Early Antipsychotic Treatment in Juvenile Rats Elicits Long-Term Alterations to the Dopamine Neurotransmitter System.

Michael De Santis,Chao Deng,Jiamei Lian,Xu-Feng Huang

doi:10.3390/ijms17111944

Abstract

Prescription of antipsychotic drugs (APDs) to children has substantially increased in recent years. Whilst current investigations into potential long-term effects have uncovered some alterations to adult behaviours, further investigations into potential changes to neurotransmitter systems are required. The current study investigated potential long-term changes to the adult dopamine (DA) system following aripiprazole, olanzapine and risperidone treatment in female and male juvenile rats. Levels of tyrosine hydroxylase (TH), phosphorylated-TH (p-TH), dopamine active transporter (DAT), and D1 and D2 receptors were measured via Western blot and/or receptor autoradiography. Aripiprazole decreased TH and D1 receptor levels in the ventral tegmental area (VTA) and p-TH levels in the prefrontal cortex (PFC) of females, whilst TH levels decreased in the PFC of males. Olanzapine decreased PFC p-TH levels and increased D2 receptor expression in the PFC and nucleus accumbens (NAc) in females only. Additionally, risperidone treatment increased D1 receptor levels in the hippocampus of females, whilst, in males, p-TH levels increased in the PFC and hippocampus, D1 receptor expression decreased in the NAc, and DAT levels decreased in the caudate putamen (CPu), and elevated in the VTA. These results suggest that early treatment with various APDs can cause different long-term alterations in the adult brain, across both treatment groups and genders.

Highlights

Prescription and use of antipsychotic drugs (APDs) in children and adolescents is increasing rapidly worldwide, despite a lack of knowledge on the safety and efficacy of APD use on the developing brain [1,2,3,4,5,6,7,8,9]
A significant effect of treatment on tyrosine hydroxylase (TH) expression was found in the ventral tegmental area (VTA) (F3,46 = 4.851, p < 0.01) (Figure 1E’,E”), whilst a trend to significant effect of Treatment was observed in the caudate putamen (CPu) (F3,46 = 2.352, p = 0.087)
This study has revealed that early APD treatment during the critical neurodevelopmental time period has the potential to cause long-lasting alterations to the DA NT system, including changes to DA synthesis markers, transporter and receptor density levels

Summary

Introduction

Prescription and use of antipsychotic drugs (APDs) in children and adolescents is increasing rapidly worldwide, despite a lack of knowledge on the safety and efficacy of APD use on the developing brain [1,2,3,4,5,6,7,8,9]. Second-generation APDs including aripiprazole, olanzapine and risperidone are commonly being prescribed (mostly off-label) for the treatment of a variety of childhood disorders, from mental illnesses including anxiety, depression and child-onset schizophrenia [5,10], to various behavioural disorders [11,12,13]. There is the potential that use of potent APDs at this critical time period of neurodevelopment has the ability to cause long-term alterations to NT systems, including DA signalling pathways, in a manner preceding normal brain functioning [8,26,28]. Mesolimbic and nigrostriatal DA NT pathways previously implicated in the pathophysiology of the mental illness state [15,21,29,30], prescription and use of APDs in the childhood/adolescent period may be potentially leading to long-term deficits in brain functioning [31]

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