Dopamine Structure, Function, Physiology, and Dysfunction
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Dopamine is a neurotransmitter, a monoamine that modulates many centrally controlled functions, including motor control, and psychological and physiological states such as emotion, cognition, and neuroendocrine function. It is intimately associated with the ability to experience pleasure and a sense of motivation, and reward.
Dopamine receptors belong to the 7 transmembrane, G protein-coupled receptor family (GPCRs). There are five receptor subtypes, D1-D5, distinguished by the different second messengers they couple to. The function and signaling of dopamine depends on the effect exerted by the type of receptor it binds. D1 and D5 form the stimulatory D1-like dopamine receptor family, and D2, D3, and D4 receptor subtypes the inhibitory D2-like family of receptors.
Synthesis and Metabolism
Dopamine (DA), a catecholamine, produced in the brain and periphery has a catechol nucleus, i.e., a benzene ring with two hydroxyl side chains, and a single amine group linked by an ethyl chain (Figure 1). Dopamine is synthesized from the aromatic amino acid precursor tyrosine, which is converted to l-3,4-dihydroxyphenylalanine (L-DOPA) by the addition of a hydroxyl group in a reaction catalyzed by tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. Further enzymatic processing by aromatic amino acid decarboxylase, decarboxylates L-DOPA to produce dopamine.
Dopamine is enzymatically degraded by two enzymes, monoamine oxidase (MAO) followed by catchecol-O-methyl transferase (COMT) to yield homovanillic acid (HVA). However, in certain adrenergic and adrenomedullary chromaffin cells, it is processed to noradrenaline by the enzyme dopamine beta hydroxylase.
Dopamine signals are essentially mediated by five receptors D1-D5, that are encoded by DRD1-DRD5 genes in humans. The receptors belong to and are structurally homologous to the G-protein coupled receptor (GPCR) superfamily, and contain the requisite seven-transmembrane domains. They are further categorized as D1-like receptors (D1 and D5) or D2-like receptors (D2, D3, D4) - referred to below as D1 or D2 receptors - based on their coupling to Gs/olf or Gi/o, respectively. D1 receptors stimulate adenylyl cyclase, triggering the production of second messenger, 3',5'-cyclic adenosine monophosphate (cAMP) that regulates protein kinase A (PKA) activity, whereas the D2 receptors have the opposite effect. Alternative splicing generates two isoforms of the D2 receptor, D2-short (D2s) and D2-long (D2L), respectively, and confers different properties that influence its signaling and pharmacology. The intracellular cAPM-PKA signaling cascades engenders all sorts of modifications of targets that include ion channels, receptors, and carries further to the molecular level. Dopamine has also been demonstrated to signal via non-G-protein mechanisms. All these differences in signaling are consequential for selecting the most effective therapeutic intervention to address disorders related to the dopaminergic system.
The binding affinity of D1 receptors is 10 to 100-fold lower than D2 receptors. The difference in affinity takes on significance as different temporal patterns of release and relative extracellular concentration of dopamine engage differently with D1 or D2 receptors. With their lower-affinity, D1 receptors are considered to activate in response to phasic dopamine signals in the micromolar range, whereas higher-affinity, D2 receptors respond to nanomolar, tonic levels. This has recently been called into question under models of normal physiological conditions, taking into account the kinetics of and relative abundance of the two, and showing both receptor subtypes respond equally to either phasic or tonic scenarios owing fundamentally to their slower unbinding of dopamine. The striatal phasic release of dopamine has been shown to be associated with reward prediction, i.e., the value of future rewards, however the tonic activity is observed to scale in response to the continually changing value of the reward.
The dopamine receptor regulation of cAMP impacts PKA and the downstream phosphorylation states of its many substrates. Regions of the brain involved in dopamine neurotransmission including, the striatum and nucleus accumbens likewise receive numerous inputs from other pathways and neurochemical signaling systems. The integration of these convergent inputs requires the activity of intracellular dopamine- and cAMP-regulated phosphoprotein (DARPP-32), which has been documented to be essential for evaluating and mounting a behavioral response to incoming stimuli. PKA phosphorylation of DARPP-32 leads to inhibition of protein phosphatase-1 (PP-1), conversely its phosphorylation by cyclin-dependent kinase 5 (CDK5) leads to inhibition of PKA activity. The phosphorylation state of DARPP-32 has implications for behaviors associated with movement, and the reward and motivational systems regulated by dopamine. This consequence of dopamine neurotransmission on the physiological state of DAARPP-32 has ramifications for appropriate signal integration and function in response to afferents, interventional pharmacological agents, and abused drugs.
