Kaplan + Sadock's Synopsis of Psychiatry, 11e

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Chapter 1: Neural Sciences

metabolites of dopamine and norepinephrine are homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), respectively.

Histamine As is the case for serotonin, the brain contains only a small portion of the histamine found in the body. Histamine is dis- tributed throughout most tissues of the body, predominantly in mast cells. Because it does not readily cross the blood–brain barrier, it is believed that histamine is synthesized within the brain. In the brain, histamine is formed by the decarboxylation of the amino acid histidine by a specific l-histidine decarbox- ylase. This enzyme is not normally saturated with substrate, so synthesis is sensitive to histidine levels. This is consistent with the observation that the peripheral administration of histidine elevates brain histamine levels. Histamine is metabolized in the brain by histamine N -methyltransferase, producing methylhis- tamine. In turn, methylhistamine undergoes oxidative deamina- tion by MAO B . Acetylcholine Acetylcholine is synthesized by the transfer of an acetyl group from acetyl coenzyme A (ACoA) to choline in a reaction medi- ated by the enzyme choline acetyltransferase (ChAT). The majority of choline within the brain is transported from the blood rather than being synthesized de novo. Choline is taken up into cholinergic neurons by a high-affinity active transport mechanism, and this uptake is the rate-limiting step in ace- tylcholine synthesis. The rate of choline transport is regulated such that increased cholinergic neural activity is associated with enhanced choline uptake. After synthesis, acetylcholine is stored in synaptic vesicles through the action of a vesicular acetylcholine transporter. After vesicular release, acetylcholine is rapidly broken down by hydrolysis by acetylcholinesterase, located in the synaptic cleft. Much of the choline produced by this hydrolysis is then taken back into the presynaptic terminal via the choline transporter. Of note, although acetylcholinester- ase is localized primarily to cholinergic neurons and synapses, a second class of cholinesterase termed butyrylcholinesterase is found primarily in the liver and plasma as well as in glia. In the treatment of Alzheimer’s disease, strategies aimed at enhancing cholinergic function, primarily through the use of cholinesterase inhibitors to prevent normal degradation of acetylcholine, have shown moderate efficacy in ameliorating cognitive dysfunction as well as behavioral disturbances. Cholinesterase inhibitors are also used in the treatment of myasthenia gravis, a disease char- acterized by weakness due to blockade of neuromuscular trans- mission by autoantibodies to acetylcholine receptors. Transporters A great deal of progress has been made in the molecular char- acterization of the monoamine plasma membrane transporter proteins. These membrane proteins mediate the reuptake of synaptically released monoamines into the presynaptic termi- nal. This process also involves cotransport of Na + and Cl − ions and is driven by the ion concentration gradient generated by the plasma membrane Na + /K + ATPase. Monoamine reuptake is an important mechanism for limiting the extent and duration

Figure 1.4-8 Synthesis of catecholamines. (From Sadock BJ, Sadock VA, Ruiz P. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry . 9 th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:69.)

norepinephrine, and MAO type B (MAO B ), which deaminates dopa- mine, histamine, and a broad spectrum of phenylethylamines. Neurons contain both MAO isoforms. The blockade of monoamine catabolism by MAO inhibitors produces elevations in brain monoamine levels. MAO is also found in peripheral tissues such as the gastrointestinal tract and liver, where it prevents the accumulation of toxic amines. For example, peripheral MAO degrades dietary tyramine, an amine that can displace norepinephrine from sympathetic postganglionic nerve endings, producing hypertension if tyramine is present in sufficient quantities. Thus patients treated with MAO inhibitors are cautioned to avoid pickled and fermented foods that typically have high levels of tyramine. Catechol-O-methyltransferase (COMT) is located in the cytoplasm and is widely distributed throughout the brain and periph- eral tissues, although little to none is found in adrenergic neurons. It has a wide substrate specificity, catalyzing the transfer of methyl groups from S -adenosyl methionine to the m -hydroxyl group of most catechol compounds. The catecholamine metabolites produced by these and other enzymes are frequently measured as indicators of the activity of catecholaminergic systems. In humans, the predominant