PHARMACODYNAMICS, TRANSDUCTION AND NEUROTRANSMISSION

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A nerve cell or neuron has 2 major distinguishing functions - propagation of the action potential along the axon, and transmission of the signal from one nerve to another nerve or cell structure to elicit a response (eg, nerve impulse, muscle contraction). While impulses conducted along an axon are caused by the movement of Na and K ions across the membrane and are electrical in nature, the transmission of impulses from one neuron to another neuron or to a non-neuronal cell is chemical and depends upon the action of certain neurotransmitters (NTs) on specific receptors.
Transmission via NTs is a highly complex and sensitive process. Synaptic relationships in the periphery involve neuron-neuron or neuron-effector interactions. Neurotransmission can be increased or decreased to accommodate any physiologic situation. Many neurologic and psychiatric diseases are caused by a pathologic over- or under activity of neuronal transmission. Many drugs can modify neurotransmission to cause adverse effects (e.g., hallucinogens) or to correct pathologic conditions (e.g., antipsychotic drugs).

Basic Principles of Neurotransmission and transduction
Neurotransmission involves (1) synthesis and storage of the NT in the prejunctional nerve structure; (2) release of the NT from the nerve terminal; (3) interaction of the NT with a specific postjunctional structure (receptor); (4) rapid termination of the NT-receptor interaction; and (5) destruction of NT or re-uptake into the terminal.
Regulation of NT amounts varies among neurons but is achieved through increased or decreased precursor uptake or activity of NT synthesizing or destroying enzymes. Also, stimulation or blockade of postsynaptic receptors can decrease or increase presynaptic NT synthesis.

Major Neurotransmitters
A neurotransmitter (NT) is defined as a chemical that is selectively released from a nerve terminal by an action potential, interacts with a specific receptor on an adjacent structure, and elicits a specific physiologic response.
Most NTs derive from amino acids (or related compounds such as choline). Certain neurons synthesize only one, neuron-specific NT; others have been shown to synthesize 2 or more NTs. Some neurons modify amino acids to form the "amine" transmitters (e.g., norepinephrine, serotonin, acetylcholine); others combine amino acids to form "peptide" transmitters (e.g., endorphins, enkephalins); and still other neurons use amino acids unchanged or synthesized as transmitters. A few NTs are not related to amino acids.