In the striatum, the GABAergic medium spiny neuron's (MSN) integrate converging glutamatergic and other excitatory cortical and thalamic signals. These gabaergic neurons in turn project to the basal ganglia output nuclei that feed into the thalamocortical circuit to complete the loop. The D1 receptors on MSNs forms a portion of the 'direct' pathway in the basal ganglia that mediates excitatory neurotransmission, facilitating activity in the descending motor pathways. D1 receptors interact with glutamate receptors at the level of the MSN to induce long-term potentiation (LTP). In contrast, the input from the MSN D2 receptors of the 'indirect' pathway functions in the opposite manner and depresses the activity of this circuit, and inducing long-term depression (LTD) at glutamatergic synapses. The function of these two pathways and the opposing activity related to the MSN D1 and D2 receptors is functionally consequential.
Dopamine Anatomy and Pathways
There are four dopaminergic pathways, each representing a set of neuronal projections that secrete dopamine (Figure 2). The substantia nigra pars compacta (SNc), is the dopamine-synthesizing region in the midbrain and is considered to be one of the nuclei of the striatum. The dopamine projections of the nigrostriatal pathway, the most substantial dopamine pathway, extend to the caudate and putamen of the basal ganglia. This pathway is vital for proper motor control, and if disturbed leads to degeneration in movement control and planning, resulting in stiffness, akinesia, and tremors. The mesocortical pathway, originates in the midbrain, ventral tegmental area (VTA), and involves dopaminergic innervation of several regions of the prefrontal cortex, and contributes to cognitive and executive function, including working memory and decision making. The mesolimbic pathway originates in the VTA and projects to the nucleus accumbens, forming part of the circuitry involving the amygdala, hippocampus, and the bed nucleus of the stria terminalis. This pathway is responsible for mediating pleasure and reward sensations, and motivation. This pathway innervates the olfactory tubercles, the ventral striatum, and parts of the limbic system. The release of dopamine also plays a role in the mammary system, where it inhibits the release of the hormone prolactin. This is a result of the tuberoinfundibular pathway projections arising from the periventricular and arcuate nuclei of the hypothalamus that project to the infundibular, median eminence. The release of dopamine into the capillaries of the hypothalamic-pituitary portal system, acts on the lactotrophs to inhibit prolactin release, disrupting milk production.
Dopamine and Movement
Various studies have elucidated the role of dopamine on movement which is mediated largely by the nigrostriatal pathway. Dopamine regulates movement by modulating the direct and indirect circuits of the basal ganglia involved in motor control. It accomplishes this by differential activation of excitatory, low-threshold D1 and the inhibitory, high-threshold D2 striatal receptors, respectively. The net effect of dopamine in the nigrostriatal projection is to facilitate movement. Dopamine receptor agonists have been shown to increase motor activity and antagonists decrease activity.
Studies on administering dopamine receptor agonist, Cabergoline, to healthy volunteers have shown that prolonged exposure recruits D1 receptors at low doses that demutes muscle tone, and shorter, high concentration exposure of D2 receptors increase muscle contractions due to heightened excitability of the motor cortex. Movement results as the agonist/antagonist muscle pairs work in concert with the rising dopamine levels that are detected prior to movement. The D1 receptors activate at lower concentrations and decrease the muscle tone of the antagonistic muscle, which eases the D2 receptor mediated contraction of the agonist muscles that follow as the dopamine concentration rises further.
Several studies have tested dopamine function based on the administration of dopamine receptor modulators in test animals. Administration of low doses of D2 receptor antagonist can stimulate pre-synaptic receptors leading to decreased locomotor function. Administration of D1 and D2 receptor antagonist injection simultaneously has a synergistic effect that causes the test animals to become cataleptic. In animal studies, dopamine regulated motor functions such as rearing, sniffing, catalepsy, and forward locomotion by binding to the five receptors.
Dopamine and Mental Function
Several well-established clinical testing protocols for dopamine are published in the U.S. National Library of Medicine. The normal value of dopamine in the urine is 65 to 400 mcg/24 hours. The dopamine signal correlates with the rewarding effects of drugs, including cocaine, and these stimulants affect genes that increase dopamine sensitivity. Dopamine modulates the circadian rhythm of certain brain areas, including the hypothalamus, striatum, and midbrain. Dopaminergic projections from the VTA and substantia nigra in the mesocortical and mesolimbic and nigrostriatal pathways respectively, underpin the circadian rhythm of mood. A study examined the effect of dopamine on circadian rhythms in healthy and cocaine-addicted adults, aged 21-55 years. Their medical history and physical condition was checked, urine, blood tests, and PET scans were conducted. The rest-activity rhythms were shown to be directly associated with higher D1 receptors. Preference for late evening’s is positively correlated with D1 receptor availability in the caudate, and a more rewarding experience in response to the psychostimulant methylphenidate. Higher D2/D3 receptors in the nucleus accumbens are associated with physical inactivity and increased sensitivity to the drug. These findings highlight how drug effects relate to circadian rhythms and offer strategies to combat drug addiction.
