Abstract
The dopamine D4 receptor (DRD4) has a predominant expression in the prefrontal cortex (PFC), brain area strictly involved in the modulation of reward processes related to both food and drug consumption. Additionally, the human DRD4 gene is characterized by a variable number of tandem repeats (VNTR) in the exon 3 and, among the polymorphic variants, the 7-repeat (7R) allele appears as a contributing factor in the neurobiological mechanisms underlying drug abuse, aberrant eating behaviors and related comorbidities. The 7R variant encodes for a receptor with a blunted intracellular response to dopamine, and carriers of this polymorphism might be more tempted to enhance dopamine levels in the brain, through the overconsumption of drugs of abuse or palatable food, considering their reinforcing properties. Moreover, the presence of this polymorphism seems to increase the susceptibility of individuals to engage maladaptive eating patterns in response to negative environmental stimuli. This review is focused on the role of DRD4 and DRD4 genetic polymorphism in these neuropsychiatric disorders in both clinical and preclinical studies. However, further research is needed to better clarify the complex DRD4 role, by using validated preclinical models and novel compounds more selective for DRD4.
Highlights
Dopamine (DA) is a catecholamine neurotransmitter expressed both in the mammalian central nervous system (CNS) and in a variety of peripheral tissues
The significant role of the DRD4 as a modulator of the neural network activity was confirmed by studies using mice lacking the DRD4, which demonstrated an increased cortical hyperexcitability in the frontal cortex [55] and hypervigilant state and abnormal behavioral responses to environmental stimuli compared to wild-type mice (WT) [56]
The prefrontal cortex (PFC) circuitry is linked with cognitive aspects of searching for food [155], self-control, salience attribution and awareness [156], reward-based decision-making [66], and a dysregulation of such circuit might lead to the development of obesity [157,158,159,160]
Summary
Dopamine (DA) is a catecholamine neurotransmitter expressed both in the mammalian central nervous system (CNS) and in a variety of peripheral tissues. The PFC is a brain region associated with executive functions, such as working memory, novelty seeking and emotional processes [49,50]; the DRD4s are positioned on inhibitory GABAergic interneurons and on excitatory glutamatergic pyramidal neurons, including the striatal projections [51,52,53] This localization is an important evidence of DRD4 ability to modulate GABAergic neurotransmission [43]. The significant role of the DRD4 as a modulator of the neural network activity was confirmed by studies using mice lacking the DRD4, which demonstrated an increased cortical hyperexcitability in the frontal cortex [55] and hypervigilant state and abnormal behavioral responses to environmental stimuli compared to wild-type mice (WT) [56] These findings suggest that DRD4 has a critical role in the regulation of neurotransmission at the level of frontocortical areas of the brain and the dysregulation of dopamine DRD4-mediated signaling might be responsible of several pathological neuropsychiatric conditions
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