Effects of risperidone on dopamine receptor subtypes in developing rat brain

Abstract

The atypical antipsychotic risperidone is often prescribed to pediatric patients with neuropsychiatric disorders, though its effects on the developing brain remain unclear. Accordingly, we studied the effects of repeated treatment of risperidone on dopamine receptors in brain regions of juvenile rat. Levels of dopamine receptors (D 1 , D 2 , D 3 , D 4 ) in forebrain regions of juvenile rats were quantified after 3 weeks of treatment with three different doses of risperidone (0.3, 1.0 and 3.0 mg/kg) and compared findings to those in adult rats treated with risperidone (3.0 mg/kg/day) previously. Risperidone (at 1.0 and 3.0 mg/kg/day) increased levels of D 1 receptors in nucleus accumbens and caudate-putamen of juvenile, but not adult rats. Conversely, all three doses of risperidone dosedependently increased D 2 labeling in medial prefrontal cortex and hippocampus, and D 4 receptor in nucleus accumbens, caudate-putamen and hippocampus of juvenile animals as well as in adults. Only the high dose of risperidone (3.0 mg/kg) increased D 2 receptors in caudate-putamen in both juvenile and adult brain. D 3 receptors were not altered by risperidone in any brain region at any dose or age. The findings indicate dose-dependent effects of risperidone on dopamine receptors in developing animals, and that juvenile animals are more sensitive than adults to the cerebral effects of risperidone.

Alterations in dopamine and glutamate neurotransmission in tetrahydrobiopterin deficient spr-/- mice: relevance to schizophrenia

“…Positron emission tomography (PET) studies which examined striatal D2 receptor levels in antipsychoticnaive schizophrenia patients reported inconsistent results, as one study reported a significant elevation of striatal D2 receptors (14) while two other studies failed to detect significant changes in striatal D2 receptors in drug-naive patients diagnosed with schizophrenia (15,16). Repeated treatment of laboratory animals with various first-and second-generation antipsychotic drugs altered concentrations of different DA receptor subtypes in cortical, limbic and extrapyramidal brain regions of mature and developing rats (17)(18)(19)(20).…”

Is Brain-derived Neurotrophic Factor a Possible Mechanism Underlying Risperidone Sensitization in Adolescent Rats?

“…Motor activity was recorded for the entire 90-min testing session. One day after the challenge test (~P 52), rats were sacrificed by live decapitation and their brains were removed for further analysis [37]. …”

Evaluating long-term consequences of adolescent antipsychotic exposure

“…There may be some support for these hypotheses. For example, increased D1 and NMDA receptor binding in the NAc was observed selectively with chronic adolescent risperidone treatment at 24 hours after this regimen (Moran-Gates et al 2007). Some changes, for example, increased D2…”

“…I also observed no change in dopamine receptor expression. A more sensitive technique such as radioligand binding which can also give a read-out of functional receptor activity may provide more information on risperidone-induced changes in dopamine receptors (Moran-Gates et al 2007). …”

“…While still limited in number, existing preclinical studies have attempted to identify short-term behavioural and neurochemical effects of adolescent APD treatment [for example, (Choi et al 2009;Lian et al 2016;Moran-Gates et al 2007;Wiley 2008;Wiley and Evans 2008)]. A few preclinical studies over the past five years have also started to examine long-term neurobiological consequences of adolescent treatment with atypical APDs (De Santis et al 2016;Milstein et al 2013;Qiao et al 2013;Vinish et al 2013).…”