As we discuss in Part 1 of MyBrainNotes.com, in Neurons, neurochemicals, and neurocircuits, each neuron has a very slender axon—a kind of nerve fiber—that projects from the neuron's cell body and transmits electrical impulses to the neuron's axon terminals. This electrical signal stimulates release of a neurotransmitter, which is produced inside the nerve cell. It is neurotransmitters that light up the brain with life.
Neurotransmitters operate in distinct systems made up of neurons communicating together in circuits. As we discuss in Part 1 of MyBrainNotes.com, a bundle of axons from neuron cell bodies appears as white matter and either projects to a given target structure (projection) or links together several target structures (pathway). We will discuss only the most prominent neurotransmitter pathways in the following narrative. For example, there are eight neural pathways in the brain that function via dopamine transmission, but we will discuss only four.
Monoamines: The major neurotransmitters we will discuss here (serotonin, dopamine, norepinephrine, and epinephrine) are all monoamines. Monoamines contain one amino group that is connected to an aromatic ring by a two-carbon chain (-CH2-CH2-). The molecular structure for the neurotransmitter serotonin is pictured at left. Serotonin is derived from the amino acid L-tryptophan.
Catecholamines: Three of the monoamines described above (dopamine, norepinephrine, and epinephrine) are also called catecholamines because they contain a catechol group. Catecholamines are a group of neurotransmitters that arise in sequence from the amino acid tyrosine. Tyrosine is created from phenylalanine via hydroxylation by the enzyme phenylalanine hydroxylase. (Tyrosine is also ingested directly from dietary protein). It is then sent to catecholamine-secreting neurons where many kinds of reactions convert it to dopamine, to norepinephrine, and eventually to epinephrine.
Action: In Evolving Brains
(2000), John Allman explains that serotonin often "does not directly excite other neurons but instead modulates the responses of neurons to other neurotransmitters." What this means is that neurotransmitters such as norepinephrine and dopamine do not act in a vacuum. The transmission of serotonin has a strong influence on the transmission of these and other neurotransmitters. One exception where serotonin directly excites neurons is in the cerebral cortex, where it excites pyramidal neurons. A pyramidal neuron's cell body, or soma, is shaped like a triangle, thus the name pyramidal neuron. In addition to a single axon and multiple basal dendrites, pyramidal neurons have a large apical dendrite arising from the apex of the soma that branches several times. Examples of pyramidal cells, the kind of cell serotonin targets in the cerebral cortex, are shown below (image links to source). These images are from the Veterinary Neurohistology Atlas produced by T.F. Fletcher and supported by the University of Minnesota College of Veterinary Medicine.
Allman illuminates the importance of serotonin in the brain. He writes:
The axons of the serotonergic neurons project in rich profusion to every part of the central nervous system (the brain and spinal cord), where they influence the activity of virtually every neuron. This widespread influence implies that the serotonergic neurons play a fundamental role in the integration of behavior. Our sense of well-being and our capacity to organize our lives and to relate to others depend profoundly on the functional integrity of the serotonergic system. There are only a few hundred thousand serotonergic neurons in the human brain, roughly one millionth of the total population of neurons in the human central nervous system. However, the serotonin receptors on the target neurons are remarkably diverse. Fourteen types of serotonin receptors have been discovered so far in the brains of mammals, located in different places and acting in different ways.
Synthesis: Most serotonin in the human body is found in the enterochromaffin cells in the gastrointestinal tract, where it is used to regulate intestinal movements. In the brain, the neurons of the raphe nuclei are the principal source of serotonin release. 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. As we discuss in Part 1 of MyBrainNotes.com, in Brain stem structures and the reticular formation, the reticular formation is the core of the brain stem, running from the lower medulla oblongata through the pons and into the mid-brain. A quotation from John Allman's Evolving Brains bears repeating here: "The cell bodies of the serotonergic neurons occupy virtually the same location in the basement of every vertebrate brain and are even in the same spot in the central nervous system of smphioxus, a primitive chordate." (As
mentioned earlier, chordates have notocords, a simple central nervous system. 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."
