Neurotransmitters (The Neuron) Part 4

Physiological and Clinical Considerations

Parkinson’s Disease. This disease is characterized by an expressionless face (clinicians sometimes refer to it as "mask-like face"), slowness of movement (bradykinesia or hypokinetic syndrome), rigidity of the extremities and the neck, and tremors in the hands. Patients with Parkinson’s disease have a gait that is characterized by short wide-based steps (sometimes referred to as "fenestrating gait"), stooped posture, and scarcity of normal limb movements. These symptoms are often accompanied by dementia. Dopaminergic neurons located in the substantia nigra are degenerated in this disease, and the release of dopamine in the caudate nucleus and putamen is decreased.

The main aim of drug therapy for this disease is to replace the deficiency of the transmitter (dopamine) in the basal ganglia (target of nigrostriatal projection). Because dopamine does not cross the blood-brain barrier, its immediate metabolic precursor (L-DOPA, or levo-dopa), which does cross this barrier, is administered orally. L-DOPA is transported into the brain via a large neutral amino acid transporter, and it permeates the striatal tissue, where it is decarboxylated to dopamine. In recent years, a combination of L-DOPA and carbidopa (Sinemet) has been prescribed for this disease. Carbidopa is an inhibitor of dopa-decarboxylase and reduces the decarboxylation of L-DOPA in the peripheral tissues, enabling a greater concentration of this precursor to reach the brain. Carbidopa does not cross the blood-brain barrier. Therefore, conversion of L-DOPA to dopamine does not diminish in the brain.

Another potentially useful but controversial approach is to implant fetal midbrain or adrenal medullary tissue into the deteriorating caudate nucleus and putamen. A future possibility is transplantation of genetically engineered cells capable of expressing tyrosine hydroxylase that is involved in the synthesis of dopamine.

Psychotic Disorders. Many adult psychotic disorders, including schizophrenia, are believed to involve increased activity at dopaminergic synapses. Many drugs that are effective in the treatment of these disorders (e.g., pheno-thiazines, thioxanthines, and butyrophenones) are believed to reduce the dopamine synaptic activity in the limbic forebrain.

Cocaine Drug Abuse. Cocaine (a local anesthetic drug) blocks the reuptake of dopamine (and norepinephrine) into the nerve terminals. Elevated levels of dopamine in certain brain circuits may be responsible for the euphoric effects of cocaine. This mechanism is not responsible for the local anesthetic effect of cocaine that is mediated via the blockade of neuronal voltage-gated Na+ channels.

Dopaminergic projections from the ventral tegmental area to the limbic structures, especially the projections to nucleus accumbens, may be involved in emotional reinforcement and motivation associated with cocaine drug addiction. Levels of dopamine in these projections are increased in individuals addicted to cocaine.


Synthesis and Removal. Initial steps in the synthesis of norepinephrine (up to the step of transport and storage of dopamine into the storage vesicles) are described in the section about dopamine. The noradrenergic neurons contain an enzyme, dopamine b-hydroxylase (DBH), which converts dopamine into norepinephrine. It should be noted that the synthesis of norepinephrine takes place in the storage vesicles (Fig. 8-12). The nore-pinephrine thus formed is ready to be released by exocy-tosis. Norepinephrine released into the synaptic cleft is removed by the mechanisms described in the dopamine section.

Autoinhibition and Negative Feedback. Activation of presynap-tic adrenergic receptors results in inhibition of the release of norepinephrine. This process is known as autoinhibi-tion and is distinct from negative feedback in which synthesis of the transmitter (norepinephrine in this case) is blocked at its rate-limiting step (i.e., conversion of tyrosine to DOPA by tyrosine hydroxylase).

Distribution. The major concentration of noradrenergic neurons is in the locus ceruleus (also known as "A6 group of neurons") that is located in the pons. These neurons send projections through the central tegmental tract and the medial forebrain bundle to the thalamus, hypothalamus, limbic forebrain structures (cingulate and parahippocampal gyri, hippocampal formation, and amygdaloid complex), and the cerebral cortex. This group of neurons modulates a variety of physiological functions (e.g., sleep and wakefulness, attention, and feeding behaviors).

