These messengers then bind to docking-station molecules called receptors. Those receptors relay the signal carried by the neurotransmitter from one cell to its neighbor. Different neurotransmitters are made in different parts of the brain. Two main brain areas produce dopamine. It sits in a region known as the midbrain. Close by is the ventral tegmental area. It, too, makes dopamine. These two brain areas are very thin and tiny. Together they are smaller than a postage stamp.
But the dopamine they produce relays signals that travel throughout the brain. Dopamine from the substantia nigra helps us begin movements and speech. 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. Our study proposes a regulatory axis from gut microbes to neurotransmitter and then to autoimmune hepatitis.
Tissue samples and serum were collected after injecting Con-A for 12 h. Twenty-four hours after the last injection, these mice were injected with Con A with or without A to induce liver damage. Alanine aminotransferase and aspartate aminotransferase in serum were measured by a Chemray Automated Chemistry Analyzer Rayto, Shenzhen, China.
To restore the gut microbiota, antibiotics-treated mice were co-housed with age-matched normal mice for 4 weeks without antibiotics treatment. Cytokines in supernatants were measured by cytometric bead array.
Then, cells were stained with antibodies against intracellular cytokines or cAMP. To measure the dopamine in portal vein, portal venous blood was collected from control or MPTP treated mice. Dopamine standard was used to determine the concentration. Actin was used as an internal control gene. The primer sequences used were as follows:. Cells or tissues were harvested and lysed with sample buffer and boiled for 10 min.
Proteins were separated by electrophoresis and detected by western blot. Error bars represent SEM. Statistical analyses were performed using student's t -test GraphPad Software. Previous studies indicate that large amount of peripheral dopamine is detected in hepatic portal vein 6. To demonstrate the role of dopamine in autoimmune hepatitis, we depleted peripheral dopamine by injecting mice with dopaminergic neuron-specific neurotoxin MPTP MPTP efficiently depleted dopaminergic neurons as indicated by reduced expression of tyrosine hydroxylase, a key enzyme for dopamine biosynthesis, in brains Figure 1A.
It is well-known that iNKT cells are the main mediators in Con A-induced acute autoimmune hepatitis These results demonstrated severer Con A-induced liver injury in MPTP treated mice than in control mice, suggesting a role of dopamine in suppressing autoimmune hepatitis. Figure 1. Depletion of dopaminergic neurons promotes Con A-induced liver injury. E Hematoxylin and eosin staining of liver tissues from mice described in C,D.
CD1d cells. To exclude the possibility that diminished cytokine production was caused by cell death, we measured lactate dehydrogenase release in culture medium.
Lactate dehydrogenase is a cytosolic enzyme and is released into culture medium when the plasma membrane is damaged. In our studies, dopamine did not increase the lactate dehydrogenase in medium, indicating normal cell viability after dopamine treatment Figure S3A.
Figure 2. Data are representative of three independent experiments. To determine which receptor was involved in the suppressive effects of dopamine, selective receptor agonists had been used to activate distinct receptor, respectively. To further prove that dopamine inhibited cytokine production through D1-like receptors, we blocked D1-like receptors with antagonist SCH These results confirmed the specificity of agonist for D1-like receptors.
Taken together, dopamine might inhibit cytokine responses in iNKT cells through D1-like receptors. Figure 3. Dopamine inhibits cytokine production in iNKT cells through D1-like receptors.
Brain was used as positive control. Data are representative of more than three independent experiments. DR, dopamine receptor. These results confirmed suppressive effect of dopamine on iNKT cell functions in vivo. D1-like receptors are coupled to G s , which activates adenylyl cyclase and promotes production of cAMP These results demonstrated that increased intracellular cAMP was responsible for the inhibitory effect of dopamine on iNKT cell functions.
Figure 4. PMA, phorbol myristate acetate; DA, dopamine. These results are consistent with previous findings that iNKT cells are main mediators of Con A-induced liver injury. Therefore, the suppressive effect of A on Con A-induced liver injury is attributed to its inhibitory effect on iNKT cell functions. Figure 5. A inhibits Con A-induced liver injury. D Hematoxylin and eosin staining of liver tissues from mice described in B. Additionally, deficiency of dopamine caused severer liver damage after Con-A injection Figure 1 , which was abrogated by another D1-like receptor agonist A These results further confirmed that the exacerbated liver injury in MPTP mice was due to the insufficient dopamine.
Figure 6. In agreement with previous findings that peripheral dopamine mainly derives from gut 5 , 6 , 27 , much higher level of tyrosine hydroxylase protein was detected in small intestines than in livers Figure 7A. It has been shown that bacteria are able to either influence the production of neurotransmitters or generate many neurotransmitters directly including gamma-aminobutyric acid GABA , norepinephrine NE , and 5-hydroxytryptamine 5HT To investigate the influence of gut microbes on peripheral dopamine synthesis and hepatic iNKT cell functions, we cleared gut microbiota with antibiotic cocktail containing four antibiotics.
Antibiotic cocktail successfully cleared major bacterial groups in feces, and co-housing antibiotics-treated mice with normal mice recovered gut microbiota Figure 7B. Importantly, antibiotics significantly reduced tyrosine hydroxylase at mRNA level and protein level in small intestines, but showed no effect in livers Figures 7C,D. Recovery of gut microbiota in antibiotics-treated mice restored expression of intestinal tyrosine hydroxylase Figures 7C,D. These results indicate that gut microbes promote synthesis of dopamine in guts.
Overall, in agreement with their role in promoting synthesis of peripheral dopamine, gut microbes suppress iNKT cell-mediated liver damage. These results further confirm that reduced dopamine synthesis in microbiota-cleared mice contributed to the severer iNKT cell-mediated liver injury. Figure 7. Gut microbes promote dopamine synthesis in small intestines.
A Expression of TH in livers and in small intestines. B 16S rRNA of four bacterial groups in feces of control mice, antibiotics-treated mice, and antibiotics-treated mice co-housed with normal mice Eubacterium rectale-Clostridium coccoides , Erec; Bacteroides , Bact; mouse intestinal Bacteroides , MIB; Enterobacteriaceae , Ent. Figure 8. Gut microbes inhibit Con A-induced liver injury. Dopamine has been previously shown as an immune modulator.
Distinct effects of dopamine on T cells have been reported, and those are mediated through different subtypes of receptor 29 , Dopamine binds to dopamine receptors. Dopamine is removed from the synaptic space by uptake pumps also called transporters. Please read the Duke Wordpress Policies. Contact the Duke WordPress team. The Pharmacology Education Partnership.
Home About Effectiveness Downloads Contact. Search Search. It's Radical! Content Background: Anatomy of the Dopamine Neuron Neurons are the principal cells of the brain; they comprise a cell body or soma , dendrites and an axon that ends at a terminal see Figure 1.
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