Pathways: 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's synthetic precursor is 3,4-dihydroxyphenylalanine (L-DOPA). 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.
Action: In Affective Neuroscience: The Foundations of Human and Animal Emotions (1998), Jaak Panksepp explains that the overall functions of the basal ganglia [corpus striata] "are under the control of one major 'power switch'—ascending brain dopamine…." Panksepp points out that dopamine circuits "appear to be major contributors to our feelings of engagement and excitement as we seek the material resources needed for bodily survival, and also when we pursue the cognitive interests that bring positive existential meanings into our lives." He explains that without dopamine, "human aspirations remain frozen…." He goes on to say that when dopamine is abundant in synapses, "a person feels as if he or she can do anything." Panksepp asks: "Is it any wonder that humans and animals eagerly work to artificially activate this system whether via electrical or chemical means? Cocaine and amphetamines are psychologically addicting because they facilitate activity in brain DA [dopamine] systems."
In Part 1 of MyBrainNotes.com, in
The corpus striata (basal ganglia) complex, we discuss how the corpus striata, often called the basal ganglia, are ancient protoreptilian structures. In Brainscapes: An Introduction to What Neuroscience Has Learned about the Structure, Function, and Abilities of the Brain (1995), Richard M. Restak points out that the corpus striata mediate the "initiation, smoothness, and precision of movement." When dopamine is available in normal amounts, the corpus striata efficiently manage the flow of sensory information from the neocortex, repeatedly recirculating information back to the cortex through the thalamus. Restak goes on to say that the corpus striata are "responsible for the automatic movements we make without thinking." And there are indications that the corpus striata—prompted by dopamine—are involved in compulsive behaviors as well as obsessions.
Synthesis: Dopamine is synthesized in cell groups in the midbrain's substantia nigrae and ventral tegmental areas (VTA). The midbrain is labeled 3 in the picture below. The term tegmental comes from tegmentum, which is Latin for "covering." MedlinePlus Dictionary defines tegmentum as "the part of the ventral midbrain above the substantia nigra formed of longitudinal white fibers with arched transverse fibers and gray matter." The term ventral refers to the part of the tegmentum located toward the front of the human body rather than the rear.
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 2), so 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. The image below is from John A Beal, Department of Cellular Biology and Anatomy, Louisiana State University. Click on the mage to link to its source and see these areas more clearly. Remember to click your BACK button to return to MyBrainNotes.com.
Medial Forebrain Bundle: 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. Within this larger and longer pathway are several shorter pathways including the nigrostriatal pathway, the mesolimbic pathway, and the mesocortical pathway—all extending from dopamine-producing neurons.
The position of the medial forebrain bundle is illustrated in the image below from the HOPES Brain Tutorial, a project of Stanford University. In real tissue, the bundle would appear white. As we discuss in Part 1 of MyBrainNotes.com, in
Gray matter, white matter, glial cells, when multitudes of axons are grouped together, they appear as white matter.
Nigrostriatal Pathway: 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.com, Brain Neurotransmitters and Illness
Mesolimbic Pathway: 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." So the term "mesolimbic" means from the middle-brain, or mid-brain as we now call it, to a part of the limbic system. We discuss the naming of brain structures in Part 1 of MyBrainNotes.com in
Broca's Limbic Lobe, Papez's Circuit, and MacLean's Limbic System.
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."
Mesocortical Pathway: 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.
Tuberoinfundibular Pathway: In addition to the mid-brain, dopamine-producing neurons are also found in the tuberal nuclei, an anatomically specific region of the hypothalamus. 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. The released DA has a hormonal role, suppressing prolactin release." Antipsychotic drugs aimed at decreasing dopamine transmission in other pathways may also decrease dopamine transmission in the tuberoinfundibular pathway. 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.g., 0.25 – 0.5 mg haloperidol, titrated slowly to 2 – 4 mg) according to McDougle and Walsh, "Treatment for Refractory OCD," (2001), In: Fineberg, Marazitti, and Stein (eds), Obsessive Compulsive Disorder: A Practical Guide.