Physiological and Clinical Considerations. Norepinephrine is released as a transmitter from postganglionic sympathetic nerve terminals. Its role in the CNS as a transmitter is not clearly understood. Norepinephrine is believed to play a role in psychiatric disorders such as depression. Drugs used in the treatment of depression (e.g., tricyclic antidepres-sants such as desimipramine) are known to inhibit the reuptake of norepinephrine at the nerve terminals and increase the synaptic levels of norepinephrine. The exact mechanism by which increased levels of norepinephrine in the CNS mediate the antidepressant action of these drugs is not clearly known.


Synthesis and Removal. The initial steps (up to synthesis and storage of norepinephrine in the storage vesicles) in the synthesis of epinephrine are identical to those of nore-pinephrine. In the adrenergic neuron (Fig. 8-13), norepinephrine stored in the vesicles leaks out into the cytoplasm and is converted into epinephrine by the enzyme phenylethanolamine-N-methyl-transferase (PNMT).

Epinephrine thus formed in the cytoplasm is actively transported back into storage vesicles in the nerve terminal (or chromaffin granules in the adrenal medulla) and stored for subsequent release. The mechanisms for removal of epinephrine are the same as those for norepinephrine and dopamine.

Steps involved in the synthesis and release of norepinephrine. COMT = catechol-O-methyltransferase.

FIGURE 8-12 Steps involved in the synthesis and release of norepinephrine. COMT = catechol-O-methyltransferase.

 Steps involved in the synthesis and release of epinephrine. COMT = catechol-O-methyltransferase; PNMT = phenylethanolamine-N-methyl-transferase.

FIGURE 8-13 Steps involved in the synthesis and release of epinephrine. COMT = catechol-O-methyltransferase; PNMT = phenylethanolamine-N-methyl-transferase.

Distribution. Two major groups of adrenergic cells have been identified in the medulla: C1 neurons located in the rostral ventrolateral medulla, and C2 neurons located in the solitary nucleus and tract (nucleus tractus solitarius).

Physiological and Clinical Considerations. The function of adrener-gic neurons in the CNS has not been clearly established.

Immunohistochemical Identification of Catecholaminergic Neurons.

Antibodies, developed for enzymes involved in the synthesis of different catecholamine neurotransmitters, have been used for immunohistochemical identification of these neurons. For example, positive staining for tyrosine hydroxylase indicates that the neuron contains a catecholamine. Positive staining for tyrosine hydroxy-lase, but not DBH, indicates that the neuron contains dopamine. Positive staining for DBH, but not PNMT, indicates that the neuron contains norepinephrine.

Positive staining for PNMT indicates that the neuron contains epinephrine.


Indoleamines are substituted indole compounds that contain an amino group. Indole consists of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Serotonin will be discussed in the indoleamine class of neurotransmitters.


Synthesis and Removal. Serotonin (5-hydroxytryptamine; 5-HT) does not cross the blood-brain barrier. Therefore, brain cells must synthesize their own serotonin. Dietary tryptophan serves as a substrate for serotonin synthesis (Fig. 8-14). Plasma tryptophan enters the brain by an active uptake process and is hydroxylated by tryptophan hydroxylase to form 5-hydroxytryptophan, which is immediately decarboxylated by aromatic L-amino acid decar-boxylase to form serotonin. Serotonin is then actively taken up via vesicular monoamine transporter and stored in vesicles where it is ready for release.

Steps involved in the synthesis and release of serotonin. The distribution of some 5-HT receptors on different components of the serotonergic synapse is also shown. AC = adenylyl cyclase; cAMP = cyclic adenosine monophosphate; DAG = diacylglycerol; Gi, Go, Gq = different G-proteins; IP3 = inositol triphosphate; 5-HT,a, 5-HT1d, 5-HT2A, 5-HT2C, 5-HT3, 5-HT4 = different 5-HT receptors.

