Dopamine (DA) is a monoamine synthesized mainly in neurons of the midbrain cores, ventral tegmental area, and substantia nigra pars compacta. The synthesis of the neurotransmitter takes place in the dopaminergic nerves [1]. Hydroxylation of the amino acid L-tyrosine is the point of regulation of the synthesis of catecholamines, including DA, in the central nervous system (CNS), and consequently, the tyrosine hydroxylase (TH) enzyme is the limiting enzyme of the synthesis of DA, norepinephrine, and adrenaline. Through their receptors, DA has been shown to have physiological functions in the CNS, such as wakefulness, attention, memory formation and consolidation, novelty-induced memory encoding, and reward/addiction ^[2][3][4][5][2,3,4,5]. DA is a neuromodulator that has the ability to diffuse away from the site of its release, activating receptors that are far from the terminal; this ability is called transmission volume [2]. In this sense, DA receptors have been identified in nonneuronal tissues, which has been related to their therapeutic potential in pathologies such as sepsis or septic shock, blood pressure, renal failure, diabetes, and obesity, among others ^[6][7][8][6,7,8]. In addition, it has been reported that DA and dopaminergic drugs such as bromocriptine, cabergoline, pramipexole, and ropinirole have shown anti-inflammatory and antioxidant functions in different kinds of cells, reducing reactive oxygen species (ROS) accumulation, preserving glutathione (GSH) and other antioxidant enzymes, and decreasing lipid peroxidation ^{[9][10][11][12][13][14]}[9,10,11,12,13,14]. Additionally, some herbal compounds have shown dopaminergic properties; for example, Hepad S1, a Korean medicinal herbal combination, is an important source of dopamine with neuroprotective properties that improve Parkinson’s symptoms; it could modulate adverse cellular events such as inflammation and oxidation in neuronal cells [15]. Curcumine has shown neuroprotective properties and is an important component of dopamine [16], and Hordenine, a natural compound of germinated barley, is an agonist of the dopamine D2 receptor [17]. These and other herbs have been mainly studied in neuronal diseases, with less research in nonneuronal diseases.

2. Dopamine Synthesis, Release, Catabolism, and Postsynaptic Action

This section describes DA and its pharmacological properties at the molecular level. The synthesis of DA (Figure 1) begins with the hydroxylation of L-tyrosine by the TH enzyme to generate L-3,4-dihydroxyphenylalanine (L-DOPA); then, aromatic L-amino acid decarboxylase (AADC or DOPA decarboxylase) allows the production of cytosolic dopamine ^[18][19][20][18,19,20]. The DA synthesized in the presynaptic terminal is loaded in synaptic vesicles by vesicular monoamine transporter 2 (VMAT-2); subsequently, DA is released to the synaptic cleft. Next, the Na⁺-dependent dopamine transporter (DAT), localized in neurons and glial cells, reuptakes the neurotransmitter [18]. DA is recycled into synaptic vesicles or degraded by specialized enzymes [21], where its catabolism takes place. In presynaptic terminal and glial cells, the monoamine oxidase (MAO) enzyme, localized in mitochondria, breaks down DA through oxidative deamination, producing 3,4-dihydroxyphenylacetaldehyde (DOPAL); in turn, aldehyde dehydrogenase (ALDH) converts DOPAL to carboxylic acid 3,4-dihydroxyphenylacetic acid (DOPAC) by oxidation, or alcohol dehydrogenase (ADH) reduces DOPAL to 3,4-dihydroxyphenylethanol (DOPET) ^[20][22][20,22]. The catechol O-methyl-transferase (COMT) enzyme, localized in the synaptic cleft, catalyzes the methylation of dopamine to 3-methoxytyramine (3-MT), which is a MAO substrate that forms 3-methoxy-4-hydroxyphenylacetaldehyde (HMPAL). Finally, the ALDH enzyme catalyzes HMPAL to generate homovanillic acid (HVA), which is the main end-product of DA degradation ^[20][22][23][20,22,23]. At the post-synapse, DA binds to D1-like and D2-like receptors, which are G-protein-coupled channels [24]. The D1-like receptor activates the G_αs/olf subunit protein that stimulates the adenylyl cyclase (AC) protein; then, it generates the cyclic adenosine monophosphate (cAMP) second messenger, which activates protein kinase A (PKA), resulting in target action and increasing protein phosphorylation. On the other hand, the D2-like receptor, by activating the G_αi/o subunit, inhibits the effector protein AC, inhibiting the cAMP second messenger and, thereby, PKA, generating a decrease in protein phosphorylation ^{[18][24][25][26]}[18,24,25,26].