Other studies aim to assess the effects of dopamine release on depression. Clinical trials of depressed subjects given an oral treatment of dopamine D2 receptor agonist, pramipexole, demonstrated improved reward learning ability. Depressed individuals with the greatest deficits in dopamine release and D2/D3 receptor availability in the ventrolateral striatum prior to treatment, fared better post-treatment. The Hamilton Rating Scale for Depression (HRSD), a widely used clinical tool measured the severity of depression. Another study showed that after weeks of antidepressant treatment there was impaired reward learning in patients with anhedonia and persistence of major depressive disorder (MDD) among those with prior compromised ability to learn from rewards. MDD subjects showed a trend for higher dopamine-releasing capacity in the ventral striatum. However, the availability of D2/D3 receptors did not change significantly impeding dopamine’s influence on the clinical features of depression, and response to the antidepressant and reward prediction error. These results need further investigation due to conflicting findings, concerning the amelioration of MDD symptoms by the dopamine agonist.
Dopamine has been studied intensively for various pathological conditions. Neuropsychiatric and neurological diseases such as addiction, depression, bipolar disorders, schizophrenia, and Parkinson’s disease have been known to result from an imbalance in dopamine neurotransmission. Therefore, the majority of the conventional antipsychotic drugs target the dopaminergic system.
Parkinson's disease is the most studied dopamine-related pathological condition. There are an estimated 1 million cases of this neurodegenerative disease in the United States. Parkinson’s disease is chronic and results from the progressive degeneration of the ventral midbrain substantia nigra dopamine neurons. These neurons project to the basal ganglia where dopamine release is crucial for well-coordinated, smooth muscle movements. The increasing loss of dopamine manifests with distinctive motor symptom’s such as rigidity, resting tremors, bradykinesia, which is a slowness of spontaneous moments, and loss of coordination and balance. Patients with Parkinson's disease may exhibit higher impulsive tendencies such as hypersexuality, pathological gambling among others.
There is no cure for Parkinson’s disease. The symptoms are controlled by a combination of Levodopa-Carbidopa that serve to replenish dopamine in the brain. The dopamine precursor L-DOPA crosses the blood brain barrier and is converted to dopamine, often with dramatic improvements in motor symptoms. The aromatic amino acid decarboxylase inhibitor, prolongs the effectiveness of L-DOPA by curtailing its conversion to dopamine externally in the plasma, allowing more to traverse the barrier and gain entry to the brain.
Although Parkinson’s disease is primarily a consequence of dopamine imbalance, this imbalance impacts neurotransmission of striatal circuits, namely NMDA mediated corticostriatal glutamatergic inputs, and GABAergic signaling. The excitatory tone of glutamatergic transmission observed in Parkinson’s disease is alleviated by administration of NMDA receptor antagonists in conjunction with L-DOPA, providing symptom relief.
Pathological conditions related to dopamine are influenced by interactions between dopamine receptors and other cell surface receptors. Heteromeric complexes of dopamine D1 and adenosine A1 receptors expressed by striatal neurons of the direct pathway have a functionally antagonistic relationship. Adenosine A1 receptor agonists impair the efficiency of the dopamine D1 receptor’s which could have implications for Parkinson's disease. Similarly, antagonists of the adenosine A2 receptors that complex with D2 receptors of the indirect striatopallidal pathway ameliorate motor activity owing to increased dopamine transmission. Therefore, adenosine receptors present attractive targets for Parkinson’s treatment without the side effects, like dyskinesia associated with L-DOPA therapy.
The history of schizophrenia has been inextricably linked with dopamine. Since the early 1950’s and 1960’s, investigations into the mechanism of action of antipsychotic drugs was discovered to involve antagonism of D2 dopamine receptors. Antipsychotic drugs are clinically effective because of their affinity for dopamine receptors. The antipsychotic agents were shown to display clinical potency in line with the D2 receptor binding affinity, evidence of D2 receptor being targeted. The dopamine hypotheses of schizophrenia postulated an underlying increase in dopamine neurotransmission, perpetrated by heightened dopamine synthesis, release, and augmented receptor sensitivity. Further evidence in favor of the dopamine hypothesis came from a review of the amassed literature revealing that the psychotic symptoms of schizophrenic patients were exacerbated by low levels of dopamine agonists, a feature of the sensitivity of dopaminergic neurotransmission.
