Dopamine in Autism Spectrum Disorders—Focus on D2/D3 Partial Agonists and Their Possible Use in Treatment

Abstract

Autism spectrum disorders (ASD) are a group of disorders characterized by impairment in social communication and repetitive and stereotyped behaviors. ASD etiology is very complex, including the effect of both genetic and environmental factors. So far, no specific treatment for the core symptoms of ASD has been developed, although attempts have been made for the treatment of repetitive behavior. The pharmacological treatment is aimed at treating non-specific symptoms such as irritability and aggression. Recent studies pointed out to the possible role of altered dopamine signaling in mesocorticolimbic and nigrostriatal circuits in ASD. In addition, several research pointed out to the association of dopamine receptors polymorphism and ASD, specifically repetitive and stereotyped behavior. In this paper, we will provide a review of the studies regarding dopamine signaling in ASD, existing data on the effects of D2/D3 partial agonists in ASD, possible implications regarding their individual receptor profiles, and future perspectives of their possible use in ASD treatment.

Gestational hypoxia in late pregnancy differentially programs subcortical brain maturation in male and female rat offspring

“…Brain regions that are sensitive to prenatal hypoxia include the cortex, basal ganglia (includes the nigrostriatal pathway), and white matter in children [78]. The nigrostriatal pathway is integral for many behaviors, such as motor function, cognition, social interactions, mood (anxiety/depression), reward, and attention [79][80][81]. Therefore, impairments of the nigrostriatal pathway can have long-term consequences, such as many neuropsychiatric disorders (e.g., Parkinson's disease [78,82], addiction [78], cognitive dysfunction [78], autism spectrum disorders [78,79], mood disorders [78,79,81], and attention deficit hyperactivity disorders [80]).…”

“…The nigrostriatal pathway is integral for many behaviors, such as motor function, cognition, social interactions, mood (anxiety/depression), reward, and attention [79][80][81]. Therefore, impairments of the nigrostriatal pathway can have long-term consequences, such as many neuropsychiatric disorders (e.g., Parkinson's disease [78,82], addiction [78], cognitive dysfunction [78], autism spectrum disorders [78,79], mood disorders [78,79,81], and attention deficit hyperactivity disorders [80]). These relationships have also been observed in clinical studies examining children exposed to gestational hypoxia (pre-eclampsia, acute perinatal hypoxic injury, and gestational sleep apnea [1][2][3][4][5]).…”

Drug repurposing candidates to treat core symptoms in autism spectrum disorder

“…The authors speculated that these complementary clinical effects of a dopamine agonist and a dopamine antagonist might be related to similar actions on dopamine autoreceptors, regulating the dopaminergic hyperactivity that has been postulated in ASD ( Dollfus, 1992 ; Dollfus et al, 1993 ). Although dopaminergic dysfunction in ASD has been widely reported, especially in the midbrain dopaminergic system, the mechanisms are not fully understood ( Pavăl and Miclutia, 2021 ; Mandic-Maravic et al, 2022 ). Interestingly, both dopamine D2 receptor agonists (pramipexole, piribedil) and an antagonist (the antipsychotic drug fluspirilene) were among the drugs showing opposite gene expression perturbations in drug versus ASD at p < 0.1 and interacting with the dopamine D2 receptor gene.…”

Linking autism spectrum disorders and parkinsonism: clinical and genetic association

“…There is also biological plausibility as both conditions may share similar pathophysiologic mechanisms. Both animal and human studies have demonstrated dopaminergic dysregulation in ASD, which is central to the pathogenesis of PD, [8][9][10] Moreover, these studies have identified dopamine receptors to be potential drug targets, though more research must be done to confirm this hypothesis. 8 Despite reports linking ASD with parkinsonian-like features, there has not been a systematic review of the clinical, genetic, and pathophysiologic data on the association between the two conditions.…”

“…There is also biological plausibility as both conditions may share similar pathophysiologic mechanisms. Both animal and human studies have demonstrated dopaminergic dysregulation in ASD, which is central to the pathogenesis of PD, 8 , 9 , 10 Moreover, these studies have identified dopamine receptors to be potential drug targets, though more research must be done to confirm this hypothesis. 8 …”