Dopamine: Functions, Signaling, and Association with Neurological Diseases

Abstract

The dopaminergic system plays important roles in neuromodulation, such as motor control, motivation, reward, cognitive function, maternal, and reproductive behaviors. Dopamine is a neurotransmitter, synthesized in both central nervous system and the periphery, that exerts its actions upon binding to G protein-coupled receptors. Dopamine receptors are widely expressed in the body and function in both the peripheral and the central nervous systems. Dopaminergic signaling pathways are crucial to the maintenance of physiological processes and an unbalanced activity may lead to dysfunctions that are related to neurodegenerative diseases. Unveiling the neurobiology and the molecular mechanisms that underlie these illnesses may contribute to the development of new therapies that could promote a better quality of life for patients worldwide. In this review, we summarize the aspects of dopamine as a catecholaminergic neurotransmitter and discuss dopamine signaling pathways elicited through dopamine receptor activation in normal brain function. Furthermore, we describe the potential involvement of these signaling pathways in evoking the onset and progression of some diseases in the nervous system, such as Parkinson's, Schizophrenia, Huntington's, Attention Deficit and Hyperactivity Disorder, and Addiction. A brief description of new dopaminergic drugs recently approved and under development treatments for these ailments is also provided.

Keywords: Central nervous system; Dopamine pathway; Neurodegenerative diseases; Neurotransmitter.

Fig. 1

Dopamine synthesis and phasic/tonic transmissions. a Primary metabolic route involving a two-step synthesis. First tyrosine hydroxylase (TH) converts tyrosine to L-DOPA which can then be converted to dopamine. Dopamine is transported from the cytosol by a vesicular monoamine transporter (VMAT2) into synaptic vesicles where it is stored until release into synaptic cleft. Dopamine degradation pathways with Monoamine oxidase (MAO) present in outer mitochondrial membrane. Dopamine receptors are present in both post and presynaptic neurons (including dopamine transporter, DAT). Moreover, there is an association between the presence of atypical levels of DAT and the onset of ADHD. b Dopamine phasic transmission is triggered by action potentials that reach the dopaminergic neuron synapse, resulting in a fast and transient dopamine release in the synaptic cleft due to synchronized burst firing. Tonic transmission occurs by slow and irregular firing in the neuron without presynaptic action potentials, being regulated by the activity of other neurons and neurotransmitter reuptake or degradation. Modified from (Bilder et al. 2004)

Fig. 2

Distribution of dopamine, dopamine receptors, and dopaminergic pathways in central and peripheral systems. a Expression of dopamine and dopamine receptors (D1/D2-like receptors) in the periphery. Dopamine (continuous black arrow) is produced in kidney and gut while dopamine receptors (dashed black arrow) are located mainly in retina, blood vessels, heart, adrenal, and kidney. b Distribution of the four main dopaminergic pathways in the central nervous system. VTA is the source of mesocorticolimbic system: dopaminergic neurons project to cortex via mesocortical pathway (blue) and, to nucleus accumbens via mesolimbic pathway (red). Dopamine neurons in the substantia nigra project to the striatum and form the nigrostriatal pathway (yellow). The tuberoinfundibular pathway (green) is formed by dopaminergic neurons that project from hypothalamic nuclei (arcuate nucleus and periventricular nucleus) to the pituitary

Fig. 3

Dopamine receptor signaling pathways and associated diseases. The main aspects of dopamine signaling and involved disorders discussed in this review are summarized. Dopamine receptors are in the super family of GPCRs associated with different types of G proteins. D1-like (D1 and D5) receptors are associated with Gα_s/olf, whereas D2-like (D2, D3, and D4) are associated with Gα_i/o having DARPP-32 as their main modulator. These receptors also elicit Gα_q, Gβγ, and crosstalk to other pathways such as MAPK-MEK–ERK. Furthermore, under specific conditions, D2 receptors may activate Akt–GSK3 pathway. In HD and Drug Addiction, there is upregulation of dopamine D1 receptors that leads to downstream effects, such as neuronal death. PD is characterized by aggregates of alpha-synuclein that promote inflammation and apoptosis. However, some studies correlated the activation of Akt and ERK signaling pathways to the prevention of dopaminergic neuronal death in PD. The presence of abnormal levels of DAT and the involvement of D4 and D5 dopamine receptors are related to the development of ADHD. In SZ, studies reported the increase of DARPP-32 activity. For all these diseases, the most relevant dopamine signaling pathways are associated with the onset and progression of these illnesses; however, various aspects of the neurobiology still need to be elucidated to promote the development of dopamine-target therapies