When the brain cells that make dopamine in this area start to die off, a person can have trouble initiating movement. Instead, this area usually sends dopamine into the brain when animals including people expect or receive a reward.
That reward might be a delicious slice of pizza or a favorite song. This dopamine release tells the brain that whatever it just experienced is worth getting more of. And that helps animals including people change their behaviors in ways that will help them attain more of the rewarding item or experience. Dopamine also helps with reinforcement — motivating an animal to do something again and again.
Dopamine is what prompts a lab animal, for instance, to repeatedly press a lever to get tasty pellets of food. Reward and reinforcement help us learn where to find important things such as food or water, so that we can go back for more. Dopamine even affects moods. Things that are rewarding tend to make us feel pretty good.
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The pathway to mitochondrial dysfunction begins with oxidative phosphorylation, which produces superoxide radicals, formed by one superoxide anion, one hydroxyl radical, and free radicals FR that come from organic compounds.
Alcoxyl, peroxyl, hydrogen peroxide, and singlet oxygen [ 25 ], are byproducts that are deposited in the mitochondria, thereby making this organelle the main site for the generation of reactive oxygen species ROS within the cell and the first line of defense against oxidative stress [ 26 ].
However, superoxide also functions as a signaling molecule, different from signals mediated by hydrogen peroxide, hydroxyl radicals, or peroxynitrite. This author suggested that superoxide signaling depends on nucleophilic reactions. It is necessary to clarify that an oxidant is an element or compound in an oxidation-reduction redox reaction that accepts an electron from another species. Due to the fact that it gains electrons, a superoxidant is often a molecule that contains many oxygen atoms and offers a high oxidant capacity.
On this basis, it was suggested that inhibitors that block the association of JNKs within the mitochondria might be useful neuroprotective agents for the treatment of PD [ 27 ], and probably dysfunction in the projections of dopaminergic neurons of the nigrostriatal DA pathway from the substantia nigra to the dorsal striatum would slowly lead to PD [ 29 ]. Oxidative stress and hydrogen peroxide H 2 O 2 have been implicated as the underlying factors in the initiation and progression of PD. Increases in endogenous H 2 O 2 in the dorsal striatum attenuated electrically evoked DA release and also decreased basal DA levels [ 30 ].
The degeneration of the nigrostriatal pathway in PD is associated with oxidative stress and oxidized DA [ 31 ]. Selenoprotein P Sepp1 and its receptor, apolipoprotein E receptor 2 apoER2 , account for brain retaining selenium better than other tissues, Sepp1-apoER2 interactions supply selenium for maintenance of brain neurons, to protect the severe neurodegeneration and death in mild selenium deficiency [ 33 ].
PD has a multifactorial mechanism. Oxidative stress and neuroinflammation, including activation of NADPH-dependent oxidases, play a major role in the progression of dopaminergic cell death [ 38 ]. A possible role for DNA repair systems in ageing and neurodegenerative diseases after DNA damage was observed in the brain of individuals affected by neurodegenerative diseases.
In neurodegenerative and cerebrovascular diseases, inflammation is increasingly being recognized as contributing negatively to neurological outcome, with NADPH oxidase as an important source of superoxide.
The activated enzyme complex transports electrons to oxygen, thus producing the superoxide anion , a precursor of reactive oxygen species, and is the advantage of a targeted NADPH oxidase inhibitor that would inhibit the production of superoxide [ 40 ]. Another possible etiology of PD could be due to the loss of serum response factor SRF , which leads to a decrease in the levels of antiapoptotic proteins, brain-derived neurotrophic factor BDNF , and Bcl-2, all of which are considered to be a key cause of increased sensitivity to oxidative stress and dysfunction of the SRF-activating mitogen-associated kinase pathway [ 42 ].
Organs with a reduced capacity for regeneration like the brain are highly affected by inflammation, and neuroinflammation is recognized as a major contributor to epileptogenesis [ 43 ]. Peripheral inflammation provokes brain immune response involving microglial activation, elaboration of proinflammatory cytokines, and reactive oxygen species. Thus, inflammation produces a secondary injury to neurons. A significant part of this response in the brain is mediated by cyclooxygenase COX and COX-2 through downstream proinflammatory prostaglandin PG signaling [ 44 ].
