimines Block Schizophrenia-Like Symptoms Induced with Apomorphine and MK-801 in Mice

Santillán-Urquiza

Herrera-Ruíz

Zamilpa

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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“…Seizure-suppressing effects could be obtained with two different hM4Di ligands: CNO or clozapine. Studies report effects of clozapine on anxiety-related behavior (both anxiolytic and anxiogenic) and locomotion (sedative effects) at doses of 0.05 mg/kg and higher in wild-type rats 21,22 and 0.5 mg/kg and higher in wildtype mice [23][24][25] . 17,18 Therefore novel ligands, such as compound 21, perlapine, JHU37160/152, and clozapine have been suggested for direct DREADD activation.…”

Section: Discussionmentioning

confidence: 99%

“…20 However, off-target effects may still occur given the interactions of clozapine with a broad range of receptors, including dopaminergic, adrenergic, serotonergic, histaminergic and muscarinergic receptors. Studies report effects of clozapine on anxiety-related behavior (both anxiolytic and anxiogenic) and locomotion (sedative effects) at doses of 0.05 mg/kg and higher in wild-type rats 21,22 and 0.5 mg/kg and higher in wildtype mice [23][24][25] . In this study such effects could not be demonstrated in the OFT after a single administration of 0.1 mg/kg clozapine or 10 mg/kg CNO to non-DREADD IHKA mice.…”

Section: Discussionmentioning

confidence: 99%

Long‐term chemogenetic suppression of spontaneous seizures in a mouse model for temporal lobe epilepsy

et al. 2019

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Objective: More than one-third of patients with temporal lobe epilepsy (TLE) continue to have seizures despite treatment with antiepileptic drugs, and many experience severe drug-related side effects, illustrating the need for novel therapies. Selective expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allows cell-type-specific reduction of neuronal excitability. In this study, we evaluated the effect of chemogenetic suppression of excitatory pyramidal and granule cell neurons of the sclerotic hippocampus in the intrahippocampal mouse model (IHKA) for temporal lobe epilepsy. Methods: Intrahippocampal IHKA mice were injected with an adeno-associated viral vector carrying the genes for an inhibitory DREADD hM4Di in the sclerotic hippocampus or control vector. Next, animals were treated systemically with different single doses of clozapine-N-oxide (CNO) (1, 3, and 10 mg/kg) and clozapine (0.03 and 0.1 mg/kg) and the effect on spontaneous hippocampal seizures, hippocampal electroencephalography (EEG) power, fast ripples (FRs) and behavior in the open field test was evaluated. Finally, animals received prolonged treatment with clozapine for 3 days and the effect on seizures was monitored. Results: Treatment with both CNO and clozapine resulted in a robust suppression of hippocampal seizures for at least 15 hours only in DREADD-expressing animals. Moreover, total EEG power and the number of FRs were significantly reduced. CNO and/or clozapine had no effects on interictal hippocampal EEG, seizures, or locomotion/anxiety in the open field test in non-DREADD epileptic IHKA mice. Repeated clozapine treatment every 8 hours for 3 days resulted in almost complete seizure suppression in DREADD animals. Significance: This study shows the potency of chemogenetics to robustly and sustainably suppress spontaneous epileptic seizures and pave the way for an epilepsy therapy in which a systemically administered exogenous drug selectively modulates specific cell types in a seizure network, leading to a potent seizure suppression devoid of the typical drug-related side effects. | 2315 DESLOOVERE Et aL.

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“…During the critical period of brain maturation, MK-801 induces locomotor hyperactivity and decreases anxiety levels in adolescent rats. 6 In the elevated plus maze (EPM) test a decrease was observed in anxiety-related behaviors caused in adult male mice by MK-801 in the early developmental period [7]. NMDA receptor blockade could reduce neuronal activity in pathways which lead to the release of GABA or monoamines, and which have themselves been implicated in anxiety-related processes [8].…”

Section: Introductionmentioning

confidence: 99%

Effect of N-Methyl-D-Aspartate Receptor Blockade on Anxiety-Like Behavior Induced in Rats by Postnatal Chronic Exposure to the Endocrine Disruptor Di-2 (Ethyl-Hexyl Phthalate) in Elevated plus Maze Test

2019

Endocrinol Diabetes Metab J

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Di-2-Ethylhexyl Phthalate (DEHP) is the widely used to convey flexibility and transparency to plastic products made of polyvinyl chloride and also in the manufacture of medical devices. DEHP disrupts reproductive tract development in an antiandrogenic manner and also may induce neurobehavioral changes. In previous works, we demonstrated that chronic postnatal exposure to DEHP alters the neuroendocrine regulation of the testicular axis, modifying the hypothalamic concentration of excitatory neurotransmitters and therefore induces an anxiogenic effect. In the Elevated Plus Maze (EPM) test, dizocilpine (MK-801) induces a decrease in anxiety-related behaviors throughout NMDA receptor blockade. The objective of this work was to investigate whether the blockade of NMDA receptors of glutamate by the non-competitive antagonist MK-801 could modify the anxiety-like behavior induced by chronic postnatal exposure to DEHP (30 mg/kg body weight/day, orally from birth) in young adult male rats in the EPM test. The results show that NMDA receptor blockade by MK-801 (0.1 mg/kg body weight, i.p.) in DEHP exposed animals is able to produce a significant decrease in time spent in closed arms (TSC) and in Freezing Time (FT) as well as an increase in time spent in open arms (TSO) in the EPM test, indicating an anxiolytic effect. In conclusion, our results suggest: 1) NMDA receptor blockade by MK-801 can reverse anxiety-like behavior induced by exposure to DEHP during the early period of life. 2) The glutamatergic system is involved in the anxiogenic effect of phthalate, which is probably triggered by its known antiandrogenic action.

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Effect of clozapine on locomotor activity and anxiety-related behavior in the neonatal mice administered MK-801

Cited by 17 publications

References 31 publications

Galphimia glauca and Natural Galphimines Block Schizophrenia-Like Symptoms Induced with Apomorphine and MK-801 in Mice

Galphimia glauca and Natural Galphimines Block Schizophrenia-Like Symptoms Induced with Apomorphine and MK-801 in Mice

Long‐term chemogenetic suppression of spontaneous seizures in a mouse model for temporal lobe epilepsy

Effect of N-Methyl-D-Aspartate Receptor Blockade on Anxiety-Like Behavior Induced in Rats by Postnatal Chronic Exposure to the Endocrine Disruptor Di-2 (Ethyl-Hexyl Phthalate) in Elevated plus Maze Test

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