Cellular and Molecular Neurobiology (2019) 39:31–59 https://doi.org/10.1007/s10571-018-0632-3 REVIEW PAPER Dopamine: Functions, Signaling, and Association with Neurological Diseases Marianne O. Klein1 · Daniella S. Battagello1 · Ariel R. Cardoso1 · David N. Hauser2 · Jackson C. Bittencourt1,3 · Ricardo G. Correa2 Received: 21 August 2018 / Accepted: 2 November 2018 / Published online: 16 November 2018 © Springer Science+Business Media, LLC, part of Springer Nature 2018 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 sys- tem 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 descrip- tion of new dopaminergic drugs recently approved and under development treatments for these ailments is also provided. Keywords Dopamine pathway · Neurotransmitter · Central nervous system · Neurodegenerative diseases Abbreviations CDK5 Cyclin-dependent kinase 5 AD Alzheimer’s disease CK1 Casein kinase 1 ADHD Attention deficit/hyperactivity disorder CK2 Casein kinase 2 ALDH Aldehyde dehydrogenase COMT Catechol-O-methyl transferase BDNF Brain-derived neurotropic factor CREB cAMP Response element-binding protein CaMKII Calcium/calmodulin-dependent kinase II CSF Cerebral spinal fluid cAMP Cyclic 3,5 adenine-monophosphate DAG Diacylglycerol DARPP-32 cAMP-Regulated phosphoprotein 32-kDa Marianne O. Klein and Daniella S. Battagello have contributed DAT Dopamine transporter equally to the work. DJ-1 PARK7 (Parkinson disease protein 7) DOPAC 3,4-Dihydroxyphenylacetic acid * Jackson C. Bittencourt DOPAL 3,4-Dihydroxyphenylaldehyde [email protected] ELKs Glutamine, leucine, lysine, and serine-rich * Ricardo G. Correa protein [email protected] ERK Extracellular-signal regulated kinases 1 Laboratory of Chemical Neuroanatomy, Department FDA US Food and Drug Administration of Anatomy, Institute of Biomedical Sciences, University GABA γ-Amino butyric acid of São Paulo (USP), São Paulo 05508-000, Brazil GIRK G protein inwardly rectifying potassium 2 Center for Translational Neuroscience, Sanford Burnham channel Prebys (SBP) Medical Discovery Institute, 10901 North GPCR G protein-coupled receptor Torrey Pines Rd., La Jolla, CA 92037, USA GRK G protein-coupled receptor kinase 3 Center for Neuroscience and Behavior, Institute GSK3 Glycogen synthase kinase 3 of Psychology, USP, São Paulo, Brazil Vol.:(0123456789)1 3 32 Cellular and Molecular Neurobiology (2019) 39:31–59 GSTM2 Glutathione transferase and sympathetic nervous systems (Loewi 1921; Dale 1935, GTP Guanosine triphosphate 1937; von Euler 1946). Subsequently, the physiological roles HVA Homovanillic acid of another chemical transmitter, dopamine, were described HD Huntington’s disease by Carlsson et al. (1957). Chemical transmitters such as HTT Huntingtin gene acetylcholine and dopamine belong to a class of molecules IGF Insulin growth factor termed neurotransmitters that are the primary mode of cell- IP3 Inositol trisphosphate to-cell communication in the nervous system and associated JNK c-Jun kinase with many diseases. L-DOPA Levodopa Typically, neurotransmitters are synthesized endoge- LB Lewy bodies nously and act as signaling molecules (Wurtman et al. 1980). LRRK2 Leucine-rich repeat kinase 2 Neurotransmitters are stored in vesicles in presynaptic ter- MAPK Mitogen-activated protein kinase minals and released into the synaptic cleft in response to an MAPT Microtubule-associated protein action potential or after a graded potential threshold is met MAT Monoamine transporter (Kanner and Schuldiner 1987; Attwell et al. 1993; Steinhardt MAO Monoamine oxidase et al. 1994). Once released, they can elicit a physiological mTORC2 mTOR complex 2 response in postsynaptic or nearby cells. In general, neuro- NAc Nucleus accumbens transmission occurs quickly and the compound is rapidly NET Norepinephrine transporter (i) metabolized by enzymes (Kanner and Schuldiner 1987), NMDA Glutamate N-methyl-D-aspartate (ii) taken back up by presynaptic neuron (Iversen 1971), or Parkin PRKN (iii) bound to postsynaptic neurons or target cells’ receptors PD Parkinson’s disease (Garris et al. 1994). PDPK1 Phosphatidylinositol-dependent kinase 1 Many compounds are released by cells, but bona fide