Predicting how equipotent doses of chlorpromazine, haloperidol, sulpiride, raclopride and clozapine reduce locomotor activity in mice

Simón, Vicente M.; Parra, Andrés; Miñarro, José; Arenas, M. Carmen; Vinader‐Caerols, Concepción; Aguilar, María José Coperías

doi:10.1016/s0924-977x(00)00070-5

Cited by 55 publications

(40 citation statements)

References 25 publications

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“…Consistent with a number of previous studies that have reported antipsychotic-induced suppression of behavior in adult male rodents (Gramling and Fowler, 1985;Simon et al, 2000;Wiley and Martin, 2003), haloperidol dose-dependently decreased locomotor activity by approximately the same magnitudes in adolescent and adult male rats over an identical dose range. In contrast, an overall greater sensitivity to the activity decreasing effects of haloperidol was observed in haloperidol-treated juvenile male rats (PN22), with this effect being most apparent at the lowest (0.03 mg/kg) haloperidol dose.…”

Section: Discussionsupporting

confidence: 89%

“…In contrast, second generation, atypical antipsychotics, such as clozapine and olanzapine, do not produce these motor effects. Preclinically, however, one of the most consistent effects observed with the acute administration of both typical and newer atypical antipsychotics is suppression of voluntary behavior, including motor activity (Simon et al, 2000;Wiley and Martin, 2003) and operant responding for food and water (Gramling and Fowler, 1985;Varvel et al, 2002). Because the ability of immature animals to acquire operant behavior quickly has not been demonstrated, motor activity was selected as the behavioral endpoint for this study.…”

Section: Introductionmentioning

confidence: 99%

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Antipsychotic-induced suppression of locomotion in juvenile, adolescent and adult rats

Wiley

2008

European Journal of Pharmacology

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Schizophrenia is a serious psychiatric disorder that is most frequently treated with the administration of antipsychotics. Although onset of schizophrenia typically occurs in late adolescence, the majority of preclinical research on the behavioral effects of antipsychotics and their mechanism(s) of action has been conducted on adult male animals. In this study, the acute effects of haloperidol (0.03 -0.3 mg/kg, i.p.) and clozapine (1 -10 mg/kg, i.p.) on locomotor activity were examined in juvenile [postnatal day 22 (PN22)], adolescent (PN40), and adult (>PN70) rats of both sexes. Subsequently, in order to determine whether tolerance to the activity suppressive effects of these drugs would occur in adolescents, PN40 rats were dosed and assessed for an additional nine days. While all groups exhibited some degree of suppression following acute administration of both drugs, juvenile rats were considerably more sensitive to this effect. With sub-chronic administration during late adolescent development (PN40-PN49), tolerance failed to develop. These results emphasize the importance of age in pharmacological characterization of antipsychotics and suggest that preadolescents may have enhanced sensitivity to the motor effects of these drugs. Further, they suggest that, similar to adults, older adolescents may not develop tolerance to the activity suppression induced by these two antipsychotics.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Antipsychotic-induced suppression of locomotion in juvenile, adolescent and adult rats

Wiley

2008

European Journal of Pharmacology

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“…was completely devoid of cataleptic effects, whereas all antipsychotics tested, in particular haloperidol, produced substantial cataleptic effects at doses either overlapping or close to those blocking hyperactivity after pharmacological challenge or in mutant animals. Results with haloperidol are consistent with previous studies, which reported that classical and atypical antipsychotics induce catalepsy in mice (Simon et al, 2000;Bardin et al, 2006;Boulay et al, 2000). Although clozapine is claimed not to produce extrapyramidal side effects in humans, it produces motor suppression and catalepsy in adult rodents (Wiley and Martin, 2003).…”

Section: The Glyt1 Inhibitor Ssr103800 Induces Fewer Side Effects Thasupporting

confidence: 90%

The Glycine Transporter-1 Inhibitor SSR103800 Displays a Selective and Specific Antipsychotic-like Profile in Normal and Transgenic Mice

