neurologic disorders
Neurotransmission
Major Neurotransmitters and Receptors
At least 100 substances can act as neurotransmitters; about 18 are of major importance. Several occur in slightly different forms. Neurotransmitters can be grouped in different classes, such as Small molecules (eg, glutamate, gamma-aminobutyric acid,glycine,adenosine, acetylcholine, serotonin, histamine, noradrenaline) Neuropeptides (eg, endorphins) Gaseous molecules (eg, nitric oxide, carbon monoxide) Endocannabinoids These amino acids (glutamate and aspartate) are the major excitatory neurotransmitters in the CNS. They occur in the cortex, cerebellum, and spinal cord. In neurons, synthesis of nitric oxide (NO) increases in response to glutamate. Excess glutamate can be toxic, increasing intracellular calcium, free radicals, and proteinase activity. These neurotransmitters may contribute to tolerance to opioid therapy and mediate hyperalgesia. Glutamate receptors (stimulated by glutamate and less strongly by aspartate) are classified as NMDA (N-methyl-d-aspartate) receptors and non-NMDA receptors. Phencyclidine (PCP, also known as angel dust) andmemantine(used to treat Alzheimer disease) bind to NMDA receptors. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. It is an amino acid derived from glutamate, which is decarboxylated by glutamate decarboxylase. After interaction with its receptors, GABA is actively pumped back into nerve terminals and metabolized.Glycine, which resembles GABA in its action, occurs principally in interneurons (Renshaw cells) of the spinal cord and in circuits that relax antagonist muscles. GABA receptors are classified as GABA-A (activating chloride channels) and GABA-B (potentiating cAMP formation). GABA-A receptors are the site of action for several neuroactive drugs, including benzodiazepines, barbiturates, picrotoxin, and muscimol. Alcohol also binds to GABA-A receptors. GABA-B receptors are activated bybaclofen, used to treat muscle spasms (eg, in multiple sclerosis). Serotonin (5-hydroxytryptamine, or 5-HT) is generated by the raphe nucleus and midline neurons of the pons and upper brain stem.Tryptophanis hydroxylated bytryptophanhydroxylase to 5-hydroxytryptophan, then decarboxylated to serotonin. Serotonin levels are controlled by the uptake oftryptophanand intraneuronal monoamine oxidase (MAO), which breaks down serotonin. Ultimately, serotonin is excreted in the urine as 5-hydroxyindoacetic acid or 5-HIAA. Serotoninergic (5-HT) receptors (with at least 15 subtypes) are classified as 5-HT1 (with 4 subtypes), 5-HT2, and 5-HT3. Selective serotonin receptor agonists (eg,sumatriptan) can abort migraines. Selective serotonin reuptake inhibitors (SSRIs) can also be used to treat several mental health disorders (eg, depression, anxiety, obsessive compulsive disorder, posttraumatic stress disorder). Acetylcholine is the major neurotransmitter of the bulbospinal motor neurons, autonomic preganglionic fibers, postganglionic cholinergic (parasympathetic) fibers, and many neurons in the CNS (eg, basal ganglia, motor cortex). It is synthesized from choline and acetyl coenzyme A by choline acetyltransferase, and its action is rapidly terminated via local hydrolysis to choline and acetate by acetylcholinesterase. Acetylcholine levels are regulated by choline acetyltransferase and by choline uptake. Levels of this neurotransmitter are decreased in patients with Alzheimer disease. Cholinergic receptors are classified as nicotinic N1 (in skeletal muscle and the neuromuscular junction) or N2 (in the central and peripheral nervous systems, including the parasympathetic and sympathetic nervous systems and the adrenal medulla) or muscarinic M1 through M5 (widely distributed in the CNS). M1 occurs in the autonomic nervous system, striatum, cortex, and hippocampus; M2 occurs in the autonomic nervous system, heart, intestinal smooth muscle, hindbrain, and cerebellum. Dopamineinteracts with receptors on some peripheral nerve fibers and many central neurons (eg, in the substantia nigra, midbrain, ventral tegmental area, and hypothalamus). The amino acid tyrosine is taken up by dopaminergic neurons and converted by tyrosine hydroxylase to 3,4-dihydroxyphenylalanine (dopa), which is decarboxylated by aromatic-l-amino-acid decarboxylase todopamine. After release and interaction with receptors,dopamineis actively pumped back (reuptake) into the nerve terminal. Tyrosine hydroxylase and MAO (which breaks downdopamine) regulatedopaminelevels in nerve terminals. Dopaminergic receptors are classified as D1 through D5. D3 and D4 receptors play a role in thought control (limiting the negative symptoms of schizophrenia); D2 receptor activation controls the extrapyramidal system. However, receptor affinity does not predict functional response (intrinsic activity). For example,ropinirole, which has high affinity for the D3 receptor, has intrinsic activity via activation of D2 receptors. Norepinephrineis the neurotransmitter of most postganglionic sympathetic fibers and many central neurons (eg, in the locus caeruleus and hypothalamus). The precursor tyrosine is converted todopamine, which is hydroxylated bydopaminebeta-hydroxylase