These data suggest that LPS induced proinflammatory gene expression in the hippocampus and isolated adult microglia is decreased by a EP 4 selective agonist. EP 4 agonists significantly reduced levels of proinflammatory cytokines and chemokines in plasma, indicating that the activation of peripheral EP 4 gives protection to the brain against systemic inflammation.
This hypothesis is supported by the work of Kato et al. The central nervous system and dopaminergic neurotransmission are associated with the development of addiction. This assertion is supported by the argument that drugs such as nicotine, cocaine, and amphetamine directly or indirectly increase the mesolimbic DA reward pathway and by the neurobiological theory that the DA pathway is pathologically altered in addicted persons [ 47 ].
Cocaine, nicotine, and amphetamine have both direct and downstream effects on dopaminergic systems. Cocaine affects the HPA axis and brain nuclei responsible for movements. Therefore, any therapeutic strategy for the abuse of these drugs should target the improvement of the efficacy and tolerability of DA transporters and other molecular targets Table 1 in clinical disorders.
Nevertheless, hyperactivation of the RAS has many consequences, among which are the aggravation of NADPH oxidase activity and exacerbation of oxidative stress and the microglial inflammatory response and dopaminergic neuron loss [ 49 ]. DA is the primary neuroendocrine inhibitor of prolactin secretion by the anterior pituitary gland [ 50 ].
The pathway to this inhibitory action begins in the hypothalamic arcuate nucleus, whose neurons produce DA, which is emptied into hypothalamohypophyseal blood vessels of the median eminence, responsible for supplying blood to the anterior pituitary gland, the location of lactotrope cells.
These cells secrete prolactin continuously in the absence of DA. Wang et al. In humans, antipsychotic drugs that have been found to reduce the activities of DA lead to impairments in concentration and reductions in motivation and inability to experience pleasure anhedonia [ 53 ].
The prolonged use of DA has been associated with tardive dyskinesia, an irreversible movement disorder [ 54 ]. Gonadal hormones are greatly affected by antipsychotic drugs. In women, these drugs are associated with low levels of estradiol and progesterone, while, in men, they significantly reduce the levels of testosterone and dehydroepiandrosterone DHEA [ 55 ].
The gynecological effects of antipsychotic drugs in women center on hyperprolactinemia, whose main consequences are amenorrhea, cessation of the normal ovarian cycle, loss of libido, occasional hirsutism, false positive pregnancy tests, and the long-term risk of osteoporosis [ 56 ].
In men, hyperprolactinemia produced by antipsychotics causes gynecomastia, lactation, impotence, loss of libido, and hypospermatogenesis [ 57 ]. Other effects of these drugs include weight gain, drooling, diabetes, sexual dysfunction, dysphoria abnormal depression and discontent , fatigue, heart rhythm problems, stroke, and heart attack [ 56 ].
Many drugs with antidepressant and antipsychotic properties, including drugs of abuse and endogenous chemicals such as DA, are primarily metabolized in the liver by cytochrome P CYPs enzymes. Moreover, this degradation can also occur in extrahepatic organs and the brain. Knowledge of brain CYP-mediated metabolism may help in understanding why patients respond differently to drugs used in psychiatry and may predict the risk for psychiatric disorders, including neurodegenerative diseases and substance abuse [ 59 ].
Wood reported the role of opioid and cannabinoid transmission in the modulation of food palatability and pleasure of food consumption and noted that this pathway is independent of brain DA [ 60 ].
This may explain why food motivation in animals is independent of brain DA concentration. Nevertheless, other consummatory pleasures as feeling or motivating to a person may be more associated with DA. The brain reward system is strongly associated with DA, which functions to provoke feelings of enjoyment and reinforcement, both of which motivate a person to perform certain works.
The release of DA in areas such as the nucleus accumbens and the prefrontal cortex is principally due to rewarding experiences such as food, sex, drugs, and neutral stimuli that are associated with them [ 61 ]. Behavioral activation and effort-related processes are regulated by DA of the mesolimbic area, a critical component of brain circuitry. The principal source of DA in the brain is the dopaminergic neurons of the midbrain.
