Fig. 4.

Genetic variants and their effects on caffeine dependence. The SLC6A4 gene encodes an integral membrane protein that transports serotonin (5-hydroxytryptpamine, 5-HT) from synaptic spaces into presynaptic neurons. SLC6A4 variant is associated with higher caffeine intake and increased activity in the serotonergic raphe nuclei. Genes encoding the DA D2 receptor (DRD2), DA transporter (DAT) and catechol-O-methyltransferase (COMT) are thought to be responsible for dopaminergic signaling in reward mechanisms implicated in caffeine addiction. DRD2 regulates the expression of dopamine D2 receptors on dopaminergic neurons. DRD2 variants regulate the expression of D2 receptors or their binding potential to DA, leading to higher DA levels and addictive behaviors. Meanwhile, the DAT eliminates DA at synapses and modulates post-synaptic dopaminergic signaling. DAT variants are associated with reduced expression of DAT, resulting in elevated synaptic DA levels and addictive behavior. COMT mediates the expression of COMT which is involved in DA degradation. COMT variants have been associated with higher DA levels and enhanced activation in the regions related to addictive action. Brain-derived neurotrophic factor (BDNF) is a member of growth factors in the neurotrophin family expressed throughout the nervous system. Caffeine consumption promotes the release of BDNF. The released BDNF can bind the TrkB receptor on the dopaminergic neurons, activate its downstream signaling pathway and promote the release of neurotransmitters, including DA, glutamate and serotonin, to enhance addictive behavior. The genes involved in caffeine metabolism, including CYP1A2, ADORA2A, AHR, POR, ABCG2, CYP2A6, PDSS2, HECTD4, and ALDH2 genes, promote caffeine metabolism. Caffeine and its metabolites act as adenosine receptor antagonists to block adenosine receptors, eventually promoting the release of neurotransmitters, including DA, serotonin, and glutamate, and enhancing addictive action