Hippocampal Formation

Neurotransmitters

I. IMPORTANT TRANSMITTERS AND THEIR PATHWAYS

A. Acetylcholine is the major transmitter of the peripheral nervous system, neuromuscular junction, parasympathetic nervous system, preganglionic sympathetic fibers, and postganglionic sympathetic fibers that innervate sweat glands and some blood vessels in the skeletal muscles (Figure 22-1). Acetylcholine is found in the neurons of the somatic and visceral motor nuclei in the brain stem and spinal cord. It is also found in the basal nucleus of Meynert, which degenerates in Alzheimer's disease.

B. Catecholamines. Figure 22-2 shows the biosynthetic pathway for catecholamines. Epinephrine, although a catecholamine, plays an insignificant role as a central nervous system neurotransmitter. In the body, epinephrine is found primarily in the adrenal medulla. In the central nervous system, it is restricted to small neuronal clusters in the brain stem (medulla).

1. Dopamine (Figure 22-3) is depleted in patients with Parkinson's disease and increased in patients with schizophrenia. Dopamine is found in the arcuate nucleus of the hypothalamus. It is the prolactin-inhibiting factor. Its two major receptors are D, and D2.

Figure 22-1. Distribution of acetylcholine-containing neurons and their axonal projections. The basal nucleus of Meynert projects to the entire cortex. This nucleus degenerates in patients with Alzheimer's disease. Striatal acetylcholine local circuit neurons degenerate in patients with Huntington's disease.

Acetylcholine (ACh)

Meynert Projects

Hippocampal formation

Figure 22-1. Distribution of acetylcholine-containing neurons and their axonal projections. The basal nucleus of Meynert projects to the entire cortex. This nucleus degenerates in patients with Alzheimer's disease. Striatal acetylcholine local circuit neurons degenerate in patients with Huntington's disease.

NeocorieJ^^^^- Local circuit neurons in striatum (caudatoputamen)

Hippocampal formation

Alzheimer Circuit Neuron

Figure 22-2. Synthesis of catecholamines from phenylalanine. Epinephrine, which is derived from norepinephrine, is found primarily in the adrenal medulla.

a. D, receptors are postsynaptic. They activate adenylate cyclase and are excitatory.

b. D2 receptors are both postsynaptic and presynaptic. They inhibit adenylate cyclase and are inhibitory. Antipsychotic drugs block D2 receptors.

2. Norepinephrine (Figure 22-4) is the transmitter of most postganglionic sympathetic neurons. Antidepressant drugs enhance its transmission, a. Norepinephrine plays a role in anxiety states. Panic attacks are believed to result from paroxysmal discharges from the locus ceruleus, where norepineph-rinergic neurons are found in the highest concentration. Most postsynaptic receptors of the locus ceruleus pathway are ß, or ß2 receptors that activate adenylate cyclase and are excitatory.

Dopamine

Limbic cortex (cingulate gyrus

Mesolimbic tract (mesocortical tract) Septal nuclei

Arcuate (tuberal) nucleus of hypothalamus

Amygdala Substantia nigra of midbrain

Ventral Tegmentum

Spinal cord

Figure 22-3. Distribution of dopamine-containing neurons and their projections. Two major ascending dopamine pathways arise in the midbrain: the nigrostriatal tract from the substantia nigra and the mesolimbic tract from the ventral tegmental area. In patients with Parkinsons disease, loss of dopaminergic neurons occurs in the substantia nigra and the ventral tegmental area. Dopaminergic neurons from the arcuate nucleus of the hypothalamus project to the portal vessels of the intundibulum. Dopaminergic neurons inhibit prolactin.

Corpus callosum

Striatum (caudate nucleus and putamen)

Nigrostriatal tract

Ventral tegmental area of midbrain

Cerebellum Pons

Medulla

Spinal cord

Figure 22-3. Distribution of dopamine-containing neurons and their projections. Two major ascending dopamine pathways arise in the midbrain: the nigrostriatal tract from the substantia nigra and the mesolimbic tract from the ventral tegmental area. In patients with Parkinsons disease, loss of dopaminergic neurons occurs in the substantia nigra and the ventral tegmental area. Dopaminergic neurons from the arcuate nucleus of the hypothalamus project to the portal vessels of the intundibulum. Dopaminergic neurons inhibit prolactin.

Norepinephrine (NE)

Locus ceruleus

Septal nuclei

Locus ceruleus

Septal nuclei

Norepinephrine Projection

Cerebellar cortex

Spinal cord

Figure 22-4. Distribution of norepinephrine-containing neurons and their projections. The locus ceruleus (located in the pons and midbrain) is the chief source of noradrenergic fibers. The locus ceruleus projects to all parts of the cent ral nervous system.