Acetylcholine (Ach), the major NT of the motoneurons, autonomic preganglionic fibers, postganglionic cholinergic (parasympathetic) fibers, and many neurons in the CNS (basal ganglia, motor cortex), is synthesized from choline and mitochondrially derived acetyl-coenzyme A by the enzyme choline acetyltransferase (CAT). Upon release, Ach stimulates cholinergic receptors of adjacent structures. This interaction is rapidly terminated by hydrolysis of Ach to choline and acetate by the enzyme acetylcholinesterase (ACE) found adjacent to the receptors. Ach levels are regulated by the activity of CAT and by choline uptake.
Dopamine (DA) is the NT of some peripheral nerve fibers and of many central neurons (e.g., substantia nigra, midbrain, hypothalamus). The amino acid tyrosine is taken up by dopaminergic neurons, converted by the enzyme tyrosine hydroxylase to 3,4-dihydroxyphenylalanine (dopa), decarboxylated by the enzyme aromatic l -amino acid decarboxylase to DA, and stored in vesicles. After release, DA interacts with dopaminergic receptors and is then "pumped" back by active processes (re-uptake) into the prejunctional neurons. DA levels are held constant by changes in tyrosine hydroxylase activity and the enzyme monoamine oxidase (MAO), which is localized in nerve terminals and metabolizes dopamine. DA is metabolized to several metabolites, including specifically homovanillic acid.
Diseases that affect the function of signal transmission can have serious consequences. Parkinson's disease has a deficiency of the neurotransmitter dopamine. Progressive death of brain cells increases this deficit, causing tremors, rigidity and unstable posture. L-dopa is a chemical related to dopamine that eases some of the symptoms (by acting as a substitute neurotransmitter) but cannot reverse the progression of the disease.
Norepinephrine (NE) is the NT of most postganglionic sympathetic fibers and many central neurons (e.g., locus ceruleus, hypothalamus). NE synthesis, like that of DA, also starts with the precursor tyrosine but continues as DA is hydroxylated by dopamine-beta-hydroxylase to form NE, which is stored in vesicles. Upon release, NE interacts with adrenergic receptors. This action is terminated largely by the re-uptake of NE back into the prejunctional neurons. Tyrosine hydroxylase and MAO regulate intraneuronal NE levels. Metabolism of NE occurs via MAO and catechol-O-methyltransferase to inactive metabolites (e.g., normetanephrine, 3-methoxy-4-hydroxyphenylethylene glycol, 3-methoxy-4-hydroxymandelic acid).
Serotonin (5-HT) is the NT of many central neurons. Its synthesis begins with the uptake of tryptophan into serotonergic neurons. Tryptophan is hydroxylated by the enzyme tryptophan hydroxylase to 5-hydroxytryptophan, and then decarboxylated to serotonin (5-hydroxytryptamine) by the enzyme aromatic l -amino acid decarboxylase. Levels of 5-HT are controlled by the uptake of tryptophan and intraneuronal MAO. Metabolism occurs mainly via MAO to 5-hydroxyindoleacetic acid.
Gamma-Aminobutyric acid (GABA) causes mostly inhibitory responses in the CNS and is found in many areas (e.g., basal ganglia, cerebellum). GABA is derived from glutamic acid, which is decarboxylated by glutamic acid decarboxylase. After interaction with its receptors, GABA is actively "pumped" back into the neuronal terminals. It is metabolized by a GABA-transaminase.
The bacterium Clostridium tetani produces a toxin that prevents the release of GABA. GABA is important in control of skeletal muscles. Without this control chemical, regulation of muscle contraction is lost; it can be fatal when it effects the muscles used in breathing.
Clostridium botulinum produces a toxin found in improperly canned foods. This toxin causes the progressive relaxation of muscles, and can be fatal. A wide range of drugs also operate in the synapses: cocaine, LSD, caffeine, and insecticides.
β-Endorphin (β-End) is a polypeptide and is the transmitter of many central neurons (e.g., hypothalamus, amygdala, thalamus, locus ceruleus). After release and interaction with peptidergic (opioid) receptors, it is hydrolyzed by peptidases into smaller, inactive peptides and amino acids.
Methionine-enkephalin and leucine-enkephalin are small peptides present in many central neurons (e.g., globus pallidus, thalamus, caudate, central gray). After release and interaction with peptidergic (opioid) receptors, the enkephalins are hydrolyzed by other peptidases into smaller, inactive peptides and amino acids.
Dynorphins are a group of 7 peptides with similar amino acid sequences and are present in the same areas as are the enkephalins. These peptides are derived from prodynorphin and are hydrolyzed after receptor activation.
Substance P is a peptide and the transmitter of many central neurons (e.g., dorsal root ganglia, basal ganglia, hypothalamus). Its synthesis and fate are similar to those of the other peptide NTs.
Glycine, glutamate, and aspartate are NTs used directly by certain neurons without change (although glycine might also be synthesized from serine). Aspartate is mainly present in the cortex, glutamate in the cerebellum and spinal cord, and glycine in the interneurons of the spinal cord. Glutamic and aspartic acid cause excitatory responses, while glycine is inhibitory.
Other neurotransmitters, whose roles in neurotransmission have not been as firmly established, include epinephrine, histamine, vasopressin, vasoactive intestinal peptide, carnosine, bradykinin, cholecystokinin, bombesin, somatostatin, corticotropin-releasing factor, neurotensin, and others.
In addition to these amino acid-related NTs, some NTs are different, e.g., adenosine.


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