Neuroplasticity and inflammatory alterations in the nucleus accumbens are corrected after risperidone treatment in a schizophrenia-related developmental model in rats

Hiram Tendilla-Beltrán,Heriberto Coatl-Cuaya,Silvia Meneses-Prado,Ruben Antonio Vázquez-Roque,Eduardo Brambila,Miguel Tapia-Rodríguez,David Martín-Hernández,Linda Garcés-Ramírez,José L.M Madrigal,Juan C Leza,Gonzalo Flores

doi:10.1016/j.schres.2021.07.014

Abstract

Increased dopaminergic activity in the striatum underlies the neurobiology of psychotic symptoms in schizophrenia (SZ). Beyond the impaired connectivity among the limbic system, the excess of dopamine could lead to inflammation and oxidative/nitrosative stress. It has been suggested that atypical antipsychotic drugs attenuate psychosis not only due to their modulatory activity on the dopaminergic/serotonergic neurotransmission but also due to their anti-inflammatory/antioxidant effects. In such a manner, we assessed the effects of the atypical antipsychotic risperidone (RISP) on the structural neuroplasticity and biochemistry of the striatum in adult rats with neonatal ventral hippocampus lesion (NVHL), which is a developmental SZ-related model. RISP administration (0.25 mg/kg, i.p.) ameliorated the neuronal atrophy and the impairments in the morphology of the dendritic spines in the spiny projection neurons (SPNs) of the ventral striatum (nucleus accumbens: NAcc) in the NVHL rats. Also, RISP treatment normalized the pro-inflammatory pathways and induced the antioxidant activity of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in this model. Our results point to the neurotrophic, anti-inflammatory, and antioxidant effects of RISP, together with its canonical antipsychotic mechanism, to enhance striatum function in animals with NVHL.

Highlights

Psychosis is defined as an altered mental condition in which the individual loses contact with reality
The neonatal ventral hippocampus lesion (NVHL) did not alter the number of neurons in the nucleus accumbens (NAcc), but ANOVA analysis revealed that RISP increased the number of neurons in both sham and NVHL animals in this region (Fig. 1D)
Concerning dendritic arborization, in the proximal levels (0-90 μm to soma) there were no differences in the vehicle or RISP-treated animals with NVHL, but in distal arbor RISP increased the arborization length (Fig. 2E)

Summary

Introduction

Psychosis is defined as an altered mental condition in which the individual loses contact with reality. Psychosis represents a disabling condition for people who suffer from it. Psychosis is the core symptom in schizophrenia (SZ), a mental disease which affects around 2% of the worldwide population, and whose etiology is still poorly understood. The neurobiology of the positive symptoms of the disease (psychotic episodes, hallucinations, delusions) has been associated with dopaminergic hyperactivity of axons from the ventral tegmental area (VTA) in the mesolimbic brain to the nucleus accumbens (NAcc) or ventral ( known as limbic) striatum (McCutcheon et al, 2019). The NAcc is a basal ganglia nucleus involved in sensory-motor integration and is mainly composed of medium-sized spiny projection neurons (SPNs)

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