The importance of norepinephrine in depression
Anatomical studies have established the existence of reciprocal relationships between the main population of monoamine, serotonin (5-HT), norepinephrine. Neurotransmitters like dopamine and serotonin cannot cross the blood-brain barrier in these regions results in cognitive impairments especially in relation to the way you neurotransmitters such as serotonin, dopamine and noradrenaline . Cocaine is a relatively "balanced" inhibitor, although facilitation of dopaminergic neurotransmission is what has been linked.
The elucidation of such relationships can help design new treatment strategies for MDD, especially treatment-resistant depression. Dopamine, Major depressive disorder, Norepinephrine, Serotonin Introduction Given that the therapeutic efficacy of the tricyclic drugs was based on their ability to inhibit norepinephrine NE and serotonin 5-HT transporters, the role of brain 5-HT and NE neurotransmissions in the mechanism of action of antidepressant drugs prompted extensive studies [ 1 — 4 ].
Dopamine DA on the other hand, despite evidence of its involvement in the action of certain antidepressants, attracted less attention [ 5 ]. First, reserpine which depletes catecholamines NE, DA, and epinephrine results in lowering mood; second, the monoamine oxidase inhibitors MAOIswhich increase the synaptic availability of catecholamines, have clinical efficacy in depression [ 67 ]. This suggests that not all antidepressants work via a single monoamine-related mechanism.
The fact that pure dopaminergic drugs, such as pramipexole, are effective antidepressants suggests that enhancing DA function may underlie, at least in part, a therapeutic response in major depressive disorder MDD [ 1011 ]. Mounting evidence indicates that acting on different systems may have a greater therapeutic effect in depression [ 1213 ].
Brain serotonin, dopamine, epinephrine, and norepinephrine - neurotransmitters - are discussed.
Understanding the relationship between the NE and DA systems, and how therapeutic drugs modulate them, may open new avenues to treat depression, particularly treatment-resistant depression. Experiments have been carried out to determine the role of DA and NE in their projection areas Figure 1.
Iontophoretic studies showed that local application of DA suppressed the firing activity of NE neurons in the LC [ 21 — 23 ]. Given this preponderant inhibitory role of DA input to the LC, the selective lesioning of VTA DA neurons resulted in a significant increase of the mean firing rate of LC NE neurons with a greater increase in neurons displaying bursting activities [ 24 ]. The term "raphe" is Greek for a ridge or seam between two parts, particularly symmetrical parts. As are most other structures in the brain, the raphe nuclei are grouped into pairs and distributed along one of the phylogenetically oldest portions of the brain, the reticular formation.
A quotation from John Allman's Evolving Brains bears repeating here: Chordates include fish and very primitive sea creatures. Allman explains that serotonin "is made from the amino acid tryptophan, which is abundant in meat and fowl. The human body cannot make tryptophan, and thus we must obtain it from dietary sources. Tryptophan deprivation alters brain chemistry and mood.
Tryptophan is obtained by the digestion of proteins in the gut and is transported in the blood plasma to the brain, where it is converted to serotonin. Axons of neurons in the lower raphe nuclei terminate in the spinal cord as well as the cerebellum's deep nuclei and cortex. Axons of neurons in the higher raphe nuclei terminate in 1 subcortical nuclei including the centrally located thalami; the surrounding corpus striata including the nucleus accumbens; the hypothalamus, hippocampus, and amygdala, 2 the cingulate cortex, including the cingulum, a tract of association fibers connecting the corpus callosum with the hippocampus, and 3 the neocortex.
If you have pictured this innervation in your mind, you now understand that serotonin innervates the entire brain, bottom to top. Dopamine action, synthesis, and pathways: If you have seen the movie Awakenings or read Oliver Sacks's novel on which the movie is based, you may remember that L-DOPA was the drug the new doctor on the ward administered to catatonic patients and that it prompted their awakening from decades-long bouts of catatonia.
Their illness was caused by an outbreak of viral encephalitis that destroyed dopamine-producing neurons in their brains. We will discuss postencephalitic Parkinsonism further when we talk about neurotransmitter-related illnesses.