Boulay

Bergis

Avenet

et al. 2009

Neuropsychopharmacol

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Schizophrenia has been initially associated with dysfunction in dopamine neurotransmission. However, the observation that antagonists of the glutamate N-methyl-D-aspartate (NMDA) receptor produce schizophrenic-like symptoms in humans has led to the idea of a dysfunctioning of the glutamatergic system via its NMDA receptor. As a result, there is a growing interest in the development of pharmacological agents with potential antipsychotic properties that enhance the activity of the glutamatergic system via a modulation of the NMDA receptor. Among them are glycine transporter-1 (GlyT1) inhibitors such as SSR103800, which indirectly enhance NMDA receptor function by increasing the glycine (a co-agonist for the NMDA receptor) levels in the synapse. This study aimed at investigating the potential antipsychotic-like properties of SSR103800, with a particular focus on models of hyperactivity, involving either drug challenge (ie, amphetamine and MK-801) or transgenic mice (ie, NMDA Nr1 neoÀ/À and DAT À/À ). Results showed that SSR103800(10-30 mg/kg p.o.) blocked hyperactivity induced by the non-competitive NMDA receptor antagonist, MK-801 and partially reversed spontaneous hyperactivity of NMDA Nr1 neoÀ/À mice. In contrast, SSR103800 failed to affect hyperactivity induced by amphetamine or naturally observed in dopamine transporter (DAT À/À ) knockout mice (10-30 mg/kg p.o.). Importantly, both classical (haloperidol) and atypical (olanzapine, clozapine and aripiprazole) antipsychotics were effective in all these models of hyperactivity. However, unlike these latter, SSR103800 did not produce catalepsy (retention on the bar test) up to 30 mg/kg p.o. Together these findings show that the GlyT1 inhibitor, SSR103800, produces antipsychotic-like effects, which differ from those observed with compounds primarily targeting the dopaminergic system, and has a reduced side-effect potential as compared with these latter drugs.

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“…Vehicle was prepared likewise. The mice were injected intraperitoneally at a dose of 0.25 mg/kg haloperidol (ED 50 of haloperidol ϭ 0.2 mg/kg (14). Higher doses of haloperidol rendered the mice catatonic.…”

Section: Methodsmentioning

confidence: 99%

Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior

Dries

Zhu²,

Brooks³

et al. 2016

Journal of Biological Chemistry

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The biological underpinnings and the pathological lesions of psychiatric disorders are centuries-old questions that have yet to be understood. Recent studies suggest that schizophrenia and related disorders likely have their origins in perturbed neurodevelopment and can result from a large number of common genetic variants or multiple, individually rare genetic alterations. It is thus conceivable that key neurodevelopmental pathways underline the various genetic changes and the still unknown pathological lesions in schizophrenia. Here, we report that mice defective of the nicastrin subunit of ␥-secretase in oligodendrocytes have hypomyelination in the central nervous system. These mice have altered dopamine signaling and display profound abnormal phenotypes reminiscent of schizophrenia. In addition, we identify an association of the nicastrin gene with a human schizophrenia cohort. These observations implicate ␥-secretase and its mediated neurodevelopmental pathways in schizophrenia and provide support for the "myelination hypothesis" of the disease. Moreover, by showing that schizophrenia and obsessive-compulsive symptoms could be modeled in animals wherein a single genetic factor is altered, our work provides a biological basis that schizophrenia with obsessivecompulsive disorder is a distinct subtype of schizophrenia.Psychiatric diseases such as schizophrenia, obsessive-compulsive disorder, attention deficit hyperactivity disorder, and autism exert devastating impact on the well-being of those affected and the society at large. The clinical symptoms and etiologies of these diseases are complex, obscure, and often overlap, and characteristics of these diseases can only be partially and incompletely captured in existing animal models. In contrast to classical neurological disorders such as Alzheimer disease, psychiatric disorders do not display overt neuropathological lesions but rather are attributed to changes in synaptic transmission, neuronal homeostasis, and neuronal networks. Both genetic and environmental factors contribute to these changes, which can result from multiple, individually rare genetic alterations or from large numbers of common genetic variants. Often, psychiatric disorders have their origins in perturbed neurodevelopment. It is therefore conceivable that key neurodevelopmental factors and pathways contribute to their neurobiological underpinnings.Several important neurodevelopmental pathways are controlled by ␥-secretase, a multisubunit, multitransmembranespanning proteolytic complex that cleaves a host of type I transmembrane proteins within the lipid bilayer (1). Although ␥-secretase is perhaps best known for its role in cleaving the amyloid precursor protein in Alzheimer disease, key ␥-secretase substrates have also been implicated in schizophrenia, most notably neuregulin-1 (Nrg1) and its receptor ErbB4 (2, 3). A recent study also demonstrated a functional interaction between the amyloid precursor protein and disrupted-in-schizophrenia-1 in cortical development (4). Moreover, multiple ...

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Predicting how equipotent doses of chlorpromazine, haloperidol, sulpiride, raclopride and clozapine reduce locomotor activity in mice

Cited by 55 publications

References 25 publications

Antipsychotic-induced suppression of locomotion in juvenile, adolescent and adult rats

Antipsychotic-induced suppression of locomotion in juvenile, adolescent and adult rats

The Glycine Transporter-1 Inhibitor SSR103800 Displays a Selective and Specific Antipsychotic-like Profile in Normal and Transgenic Mice

Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior

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