DA is involved in the control of movement and in error signals for reward prediction, motivation, and cognition [ 61 ]. Schizophrenia, autism, attention deficit hyperactivity disorders, and drug abuse are other pathological disorders that have been associated with DA dysfunction. The firing of dopaminergic neurons has been hypothesized to be motivational as a consequence of reward anticipation. The basis of this hypothesis hinges on the fact that a greater reward than expected leads to an increase in the firing of dopaminergic neurons, which consequently increases desire or motivation towards the reward [ 61 ].
Nevertheless, recent findings have revealed that some dopaminergic neurons react in consonance with the expectations of reward neurons, while others seem to respond to unpredictability. Moreover, the same findings showed a predominance of reward neurons in the ventromedial region of the substantia nigra pars compact and in the ventral tegmental area. Neurons in these areas project mainly to the ventral striatum and thus might transmit value-related information in regard to reward values [ 62 ].
Nonreward neurons are predominant in the dorsolateral area of the substantia nigra pars compacta, which projects to the dorsal striatum and may relate to orienting behavior. Ideas on the role of DA in desire, motivation, and pleasure emanated from studies carried out in animals. Foraging behavior is modulated by DA through the activation of brain systems that register reward upon finding a food source [ 63 ]. Highly palatable food raises DA levels in monkey, but a prolonged presence of this palatable food makes DA levels decline [ 64 ].
DA in the mesolimbic pathway increases general arousal and goal directed behaviors and decreases latent inhibition. These effects augment the creative drive to generate ideas. Thus, creativity is a three-factor model in which the frontal lobes, the temporal lobes, and the mesolimbic DA system [ 65 ] play a part.
Some authors suggest that the frontal cortex and striatum are more sensitive to oxidative burden, which could be related to the parallel monoamine perturbations [ 66 ].
Individuals suffering from schizophrenia display an increase in the activity of the dopaminergic system in the mesolimbic pathway. There is decreased activity in the mesocortical pathway.
Therefore, these two pathways are blamed for the different sets of symptoms in schizophrenia. Antipsychotic drugs act as DA antagonists [ 67 ]. Psychosis and schizophrenia produce highly abnormal dopaminergic transmission. Nevertheless, clinical studies associating schizophrenia with brain DA metabolism have produced controversial or negative results [ 68 ]. The levels of HVA in the cerebrospinal fluid are the same in schizophrenics and controls [ 69 ].
Antipsychotic drugs have an inhibitory effect on DA at the level of the receptors and block the neurochemical effects in a dose-dependent manner.
Typical antipsychotics commonly act on D 2 receptors while they atypically act on D 2 and D 1 , D 3 and D 4 receptors, with a low affinity for DA receptors in general [ 70 ]. Levodopa is a DA precursor used in various forms to treat PD and dopa-responsive dystonia. Other inhibitors that can be coadministered with levodopa use an alternative metabolic route for producing DA involving catechol-O-methyl transferase.
However, oxidative stress and mitochondrial dysfunction can be produced by an increase in endogenous 6-OHDA [ 71 ]. As a theoretical possibility, an increase in endogenous 6-OHDA would trigger the formation of Lewy bodies in dopaminergic neurons and eventually lead to their degeneration. This would ultimately delay the progression of PD [ 72 ]. This bond is naturally cleaved in the plasma and brain. The effects of DA on immune cells depend on their physiological state. DA can activate resting T cells, but it can also inhibit them on being activated [ 74 ].
This chapter could provide a novel insight into our understanding of the biological mechanisms of neurological disorders and a potential explanation that showed perspectives associated with DA deficits in common clinical disorders that have remained in humans through evolution. Amphetamine acts to increase DA concentration in the synaptic gap through a mechanism that is different from that of cocaine.
The structures of amphetamine and methamphetamine are similar to those of DA [ 75 ]. Both have two pathways of entrance into the presynaptic terminal bouton, direct diffusion through the neuronal membrane or uptake via DA transporters [ 76 ].