FIGURE 8-14 Steps involved in the synthesis and release of serotonin. The distribution of some 5-HT receptors on different components of the serotonergic synapse is also shown. AC = adenylyl cyclase; cAMP = cyclic adenosine monophosphate; DAG = diacylglycerol; Gi, Go, Gq = different G-proteins; IP3 = inositol triphosphate; 5-HT,a, 5-HT1d, 5-HT2A, 5-HT2C, 5-HT3, 5-HT4 = different 5-HT receptors.

Major serotonin-containing neurons and their projections.

FIGURE 8-15 Major serotonin-containing neurons and their projections.

After its release, serotonin is removed from the synaptic cleft by the mechanisms of reuptake and metabolism. Reuptake involves entry of serotonin into the neuronal terminals by active transport via plasma membrane serotonin transporter proteins (SERT). Metabolism involves deamination of serotonin by MAO to form 5-hydroxyindoleacetaldehyde, which is then oxidized by aldehyde dehydrogenase to form 5-hydroxyindoleacetic acid. The latter is excreted through the urine.

Distribution. Serotonin-containing neurons have been identified in the midline raphe nuclei of the medulla, pons, and upper brainstem. The raphe nuclei are located in the central portion of the medullary, pontine, and midbrain reticular formation. In the caudal to rostral direction, the names of these nuclei are raphe obscurus, raphe magnus, and raphe pallidus in the medulla; raphe pontis and inferior central nucleus in the pons; and superior central nucleus and dorsal raphe nucleus in the midbrain. The caudal raphe nuclei (i.e., the medullary raphe nuclei) project to the spinal cord and brain stem. The rostral nuclei located in the pons (i.e., raphe pontis, raphe centra-lis, also called "median raphe nucleus") and midbrain (dorsal raphe nucleus) project to the thalamus, limbic system, and cortex (Fig. 8-15). Projections from the raphe nuclei terminating in the dorsal horn regulate the release of enkephalins.

Physiological and Clinical Considerations. Serotonin-containing cells in the raphe regions of the brainstem are believed to play a role in descending pain-control systems. Other serotonin-containing neurons may play a role in mediating affective processes, such as aggressive behavior and arousal. Serotonin synthesized in the pineal gland serves as a precursor for the synthesis of melatonin, which is a neurohor-mone involved in regulating sleep patterns.

Serotonin is also believed to play an important role in depression. Selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitors (SSRIs) are used in the treatment of depression, anxiety disorders, and some personality disorders. These drugs inhibit reuptake of serotonin into the presynaptic terminal and increase the extracellular level of the serotonin available for binding to the postsynaptic receptor. For example, fluoxetine (Prozac) selectively blocks reuptake of serotonin and enhances serotonin levels in the brain. It may produce beneficial effects in mental depression via enhancement of transmission through 5-HT1A receptors. Sumatriptan (Imitrex) is a 5-HT1D receptor agonist. It is a vasoconstrictor of intracra-nial arteries and has proved useful in treating migraine headaches. Sumatriptan-induced constriction of intracra-nial arteries is mediated via 5-HT1B 5-HT1D receptors that are located in the smooth muscle and endothelial cells of these arteries.

"Designer Drugs" of Abuse and Their Relationship With Serotonin.

Some drugs of abuse mediate their effects through serotonin-containing neurons. For example, Ecstasy has been used as a recreational drug by young adults, especially in large dance parties know as "raves." Ecstasy includes two drugs, MDMA (3,4, methylene-dioxy-methamphetamine) and MDEA (3,4, methylene-dioxy-ethamphetamine). These drugs, generally called "Adam" and "Eve," respectively, by drug abusers, have been reported to induce sensory enhancement (a feeling that "all is right with this world") and empathogenesis (a feeling of closeness with others and removal of barriers in communication, especially in intimate relationships). These effects are believed to be due to the initial release of serotonin by these drugs. Toxic effects of these drugs are dehydration, hyperthermia, tachycardia (increase in heart rate), and sweating. Undesirable side effects following prolonged use of Ecstasy are believed to be caused by the degeneration of the projections of serotonin-containing neurons.

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