Early antipsychotic exposure affects NMDA and GABAA receptor binding in the brains of juvenile rats

Abstract

Antipsychotics were developed to treat schizophrenia in adults; however they have been increasingly prescribed in children and adolescents. The NMDA and GABAA receptors are involved in neurodevelopment and the pathophysiology of various mental disorders in children and adolescents. Male and female juvenile rats were treated orally with risperidone (0.3 mg/kg, 3 times/day), aripiprazole (1 mg/kg), olanzapine (1 mg/kg) or vehicle (control), starting from postnatal day (PD) 23 (±1 day) for 3 weeks (corresponding to the childhood-adolescent period in humans). Quantitative autoradiography was used to detect the binding density of [ 3 H]MK-801 (an NMDA receptor antagonist) and [ 3 H]muscimol (a selective GABAA receptor agonist). Aripiprazole elevated the [ 3 H]MK801 binding levels in the NAcC of male rats, and the NAcS and CPu of female rats. Risperidone increased [ 3 H]MK801 levels in the CPu of female rats, and the NAcS of male rats. Aripiprazole upregulated [ 3 H]muscimol binding levels in the CPu and NAcC of male rats, while it elevated the [ 3 H]muscimol levels in the PFC of female rats, compared to controls. These results suggest that early treatment with these antipsychotics modulates NMDA and GABAA neurotransmission in juveniles, which may play a role in their clinical efficacy in the control of mental disorders in children and adolescents.

Region-specific and dose-specific effects of chronic haloperidol exposure on [3H]-flumazenil and [3H]-Ro15-4513 GABAA receptor binding sites in the rat brain

“…Previous QAR studies in naïve adult rats provide evidence that chronic exposure to different antipsychotics influences the binding of both [ 3 H]-muscimol (indexing GABA A R binding) and [ 3 H]-flunitrazepam (indexing BZ-site binding) in a region-specific manner that is also dependent on the duration of drug exposure, the mode of administration and the sex of the animal ( Dean et al., 2001 ; McLeod et al., 2008 ; See et al., 1990 , 1989 ; Shirakawa and Tamminga, 1994 ; Skilbeck et al., 2008 , 2007 ; Zink et al., 2004 ). For example, a 21 day oral exposure to aripiprazole (1 mg/kg), olanzapine (1 mg/kg) or risperidone (03.mg/kg) increased [ 3 H]-muscimol binding in the striatum and nucleus accumbens of adolescent male rats, whilst in adolescent female rats binding was only increased in the prefrontal cortex ( Lian and Deng, 2019 ). By contrast, a 12-day exposure to haloperidol (1 mg/kg/d) via intraperitoneal injections was reported to decrease [ 3 H]-flumazenil binding in several regions of the rat brain ( McLeod et al., 2008 ).…”

Region-specific and dose-specific effects of chronic haloperidol exposure on [3H]-Flumazenil and [3H]-Ro15-4513 GABAA receptor binding sites in the rat brain

“…Previous QAR studies in naïve adult rats provide evidence that chronic exposure to different antipsychotics influences the binding of both [ 3 H]-muscimol (indexing GABA A R binding) and [ 3 H]-flunitrazepam (indexing BZ-site binding) in a region-specific manner that is also dependent on the duration of drug exposure, the mode of administration and the sex of the animal (Dean et al, 2001;McLeod et al, 2008;See et al, 1990See et al, , 1989Shirakawa and Tamminga, 1994;Skilbeck et al, 2008Skilbeck et al, , 2007Zink et al, 2004). For example, a 21 day oral exposure to aripiprazole (1mg/kg), olanzapine (1mg/kg) or risperidone (03.mg/kg) increased [ 3 H]-muscimol binding in the striatum and nucleus accumbens of adolescent male rats, whilst in adolescent female rats binding was only increased in the prefrontal cortex (Lian and Deng, 2019). By contrast, a 12-day exposure to haloperidol (1 mg/kg/d) via intraperitoneal injections was reported to decrease [ 3 H]-flumazenil binding in several regions of the rat brain (McLeod et al, 2008).…”

Signaling pathways that are influenced by SHANK3 mutation and related treatment for autism

“…These pathways are found inactivated in Shank3 mutated model. Administration of IGF-1 significantly rescues cellular structure and motor skills through activation of these pathways and improvement of AMPA and NMDA mediated response [12].…”