The main target of many drugs, such as psychostimulants, nootropics, antidepressants, and some recreational drugs including cocaine, is the DAT. Some stimulants increase the concentration of DA in the presynaptic cleft, an increase that gives rise to an excitatory effect when these drugs are consumed [ 77 ]. By increasing the action of the direct pathway in the basal ganglia, DA reduces the effect of the indirect pathway.
Macchi et al. In addition to the above functions, DA also plays an important role in the neurocognitive function of the frontal lobe by controlling the flow of information from the brain. Hence, DA disorders in this region of the brain can cause a decline in neurocognitive functions, especially in memory, attention, and problem-solving.
Moreover, decreased concentrations of DA in the prefrontal cortex are thought to contribute to attention deficit disorder [ 79 ]. Disorders such as schizophrenia and PD are associated with altered immune function and changes in brain DA receptors and DA signaling pathways. L-DOPA, DA agonists, inhibitors of DA metabolism, or brain grafts with cells expressing a high level of TH are possible treatment methods for PD because of their ability to correct or bypass an enzymatic deficiency that is the key characteristic of this disease.
Treatment can also be achieved using agonists with the potential to impact pro- and anti-inflammatory cytokine expression in immune cells at the transcriptional level [ 80 ]. Intrastriatal expression of DA synthesizing enzymes could be a promising approach to gene therapy. The detention or removal of nitrating agents may protect against protein inactivation and limit neuronal injury in PD, thus suggesting the necessity of developing therapeutic agents capable of doing this without interfering with normal neuronal function [ 81 ].
The emergence of a highly interesting new area of nonpharmacological treatment of TH dysfunction has occurred in the past few years. TH normalization could provide neuroprotection in PD patients. These new approaches focus on the use of dietetic therapy or the active constituents of plants and phytomedicines, which are believed to provide protection for people suffering from PD [ 82 ].
Zhang et al. These authors suggest that Akt-signaling pathway disinhibition could provide a valuable strategy to enhance survival, function, and integration of grafted DA neurons within the host striatum and improve survival and integration of different forms of neural grafts.
In the last few years, the identification of the relationship between immune and neurodegenerative diseases has been demonstrated based on the effect of monoclonal antibodies. In fact, clinical trials on PD have shown that transplants of embryonic mesencephalic DA neurons form new functional connections within the host striatum, but the therapeutic benefits have been highly variable.
One obstacle has been poor survival and integration of grafted DA neurons [ 85 ]. This mini review indicates that novel therapies may offer significant improvements and target new mechanisms of neurological disorders. These novel therapeutic strategies involve drugs that act not only on the targets of the dopamine transporter but also on other molecular targets to improve drug efficacy and tolerability and obtain the needed improvements in protein homeostasis to alter the metabolism of DA.
We recommend that further studies be carried out in different animal and human models. The authors declare that there is no conflict of interests regarding the publication of this paper.
This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors.
Read the winning articles. Journal overview. Special Issues. Academic Editor: Anne-Laure Bulteau. Received 10 Jun Revised 21 Jul Accepted 26 Aug Published 06 Dec Abstract Dopamine is a neurotransmitter that is produced in the substantia nigra, ventral tegmental area, and hypothalamus of the brain.
Introduction to Dopamine Dopamine DA plays a vital role in reward and movement regulation in the brain. It worked. The rabbits recovered. Instead, Carlsson found the brains awash in dopamine. After developing a new technique to measure dopamine, Carlsson and his colleagues discovered that an area of the rabbit brain called the striatum housed high concentrations of dopamine under normal conditions despite the fact that it had very little norepinephrine. It was a radical idea — it went against the prevailing theory of electrical neural transmission in the brain and suggested that some brain cells used dopamine to communicate.
Soon after Carlsson published his seminal papers in and , other researchers reported the presence of large quantities of dopamine in the basal ganglia of normal human brains.
Patients who had been immobile and bedridden not only sat up, but could stand and walk. Some even ran and jumped. The drug also allowed some patients to speak normally for the first time in years.
Unfortunately, treatment with L-dopa frequently caused severe nausea and vomiting, limiting its practical use. In , the U. However, L-dopa is not a cure. Almost half a century later, the drug remains the most common and effective treatment of the disease.
The s saw an explosion of dopamine research as scientists tried to understand exactly how it exerts its influence in the nervous system.
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