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.g., 0.25 – 0.5 mg haloperidol) that mitigate symptoms. Part 3 of MyBrainNotes.com includes more information in the section titled OCD Treatments Including Antipsychotic Medications
I should note here that norepinephrine and noradrenaline are different names for the same neurotransmitter. The British prefer the term "noradrenaline."
Action: As we discuss in ANS—the autonomic nervous system, norepinephrine has multiple roles. First, it relays messages in the sympathetic nervous system, as part of the autonomic nervous system's fight-or-flight response. Secondly, norepinephrine prepares the brain to encounter and respond to stimuli from the environment, thereby facilitating vigilance. So in both roles, norepinephrine mediates arousal.
Synthesis: Neurons in the loci coerulei, a pair of structures located within the pons of the brain stem (see Brain stem structures and the reticular formation), synthesize norepinephrine. You can see the pons in the image to the right, labeled 4. John A. Beal of Louisiana State University provides this image. The term locus coeruleus is derived from the Latin words "caeruleus" and "locus" meaning, literally, "the blue spot" due to the blue appearance of each nucleus. The blue color is the result of melanin, a class of pigments that are derivatives of the amino acid tyrosine. Melanin is also responsible for the dark color of the substantia nigrae.
Pathways: The axons of neurons in the loci coerulei project to both sides of the brain where they release norepinephrine. A single neuron in the locus coeruleus can innervate tissue in wide-ranging areas. The branching axons of norepinephrine-producing neurons in the loci coerulei innervate the brain stem, spinal cord, and cerebellum, as well as the hypothalami, thalamic relay nuclei, amygdalae, and neocortex. Marianne Fillenz provides details of research in her book, Noradrenergic Neurons, suggesting "that terminals in the cerebellum and cortex could be derived from collaterals of the same neuron." The term collaterals here refers to branches of a single neuron's axon.
The term epinephrine is derived from the Greek roots epi- and nephros, and literally means "on the kidney," in reference to the anatomical location of the adrenal gland. The Latin roots ad- and renes have similar meanings, and give rise to the word "adrenaline," which is the British term for epinephrine. As mentioned earlier, epinephrine is a catecholamine. Many kinds of reactions convert tyrosine to dopamine, to norepinephrine, and eventually to epinephrine.
Action: Epinephrine drives the autonomic nervous system's fight-or-flight response (see ANS—the autonomic nervous system). Epinephrine is synthesized in the adrenal glands (described below) and released into the bloodstream when dangerous circumstances occur, in an emergency requiring immediate action, and in stressful situations or environments. When in the bloodstream, epinephrine rapidly prepares the body for action. It boosts the supply of oxygen and glucose to the brain and muscles while suppressing other non-emergency bodily processes (digestion in particular).
Epinephrine increases heart rate and stroke volume, dilates the pupils, and constricts arterioles in the skin and gastrointestinal tract while dilating arterioles in skeletal muscles. It increases catabolism of glycogen to glucose in the liver, thereby elevating the blood sugar level. At the same time, epinephrine begins the breakdown of lipids in fat cells. Like some other stress hormones, epinephrine has a suppressive effect on the immune system.
The hypothalamus prompts the anterior lobe of the pituitary gland in the brain to release a protein hormone called adrenocorticotropic hormone (ACTH) into the bloodstream. ACTH stimulates the adrenal cortex to release cortisol, which increases the expression of phenylethanolamine N-methyltransferase (PNMT), an enzyme found primarily in what are called chromaffin cells, deep within the adrenal medulla. Within the adrenal medulla, PNMT uses S-adenosylmethionine (SAMe) as a cofactor to convert norepinephrine (noradrenaline) to epinephrine (adrenaline).
It is important to note that ACTH and cortisol are more commonly referred to as "stress hormones." Adverse conditions prompt release of these chemicals that in turn exacerbate many illnesses and negatively affect health in general.
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