Dopamine D4 receptor and anxiety: Behavioural profiles of clozapine, L-745,870 and L-741,742 in the mouse plus-maze

Cao, Bo-Jin; Rodgers, R.J.

doi:10.1016/s0014-2999(97)01234-x

Cited by 40 publications

(26 citation statements)

References 39 publications

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“…For the evaluation, we performed EPM tests in which KO mice showed strong reproducible abnormalities in repeated pilot experiments (data not shown). A low dose (0.4 mg/kg) was chosen, because administration of higher doses inhibits all active behavior in mice in the EPM [20]. The time spent in the open arm was not influenced by a single dose of clozapine at 0.4 mg/kg (Figure 8A).…”

Section: Resultsmentioning

confidence: 99%

Impaired Cognitive Function and Altered Hippocampal Synapse Morphology in Mice Lacking Lrrtm1, a Gene Associated with Schizophrenia

et al. 2011

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Recent genetic linkage analysis has shown that LRRTM1 (Leucine rich repeat transmembrane neuronal 1) is associated with schizophrenia. Here, we characterized Lrrtm1 knockout mice behaviorally and morphologically. Systematic behavioral analysis revealed reduced locomotor activity in the early dark phase, altered behavioral responses to novel environments (open-field box, light-dark box, elevated plus maze, and hole board), avoidance of approach to large inanimate objects, social discrimination deficit, and spatial memory deficit. Upon administration of the NMDA receptor antagonist MK-801, Lrrtm1 knockout mice showed both locomotive activities in the open-field box and responses to the inanimate object that were distinct from those of wild-type mice, suggesting that altered glutamatergic transmission underlay the behavioral abnormalities. Furthermore, administration of a selective serotonin reuptake inhibitor (fluoxetine) rescued the abnormality in the elevated plus maze. Morphologically, the brains of Lrrtm1 knockout mice showed reduction in total hippocampus size and reduced synaptic density. The hippocampal synapses were characterized by elongated spines and diffusely distributed synaptic vesicles, indicating the role of Lrrtm1 in maintaining synaptic integrity. Although the pharmacobehavioral phenotype was not entirely characteristic of those of schizophrenia model animals, the impaired cognitive function may warrant the further study of LRRTM1 in relevance to schizophrenia.

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Section: Resultsmentioning

confidence: 99%

Impaired Cognitive Function and Altered Hippocampal Synapse Morphology in Mice Lacking Lrrtm1, a Gene Associated with Schizophrenia

et al. 2011

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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%

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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“…Both olanzapine and clozapine have been found to increase water licking of an electrified water bottle in the Geller-Seifter conflict task (Moore et al, 1992)(Moore, Tye et al, 1992), demonstrating that these atypical antipsychotics may possess anxiolytic activity. However, there are other reports that fail to confirm this anxiolytic activity (Cao and Rodgers, 1997; Fernandez-Tome et al, 1979; Masson et al, 2003; Shadach et al, 1999). Still others even suggest an anxiogenic activity (Karl et al, 2006; Manzaneque et al, 2002).…”

Section: Introductionmentioning

confidence: 86%

Clozapine and olanzapine exhibit an intrinsic anxiolytic property in two conditioned fear paradigms: Contrast with haloperidol and chlordiazepoxide

Mead

Kapur

2008

Pharmacology Biochemistry and Behavior

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Dopamine D4 receptor and anxiety: Behavioural profiles of clozapine, L-745,870 and L-741,742 in the mouse plus-maze

Cited by 40 publications

References 39 publications

Impaired Cognitive Function and Altered Hippocampal Synapse Morphology in Mice Lacking Lrrtm1, a Gene Associated with Schizophrenia

Impaired Cognitive Function and Altered Hippocampal Synapse Morphology in Mice Lacking Lrrtm1, a Gene Associated with Schizophrenia

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

Clozapine and olanzapine exhibit an intrinsic anxiolytic property in two conditioned fear paradigms: Contrast with haloperidol and chlordiazepoxide

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