Spinal cord

Hippocampal formation

Cerebellar cortex

Figure 22-4. Distribution of norepinephrine-containing neurons and their projections. The locus ceruleus (located in the pons and midbrain) is the chief source of noradrenergic fibers. The locus ceruleus projects to all parts of the cent ral nervous system.

b. The catecholamine hypothesis of mood disorders states that reduced norepinephrine activity is related to depression, and that increased norepinephrine activity is related to mania.

C. Serotonin [5-hydroxytryptamine (5-HT)] is an indolamine (Figure 22-5). Serotonin* containing neurons are found only in the raphe nuclei of the brain stem.

1. The permissive serotonin hypothesis states that when 5-HT activity is reduced, decreased levels of catecholamines cause depression and insomnia. In addition, when 5-HT activity is increased, elevated levels of catecholamines cause mania. Dysfunction of 5-HT may underlie obsessive-compulsive disorder.

2. Certain antidepressants increase 5-HT availability by reducing its reuptake. 5-HT agonists that bind 5-HT!A and those that block 5-HT, have antidepressant properties. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI).

D. Opioid peptides (endogenous opiates) induce responses similar to those of heroin and

1. Endorphins include ^-endorphin, which is the major endorphin found in the brain. It is one of the most powerful analgesics known (48 times more potent than morphine). Endorphins are found exclusively in the hypothalamus.

2. Enkephalins are the most widely distributed and abundant opiate peptides. They are found in the highest concentration in the globus pall idus. Enkephalins coexist with dopamine, 7-aminobutyric acid (CABA), norepinephrine, and acetylcholine. They are colocalized in CABA-ergic pallidal neurons, and they play a role in pain suppression.

3. Dynorphins follow the distribution map for enkephalins.

E. Nonopioid neuropeptides

1. Substance P plays a role in pain transmission. It is most highly concentrated in the substantia nigra. It is also found in the dorsal root ganglion cells and substantia gelatinosa. It is colocalized with GABA in the striatonigral tract and plays a role in movement disorders. Substance P levels are reduced in patients with Huntington's disease.

morphine.

Serotonin (5-HT)

Septa

Septa

Cerebral Artery Map

Tryptophan

Cerebellar cortex

Spinal cord

Spinal cord

Hippocampal formation

Tryptophan

I Tryptophans-hydroxylase 5-Hydroxytryptophan

Cerebellar cortex

I Aromatic L-amino acid decarboxylase Serotonin (5-Hydroxytryptamine)

Figure 22-5. Distribution of 5-hydroxytryptamine (serotonin)-containing neurons and their projections. Serotonin-containing neurons are found in the nuclei of the raphe. They project widely to the forebrain, cerebellum, and spinal cord. The inset shows the synthetic pathway of serotonin

2. Somatostatin (somatotropin-release inhibiting faci >r). Somatostatinergic neurons from the anterior hypothalamus project their axons to the median eminence, where somatostatin enters the hypophyseal portal system and regulates the release of growth hormone and thyroid-stimulating hormone. The concentration of somatostatin in the neocortex and hippocampus is significantly reduced in patients with Alzheimer's disease. Striatal somatostatin levels are increased in patients with Huntington's disease.

F. Amino acid transmitters

1. Inhibitory amino acid transmitters a. GAB A (Figure 22-6) is the major inhibitory neurotransmitter of the brain. Pur-kinje, stellate, basket, and Golgi cells of the cerebellar cortex are GABA-ergic. (1) GABA-ergic striatal neurons project to the globulus pall id us and sub stantia nigra.

(2) GABA-ergic pallidal neurons project to the thalamus.

(3) GABA-ergic nigral neurons project to the thalamus.

(4) GABA receptors (GABA-A and GABA-B) are intimately associated with benzodiazepine-binding sites. Benzodiazepines enhance GABA ac ta) GABA-A receptors open chloride channels, (b) GABA-B receptors are found on the terminals of neurons that use another transmitter (i.e., norepinephrine, dopamine, serotonin). Activation of GABA-B receptors decreases the release of the other transmitter.

b. Glycine is the major inhibitory neurotransmitter of the spinal cord. It is used by the Renshaw cells of the spinal cord.

tivity.

Y-Aminobutyric acid (GABA)

Stantia Nigra Anatomy

Neoco rt(

Local circuit GABA neurons

Striatum Globus pallidus Hypothalamocortical tract Striatonigral tract

Hypothalamus Substantia nigra (pars reticularis) Lateral vestibular nucleus

Local circuit GABA neuron

Thalamus

Pallidothalamic tract

Local circuit GABA neurons Nigrothalamic tract Cerebellar nuclei Cerebellar cortex

Purkinje cells of cerebellar cortex

Figure 22-6. Distribution of 7-aminohutyric acid (GABA)-containing neurons and their projections. GABA-ergic neurons are the major inhibitory cells of the central nervous system. GABA local circuit neurons are found in the neocortex, hippocampal formation, and cerebellar cortex (Purkinje cells). Striatal GABA-ergic neurons project to the thalamus and subthalamic nucleus (nor shown).