Cocaine and amphetamines are psychologically addicting because they facilitate activity in brain DA [dopamine] systems. Restak points out that the corpus striata mediate the "initiation, smoothness, and precision of movement. Restak goes on to say that the corpus striata are "responsible for the automatic movements we make without thinking. Dopamine is synthesized in cell groups in the midbrain's substantia nigrae and ventral tegmental areas VTA.
Neurotransmitters of the brain: serotonin, noradrenaline (norepinephrine), and dopamine.
The midbrain is labeled 3 in the picture below. The term tegmental comes from tegmentum, which is Latin for "covering. If you look carefully at the image below, you can see two blackish areas, mirror images of each other, in the area labeled 3.
These are the substantia nigrae. The VTA structures are located just above the substantia nigrae. The corpus striata surrounds the centrally located thalami labeled 2so you can see that axonal connections from the substantia nigrae could easily innervate the corpus striata. I discuss these connections, referred to as the nigrostriatal pathway, as well as VTA pathways, later in this narrative.
Click on the mage to link to its source and see these areas more clearly.
The importance of norepinephrine in depression
The medial forebrain bundle MFB is a prominent tract of nerve fibers, both ascending and descending, that connects areas of the brain stem with subcortical areas of the brain. In real tissue, the bundle would appear white. The axons of neurons in the substantia nigrae ascend via the MFB but terminate in the caudate-putamen areas of the corpus striata complex. These axons are together named the nigrostriatal pathway.
This pathway is particularly associated with movement. Depletion of dopamine in the nigrostriatal pathway causes Parkinson's disease. We will discuss Parkingon's disease in the next page of MyBrainNotes. The axons of a subset of neurons in the VTA ascend via the MFB but terminate in the nucleus accumbens also part of the corpus striata complex. These axons are together named the mesolimbic pathway.
The prefix "meso" is Greek for "middle. We discuss the naming of brain structures in Part 1 of MyBrainNotes. Regarding the nigrostriatal pathway and the mesolimbic pathway, Panksepp explains in Affective Neuroscience that reciprocating, descending nerve pathways exit the corpus striata and run back to respective cell groups in the substantia nigrae and VTA structures.
These reciprocating loops are probably intended, explains Panksepp, "to help protect the system from excessive arousal when it is perturbed by an overabundance of incoming stimulation. The axons of a second subset of neurons in the VTA ascend via the MFB into the nucleus accumbens within the corpus striata and continue on to innervate the frontal cortex. These axons are together named the mesocortical pathway.
In addition to the mid-brain, dopamine-producing neurons are also found in the tuberal nuclei, an anatomically specific region of the hypothalamus.
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Axons from these neurons project to an anatomically specific area of the pituitary gland called the infundibulum. Thus, in very general terms, the tuberoinfundibular pathway connects the hypothalamus with the pituitary gland. In the Color Atlas of Neuroscience: Neuroanatomy and Neurophysiology, Adam Greenstein explains that the tuberoinfundibular pathway projects "from the hypothalamic arcuate nucleus to the median eminence, where the terminals release DA [dopamine] into the pituitary portal blood.
Serotonin–norepinephrine–dopamine reuptake inhibitor
The released DA has a hormonal role, suppressing prolactin release. The use of these drugs always comes with a caution since higher doses result in a greater likelihood that increased blood prolactin levels hyperprolactinaemia will develop.
In both men and women, hyperprolactinaemia may produce breast lactation and result in loss of bone mineral density leading to osteoporosis. Hyperprolactinaemia may also disrupt the menstrual cycle in women. In men, the condition may reduce testosterone as well as contribute to erectile dysfunction and infertility.
Generally, very low doses of antipsychotics are recommended for OCD e. Lower doses of dopamine antagonist drugs are less likely to produce side-effects such as hyperprolacti naemia. Side effects have to be weighed against benefits. From personal experience, I believe that many patients with OCD would benefit from very low doses of medication e. Part 3 of MyBrainNotes. Norepinephrine action, synthesis, and pathways: I should note here that norepinephrine and noradrenaline are different names for the same neurotransmitter.
The British prefer the term "noradrenaline. First, it relays messages in the sympathetic nervous system, as part of the autonomic nervous system's fight-or-flight response.Neurotransmitters Overview
Secondly, norepinephrine prepares the brain to encounter and respond to stimuli from the environment, thereby facilitating vigilance.