3. Chemical Compounds and Drugs Related to the Dopaminergic System

There are more than 200 chemical compounds and drugs related to the dopaminergic system ^[27][28][29][27,28,29], and mentioning each of them is beyond the scope of this discussiwonrk; however, they can be grouped, according to their activity, as precursors ^{[30][31][32][33]}[30,31,32,33], agonists and antagonists of receptors [34], DA reuptake inhibitors ^[35][36][35,36] DA releasing agents ^[36][37][36,37], activity enhancers ^[38][39][40][38,39,40], and enzyme inhibitors [41], among others. Three DA precursors are used in the clinic, L-phenylalanine, L-tyrosine, and L-DOPA; tyrosine is a nonessential amino acid that is synthesized from the essential aromatic amino acid phenylalanine, and both amino acids constitute the two initial steps in the biosynthesis of DA [31]. Levodopa (L-DOPA) is a dopamine precursor and is the most effective and commonly used drug for the treatment of Parkinson’s disease. Levodopa is prescribed in most cases with Carbidopa, which is an inhibitor of L-amino acid decarboxylase, the enzyme that metabolizes levodopa peripherally [42]. DA agonists exert their effects by acting directly on dopamine receptors and mimicking endogenous neurotransmitters. There are two subclasses, ergoline, and nonergoline agonists, with a variable affinity for different DA receptors ^[43][44][43,44]. DA antagonists block the effects of dopamine or its agonists by binding to DA receptors. A variety of DA antagonists are used for the treatment of psychotic disorders; however, their therapeutic effects are mostly due to long-term adjustments rather than acute blockade of DA receptors [29]. Some DA antagonists have been used to treat Tourette’s syndrome or hiccups ^[45][46][45,46], and they have also been used as antiemetics to treat various causes of nausea and vomiting [47]. Table 1 details the mechanisms of action and indications of DA precursors and the most representative dopaminergic agonist and antagonist drugs. On the other hand, DA reuptake inhibitors may be classified as DAT inhibitors and VMAT inhibitors. The former block the action of DAT, and DA reuptake inhibition occurs when extracellular DA, which does not bind to the postsynaptic neuron, is blocked from re-entering the presynaptic neuron, resulting in increased extracellular concentrations of DA and an increase in dopaminergic neurotransmission [80]. DAT inhibitors are indicated for the treatment of attention deficit hyperactivity disorder, major depressive disorder, and seasonal affective disorder and as an aid to smoking cessation; examples are methylphenidate ^[27][29][27,29]. On the other hand, VMAT inhibitors prevent the reuptake and storage of monoamine neurotransmitters in synaptic vesicles, making them vulnerable to metabolism by cytosolic enzymes. Inhibition of VMAT-2 results in decreased reuptake of monoamines and depletion of their reserves in nerve terminals. They are used to treat chorea due to neurodegenerative diseases or dyskinesias due to neuroleptic medications; examples are tetrabenazine, deutetrabenazine, and valbenazine ^{[27][42][81][82][83]}[27,42,81,82,83]. DA-releasing agents are a type of drug that induces, through various mechanisms, the release of DA from the presynaptic neuron into the synaptic cleft, leading to an increase in extracellular concentrations of the neurotransmitter. Examples are amphetamine, lisdexamfetamine (L-lysine-d-amphetamine; vyvanse), methamphetamine, methylenedioxymethamphetamine (MDMA), and 4-methylaminorex ^{[27][84][85][86][87]}[27,84,85,86,87]. Moreover, (-)1-(benzofuran-2-yl)-2-propylaminopentane, (-)BPAP, (-)-1-phenyl-2-propylaminopentane, and (-)PPAP are enhancers of dopamine activity. BPAP and PPAP act as potent stimulants of neurotransmitter release in dopaminergic neurons, leaving MAO activity largely unchanged. BPAP and PPAP controllably increase the quantity of neurotransmitters that are released when a neuron is stimulated by a neighboring neuron, and they are currently in the research phase ^[39][88][89][39,88,89]. DA enzyme inhibitors can be classified into DA synthesis inhibitors and DA degradation inhibitors. There are three kinds of dopamine synthesis inhibitors: (1) TH inhibitors (for example, 3-iodo-tyrosine and metyrosine), which are able to inhibit TH activity, the rate-limiting enzyme in DA biosynthesis [90]; (2) phenylalanine hydroxylase inhibitors (for example, 3,4-dihydroxystyrene), which inhibit the enzyme that converts phenylalanine to tyrosine [91]; and (3) DOPA decarboxylase inhibitors, which block the biosynthesis of L-DOPA to DA. Examples of these inhibitors are benserazide and carbidopa, commonly used in combination with levodopa. Since they can hardly cross the blood–brain barrier, they prevent the formation of dopamine in extracerebral tissues, minimizing the occurrence of extracerebral side effects ^[92][93][92,93]. Finally, the main DA degradation inhibitors can be classified into MAO and COMT inhibitors. The most prescribed MAO inhibitors are selegiline, isocarboxazid, phenelzine, and tranylcypromine. They have in common the ability to block oxidative deamination of DA and subsequently provoke its elevation in brain levels, enhancing dopaminergic activity ^[29][94][29,94]. Selegiline is close structurally to (-) methamphetamine and is a selective and irreversible inhibitor of monoamine oxidase type B (MAO-B). Selegiline is the first catecholaminergic activity-enhancing substance in clinical use that does not continually release catecholamines and is, therefore, free of amphetamine dependence ^[38][40][38,40]. Likewise, the most common COMT inhibitors are entacapone, opicapone, and tolcapone. They inhibit the COMT enzyme and are frequently used in the treatment of Parkinson’s disease as an adjunct to levodopa/carbidopa medication ^[95][96][97][95,96,97]. Many Parkinson’s disease patients treated with levodopa plus carbidopa experience motor complications over time; when COMT inhibitors are administered, plasma levodopa levels are increased and maintained, resulting in more consistent dopaminergic stimulation, leading to further reduction of the manifestations of parkinsonian syndrome [98]. In summary, dopaminergic compounds and drugs act through a variety of mechanisms of action within the process of synthesis, release, catabolism, and postsynaptic action of dopamine, as shown in Figure 2. It should be noted that these main mechanisms are often accompanied by secondary mechanisms (such as antioxidant or anti-inflammatory mechanisms, see below, which are not yet fully understood) that give a wide variety of effects and indications as potential adjuvants in most chronic and degenerative diseases.