2. Excitatory amino acid transmitters a. Glutamate (Figure 22-7) is the major excitatory transmitter of the brain.

Neocortical glutamatergic neurons project to the striatum, subthalamic nucleus, and thalamus.

(1) Glutamate is the transmitter of the cerebellar granule cells.

(2) Glutamate is also the transmitter of nonnociceptive, large, primary afferent fibers that enter the spinal cord and brain stem.

(3) Glutamate is the transmitter of the corticobulbar and corticospinal tracts.

Glutamate

Proprioceptive Fibers The Brain

Corticostriatal fibers

Septal nuclei Corticobulbar and corticospinal tracts

Pyramidal neurons of neocortex

Striatum Fornix

Pyramidal cell of hippocampal formation

Granule cells of cerebellar cortex

Proprioceptive fibers in dorsal roots

Figure 22-7. Distribution of glutamate-containing neurons and their projections. Glutamate is the major excitatory transmitter of the central nervous system. Cortical glutamatergic neurons project to the striatum. Hippocampal and subicular glutamatergic neurons project through the fornix to the septal area and hypothalamus. The granule cells of the cerebellum are glutamatergic.

b- Aspartate, a major excitatory transmitter of the brain, is the transmitter of the climbing fibers of the cerebellum. Neurons of climbing fibers are found in the inferior olivary nucleus.

C. Behavioral correlation. Glutamate, through its N-methyl-D-aspartate (NMDA) receptors, plays a role in long-term potentiation (a memory process) of hippocampal neurons. Glutamate plays a role in kindling and subsequent seizure activity. Under certain conditions, glutamate and its analogs are neurotoxic.

d. Glutamate excitotoxicity. GLU is released in the striatum and binds to its receptors on striatal neurons resulting in an action potential. GLU is removed from the extracellular space by astrocytes. In Huntington's disease GLU is bound to the N-methyl-D-aspartate (NMDA) receptor resulting in an influx of calcium ions and subsequent cell death. This cascade of events with neuronal death most likely occurs in cerebrovascular accidents (stroke).

3. Nitric oxide is a recently discovered gaseous neurotransmitter that is produced when nitric oxide-synthase converts arginine to citrulline.

a. It is located in the olfactory system, striatum, neocortex, hippocampal formation, supraoptic nucleus of the hypothalamus, and cerebellum.

b. Nitric oxide is responsible for smooth muscle relaxation of the corpus caver-nosum and thus penile erection. It is also believed to play a role in memory formation because of its long-term potentiation in the hippocampal formation. In addition, nitric oxide functions as a nitrovasodilator in the cardiovascular system.

II. FUNCTIONAL AND CLINICAL CONSIDERATIONS

A. Parkinson's disease results from degeneration of the dopaminergic neurons that are found in the pars compacta of the substantia nigra. It causes a reduction of dopamine in the striatum and substantia nigra (see Chapter 21 III A).

B. Huntington's disease (chorea) results from a loss of acetylcholine- and GABA-containing neurons in the striatum (caudatoputamen). The effect is a loss of GABA in the striatum and substantia nigra (see Chapter 21 III C).

C. Alzheimer's disease results from the degeneration of cortical neurons and cholinergic neurons in the basal nucleus of Meynert. It is associated with a 60% to 90% loss of choline acetyltransferase in the cerebral cortex. Histologically, Alzheimer's disease is characterized by the presence of neurofibrillary tangles, senile (neuritic) plaques, amyloid substance, granulovacuolar degeneration, and Hirano bodies.

D. Myasthenia gravis results from autoantibodies against the nicotinic acetylcholine receptor on skeletal muscle. These antibodies block the postganglionic acetylcholine binding site. Thymic cells augment B-cell production of autoantibodies. The cardinal manifestation is fatigable weakness of the skeletal muscle. The extraocular muscles, including the levator palpebrae, are usually involved. Edrophonium or neostigmine injection is used for diagnosis.

E. Lambert-Eaton myasthenic syndrome is caused by a presynaptic defect of acetylcholine release. It causes weakness in the limb muscles, but not in the bulbar muscles. Fifty percent of cases are associated with neoplasms (i.e., lung, breast, prostate). In these patients, muscle strength improves with use. (In myasthenia gravis, muscle use results in muscle fatigue.) Autonomic dysfunction includes dry mouth, constipation, impotence, and urinary incontinence.

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