THE EFFECT OF ATYPICAL GABAA/BENZODIAZEPINE RECEPTOR AGONIST ZOPICLONE ON EXPERIMENTAL SCHIZOPHRENIA MODELS

Schizophrenia is a disorder characterized by positive and negative symptoms and impairments in cognitive functions (1). Current medications in treatment are mostly effective on the positive symptoms of the disease; but has limited effectiveness on negative and cognitive symptoms (1). Two main hypotheses for schizophrenia pathophysiology are the increased dopaminergic transmission and decreased glutamatergic transmission in the brain (2). However, the symptoms of schizophrenia can nor fully explained by these hypotheses (2). Several other mechanisms are also targeted to explore the pathophysiology of schizophrenia such as the alteration of gamma-amino butyric acid (GABA) transmission (3)

Zopiclone (ZO) is a non-benzodiazepine drug acting by binding to GABAA receptor complex (4). We aimed to investigate the chronic effects and mechanisms of action of of ZO on experimental schizophrenia models in rats and mice.

Wistar-male rats and cd1-male mice were used in the study. ZO were administered by oral gavage chronically for 5 days at doses of 10, 20 and 40mg/kg in rats and at a dose of 20mg/kg in mice. ZO 20mg/kg was also administered in combination with GABA analogue muscimol (1 mg/kg) and GABAA receptor anatagonist bicuculline (1 mg/kg) in rats. Apomorphine (APO-0,5mg/kg)-induced disruption of prepulse inhibition (PPI) was used as experimental schizophrenia model in rats while catalepsy, MK-801 (0,3mg/kg)-induced hyperlocomotion, and APO (1,5mg/kg)-induced climbing tests were used as experimental schizophrenia models in mice. Additionally, the effect of ZO was compared with two antipsychotic drugs in clinical use, typical antipsychotic haloperidol(1mg/kg) and atypical antipsychotic olanzapine (3mg/kg). Drug treatments were administered for 5 days, and on the fifth day, animals were tested on experimental schizophrenia models one hour after drug treatments. Statistical analyzes were evaluated with one-way ANOVA.

APO significantly decreased %PPI compared to control (p<0,05) while ZO 20mg/kg reversed the PPI disruption induced by APO comparable to haloperidol and olanzapine (p<0,05). Bicuculline antagonized the effect of ZO on PPI. APO significantly increased the climbing duration in mice compared to control (P<0,001). Haloperidol and olanzapine significantly decreased APO-induced climbing duration (p<0,05) while ZO was ineffective (p>0,05). MK-801 significantly increased the number of total movements and distance moved compared to control (P<0,001) while ZO decreased these parameters induced by MK-801 comparable to haloperidol and olanzapine (P<0,01). Haloperidol and olanzapine significantly increased catalepsy time compared to control (P< 0,001, P< 0,01, respectively) while ZO did not increase catalepsy time compared to control (p>0,05).

We suggest that ZO may have an antipsychotic-like effect comparable to the reference antipsychotics haloperidol and olanzapine. This effect seems to be mediated by GABAA receptors, probably by the interaction between dopaminergic, and GABA’ ergic glutamatergic systems. ZO reversed APO-induced PPI disruption in rats but did not reverse APO-induced climbing in mice. However, we only used 20mg/kg of ZO in this test and further studies are needed to extend the studies on antipsychotic-like effect of ZO such as using at different doses and to clarify the exact mechanism of action.

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4.Louzada LL, Machado FV, Quintas JL, Ribeiro GA, Silva MV, Mendonç a-Silva DL, Gonç alves BSB, Nó brega OT, Camargos EF. The efficacy and safety of zolpidem and zopiclone to treat insomnia in Alzheimer's disease: a randomized, triple-blind, placebo-controlled trial. Neuropsychopharmacology. 2022 Jan;47(2):570-579. doi: 10.1038/s41386-021-01191-3. Epub 2021 Oct 11. PMID: 34635802; PMCID: PMC8674235.