neu- PIP2 Phosphatidylinositol-2-phosphate rotransmitters must meet a distinct set of criteria (Sourkes PIP3 Phosphatidylinositol-3-phosphate 2009): (i) the compound should be synthesized in presyn- PKA Protein kinase A aptic neurons; (ii) when the presynaptic neuron is activated, PKC Protein kinase C the release of this compound should lead to an effect on PLC Phospholipase C postsynaptic neuron(s) or target cell(s); (iii) when adminis- PP1 Protein phosphatase 1 tered exogenously, similar outcomes to endogenous stimula- PP2A Protein phosphatase 2A tion would occur; and (iv) a mechanism of neurotransmitter PP2B Protein phosphatase 2B removal, from synaptic cleft after signaling, should be in RGS Regulators of G protein signaling place. RIM Rab3a-interacting molecule Neurotransmitters can be subdivided according to their ROS Reactive oxygen species molecular identity: small organic molecules, peptides, mon- RTK Receptor tyrosine kinase oamines, nucleotides, and amino acids (Kandel et al. 2013). SNCA α-Synuclein A functional classification may also be utilized, since these STEP Striatal-enriched tyrosine phosphatase molecules can act as excitatory or inhibitory transmitters SZ Schizophrenia and can also bind to fast response ionotropic receptors or TAAR​ Trace amine-associated receptors slower response metabotropic receptors (Kandel et al. 2013). VMAT2 Vesicular monoamine transporter For instance, glutamate-containing synapses are mainly fast VTA Ventral tegmental area excitatory and frequently observed in memory storage ele- ments (Dingledine et al. 1999). In contrast, γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in Background the central nervous system (CNS) and binds to ionotropic (GABAA) and metabotropic (GABAB) receptors (Werhahn Initially, studies on neural cell communication focused et al. 1999). Acetylcholine is the neurotransmitter that sig- exclusively on electrophysiological aspects but, in the begin- nals from neuron to muscle at the neuromuscular junction, ning of twentieth century, scientists such as John N. Lang- and is also present in many brain regions where it binds to ley and Thomas R. Elliot introduced the concept of chemi- muscarinic (metabotropic) or nicotinic (ionotropic) receptors cal release upon nerve stimulation (Elliott 1905; Sourkes (Fambrough et al. 1973; Whitehouse et al. 1986; Jones et al. 2009; Starke 2014). These ideas were confirmed later by 2012). Recently, a number of reports have indicated that the work of Otto Loewi, Henry Dale, Ulf von Euler, and neuron terminals can co-release different neurotransmitters others, who demonstrated that acetylcholine and adrena- which may present synergistic functions (Bartfai et al. 1988; line acted as chemical transmitters in the parasympathetic Hnasko and Edwards 2012). 1 3 Cellular and Molecular Neurobiology (2019) 39:31–59 33 The monoamine transmitters share many biochemical the primary metabolic route involves a two-step synthesis in characteristics, i.e., they are small charged molecules, nor- the cytosol. Tyrosine hydroxylase (the rate-limiting enzyme) mally cannot cross the blood–brain barrier (Kortekaas et al. converts tyrosine to levodopa (L-DOPA) using tetrahydrobi- 2+ 2005), synthesized from amino acids by short metabolic opterin, oxygen (O 2), and iron (Fe ) as cofactors. L-DOPA routes and regulated by one rate-limiting enzymatic reaction can then be converted to dopamine by aromatic L-amino (Stahl 1985). In general, monoamine neurotransmitters exert acid decarboxylase (DOPA decarboxylase), having pyridoxal their actions on neuronal circuitry by binding to metabo- phosphate as a cofactor (Christenson et al. 1970). A minor tropic receptors, and have a slower modulation compared synthesis pathway may also occur, in which p-tyramine can to the fast neurotransmission mediated by glutamate and be converted to dopamine through Cytochrome P450 2D6 GABA (Beaulieu and Gainetdinov 2011), with the excep- activity in the substantia nigra (Bromek et al. 2011; Fergu- tion of serotonin which can also bind to ionotropic receptors son and Tyndale 2011). Following synthesis in dopaminergic (MacDermott et al. 1999; Lee et al. 2010).