Underlying Susceptibility to Eating Disorders and Drug Abuse: Genetic and Pharmacological Aspects of Dopamine D4 Receptors

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.

Dopamine in Health and Disease: Much More Than a Neurotransmitter

“…Splice variants are mainly described for the D 2 and the D 4 receptors; importantly, other gene polymorphisms described for all five receptors, including single nucleotide polymorphism, may be associated with a variety of addictions (drugs, alcohol, etc.) and obesity [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]; other non-dopamine-receptor-related factors also influence addictive behaviors.…”

“…Both imbalances in dopamine neurotransmission and alterations of brain circuits where dopamine is a key factor are involved in a variety of neurological and neuropsychiatric diseases, from alcohol/drug addiction to schizophrenia [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 59 , 60 , 61 , 62 ]. In fact, typical antipsychotics act “almost exclusively on the dopamine system” [ 63 ].…”

Obesity and Related Type 2 Diabetes: A Failure of the Autonomic Nervous System Controlling Gastrointestinal Function?

“…Regarding the ligands of the D1 and D2 receptors (agonists, antagonists, and partial agonists), selective compounds with new pharmacological targets in relation to the interactions with the dopamine-glutamate systems have been experimented in different diseases; this may lead to the discovery of a drug suitable for addressing the complexity of dopamine receptors' hetero-complexes in native systems using multiple intra-cell markers and benefiting from more selective tools available for studying the dopamine receptors [125]. In particular, the DRD4 receptor, which is part of the D2-like family, has a predominant expression in the prefrontal cortex (PFC), a brain area closely involved in the modulation of reward processes related to both food and drug consumption [126]. Several human studies have revealed a possible involvement of DRD4 in eating disorders and obesity [126].…”

“…In particular, the DRD4 receptor, which is part of the D2-like family, has a predominant expression in the prefrontal cortex (PFC), a brain area closely involved in the modulation of reward processes related to both food and drug consumption [126]. Several human studies have revealed a possible involvement of DRD4 in eating disorders and obesity [126]. Hence, DRD4 is an important pharmacological target to be explored for innovative selective drugs in the treatment of addictive disturbances such as eating disorders and related comorbidities [126].…”

“…Several human studies have revealed a possible involvement of DRD4 in eating disorders and obesity [126]. Hence, DRD4 is an important pharmacological target to be explored for innovative selective drugs in the treatment of addictive disturbances such as eating disorders and related comorbidities [126].…”