tonorepinephrine. After release and interaction with receptors, somenorepinephrineis degraded by catecholO-methyltransferase (COMT), and the remainder is actively taken back into the nerve terminal, where it is degraded by MAO. Tyrosine hydroxylase,dopaminebeta-hydroxylase, and MAO regulate intraneuronalnorepinephrinelevels. Adrenergic receptors are classified as alpha-1 (postsynaptic in the sympathetic system), alpha-2 (presynaptic in the sympathetic system and postsynaptic in the brain), beta-1 (in the heart), or beta-2 (in other sympathetically innervated structures). Endorphins and enkephalins are opioids. Endorphinsare large polypeptides that activate many central neurons (eg, in the hypothalamus, amygdala, thalamus, and locus caeruleus). The cell body contains a large polypeptide called pro-opiomelanocortin, the precursor of alpha-, beta-, and gamma-endorphins. Pro-opiomelanocortin is transported down the axon and cleaved into fragments; one is beta-endorphin, contained in neurons that project to the periaqueductal gray matter, limbic structures, and major catecholamine-containing neurons in the brain. After release and interaction with receptors, beta-endorphin is hydrolyzed by peptidases. Enkephalinsinclude met-enkephalin and leu-enkephalin, which are small polypeptides present in many central neurons (eg, in the globus pallidus, thalamus, caudate, and central gray matter). Their precursor, proenkephalin, is formed in the cell body, then split by specific peptidases into the active peptides. These substances are also localized in the spinal cord, where they modulate pain signals. The neurotransmitters of pain signals in the posterior horn of the spinal cord are glutamate and substance P. Enkephalins decrease the amount of neurotransmitter released and hyperpolarize (make more negative) the postsynaptic membrane, reducing the generation of action potentials and pain perception at the level of the postcentral gyrus. After release and interaction with peptidergic receptors, enkephalins are hydrolyzed into smaller, inactive peptides and amino acids. Rapid inactivation of exogenous enkephalins prevents these substances from being clinically useful. More stable molecules (eg,morphine) are used as analgesics instead. Endorphin-enkephalin (opioid) receptors are classified as mu-1 and mu-2 (affecting sensorimotor integration and analgesia), delta-1 and delta-2 (affecting motor integration, cognitive function, and analgesia), and kappa-1, kappa-2, and kappa-3 (affecting water balance regulation, analgesia, and food intake). Sigma receptors, currently classified as nonopioid and mostly localized in the hippocampus, bind PCP. New data suggest the presence of many more receptor subtypes, with pharmacologic implications. Components of the molecular precursor to the receptor protein can be rearranged during receptor synthesis to produce several receptor variants (eg, 27 splice variants of the mu opioid receptor). Also, two receptors can combine (dimerize) to form a new receptor. Dynorphins are a group of 7 peptides with similar amino acid sequences. They, like enkephalins, are opioids. Substance P, a peptide, occurs in central neurons (in the habenula, substantia nigra, basal ganglia, medulla, and hypothalamus) and is highly concentrated in the dorsal root ganglia. Its release is triggered by intense afferent painful stimuli. It modulates the neural response to pain and mood; it modulates nausea and vomiting through the activation of NK1A receptors that are localized in the brain stem. Nitric oxide (NO) is a labile gas that mediates many neuronal processes. It is generated fromarginineby NO synthase. Neurotransmitters that increase intracellular calcium (eg, substance P, glutamate, acetylcholine) stimulate NO synthesis in neurons that express NO synthetase. NO may be an intracellular messenger; it may diffuse out of a cell into a second neuron and produce physiologic responses (eg, long-term potentiation [strengthening of certain presynaptic and postsynaptic responses—a form of learning]) or enhance glutamate (NMDA-receptor–mediated) neurotoxicity (eg, in Parkinson disease, stroke, or Alzheimer disease). NO affects other neurotransmitters (eg, GABA and acetylcholine) by changing the influx of calcium into cells to increase the release of other neurotransmitters. Additional gaseous neurotransmitters include carbon monoxide (CO) and hydrogen sulfide (H2S). These transmitters are produced in cells throughout the body (including the brain). Endogenous CO is generated from the metabolism of heme and can participate in processes that involve fever generation, inflammation, cell survival, and control of blood vessel dilation. Several enzymes are involved in the production of H2S, which is believed to be necessary for the brain to form and retain memories. Substances with less firmly established roles in neurotransmission include histamine,vasopressin, vasoactive intestinal peptide, carnosine, bradykinin, cholecystokinin, bombesin, somatostatin,corticotropin-releasing factor, neurotensin, and possiblyadenosine. Endocannabinoids are endogenous lipid-based neurotransmitters that modulate brain, endocrine, and immune system function. 