The etiology of schizophrenia involves dopamine receptor dysfunction that is responsible for the observed hypersensitivity of this signaling system. A recent, small clinical study showed that striatal D2 receptor dimerization was increased more than twofold in schizophrenic patients. Another smaller study demonstrated greater heteromerization of presynaptic D1 and D2 receptors in the globus pallidus of schizophrenic patients, indications of elevated dopamine neurotransmission. It has to be noted that schizophrenia and therapeutic interventions involves multiple areas and neurotransmitter systems.
Our understanding over decades has led to the reformulation of the dopamine hypothesis reviewed in Kesby, at al. The renewed construct posits dopaminergic hyperactivity in subcortical pathways, including the mesolimbic projections to the nucleus accumbens, which would account for the positive symptoms of hallucinations and delusions experienced by people with schizophrenia, and increased activity in the hippocampus important for episodic memory; a reduction in prefrontal cortex dopaminergic activity is now considered to be associated with the negative symptoms related to the cognitive, memory and executive function deficits.
The first generation antipsychotic drugs such as haloperidol acting predominantly through the dopaminergic system cause extreme side effects of extrapyramidal symptoms and tardive dyskinesia; the later developed second generation drugs such as clozapine, additionally recruit the serotonergic system resulting in a better side-effect profile.
Dopamine in the Periphery
In addition to its conventional role in the central nervous system signaling , evidence is mounting for the role of dopamine in the periphery, where it is known to be released and dopamine receptors are known to be widely expressed in different cell types. Dopamine is involved in endocrine and cardiovascular function, and has effects on the kidneys and the gastrointestinal tract. Polymorphisms of the DRD2 gene encoding the D2 receptor are associated with the risk of inflammatory bowel disease. The periphery has a higher concentration of dopamine than the central nervous system, and there is a growing body of evidence to suggest that this also has an impact centrally.
Dopamine is known to modulate the immune system, especially by acting on T cells. This has an influence on the neurodegeneration observed in Parkinson's disease. Furthermore, D3 and D5 receptors can regulate T lymphocyte activation through activation of the mitogen-activated protein kinase (MAPK) pathway and the regulation of cAMP levels. This affects the immune response in various diseases.
Extensive studies are still ongoing to reveal more detailed and definitive mechanisms regarding the role of dopamine in various diseases and disorders. In light of the widespread actions of dopamine, it is crucial to gain an understanding of the interaction between central and peripheral dopaminergic systems. Safer deployment of drugs for treating dopamine related disorders entails characterizing the mechanisms at play both centrally and peripherally.
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- ↑ Perreault, Melissa L.; Hasbi, Ahmed; Alijaniaram, Mohammed; Fan, Theresa; Varghese, George; Fletcher, Paul J.; Seeman, Philip; O'Dowd, Brian F.; George, Susan R. (2010). "The Dopamine D1-D2 Receptor Heteromer Localizes in Dynorphin/Enkephalin Neurons". Journal of Biological Chemistry. 285 (47): 36625–36634. doi:10.1074/jbc.M110.159954. PMC 2978591. PMID 20864528.CS1 maint: PMC format (link)
- ↑ Martel, Jean Claude; Gatti McArthur, Silvia (2020). "Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia". Frontiers in Pharmacology. 11: 1003. doi:10.3389/fphar.2020.01003. ISSN 1663-9812. PMC 7379027. PMID 32765257.CS1 maint: PMC format (link)
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- ↑ Magro, F.; Cunha, E.; Araujo, F.; Meireles, E.; Pereira, P.; Dinis-Ribeiro, M.; Veloso, F. Tavarela; Medeiros, R.; Soares-da-Silva, P. (2006). "Dopamine D2 Receptor Polymorphisms in Inflammatory Bowel Disease and the Refractory Response to Treatment". Digestive Diseases and Sciences. 51 (11): 2039–2044. doi:10.1007/s10620-006-9168-3. ISSN 0163-2116.
- ↑ Sarkar, Chandrani; Basu, Biswarup; Chakroborty, Debanjan; Dasgupta, Partha Sarthi; Basu, Sujit (2010). "The immunoregulatory role of dopamine: An update". Brain, Behavior, and Immunity. 24 (4): 525–528. doi:10.1016/j.bbi.2009.10.015. PMC 2856781. PMID 19896530.CS1 maint: PMC format (link)
- ↑ Franz, Dafne; Contreras, Francisco; González, Hugo; Prado, Carolina; Elgueta, Daniela; Figueroa, Claudio; Pacheco, Rodrigo (2015). "Dopamine receptors D3 and D5 regulate CD4+T-cell activation and differentiation by modulating ERK activation and cAMP production". Journal of Neuroimmunology. 284: 18–29. doi:10.1016/j.jneuroim.2015.05.003.