A large number of molecules act as neurotransmitters at chemical synapses. These neurotransmitters are present in the synaptic terminal, and their action may be blocked by pharmacologic agents. Some presynaptic nerves can release more than one transmitter; differences in the frequency of nerve stimulation probably control which transmitter is released. Some common transmitters are listed in Table 3–5.
Some neurons in the CNS also accumulate peptides. Some of these peptides act much like conventional transmitters; others appear to be hormones. Some relatively well-understood neurotransmitters are discussed next.
ACh is synthesized by choline acetyltransferase and is broken down after release into the synaptic cleft by acetylcholinesterase (AChase). These enzymes are synthesized in the neuronal cell body and are carried by axonal transport to the presynaptic terminal; synthesis of ACh occurs in the presynaptic terminal.
ACh acts as a transmitter at a variety of sites in the PNS and CNS. ACh is responsible for excitatory transmission at the neuromuscular junction (N-type, nicotinic ACh receptors). It is the transmitter in autonomic ganglia and is released by preganglionic sympathetic and parasympathetic neurons. Postganglionic parasympathetic neurons, as well as one particular type of postganglionic sympathetic axon (ie, the fibers innervating sweat glands), use ACh as their transmitter (M-type, muscarinic receptors).
Within the CNS, several well-defined groups of neurons use ACh as a transmitter. These include neurons that project widely from the basal forebrain nucleus of Meynert to the cerebral cortex and from the septal nucleus to the hippocampus. Cholinergic neurons, located in the brain stem tegmentum, project to the hypothalamus and thalamus, where they use ACh as a transmitter.
The amino acid glutamate has been identified as a major excitatory transmitter in the mammalian brain and spinal cord. Four types of postsynaptic glutamate receptors have been identified. Three of these are ionotropic and are linked to ion channels. These receptors are named for drugs that bind specifically to them. The kainate and AMPA types of glutamate receptor are linked to Na+ channels, and when glutamate binds to these receptors they produce EPSPs. The NMDA receptor is linked to a channel that is permeable to both Ca2+ and Na+. The NMDA-activated channel, however, is blocked (so that influx of these ions cannot occur) unless the postsynaptic membrane is depolarized. Thus, NMDA-type synapses mediate Ca2+ influx, but only when activity at these synapses is paired with excitation via other synaptic inputs that depolarize the postsynaptic neuron. The Ca2+ influx mediated by these synapses may lead to structural changes that strengthen the synapse. It has been hypothesized that this alteration may provide a basis for memory.
CLINICAL CORRELATIONS A. Myasthenia Gravis and Myasthenic Syndrome
Myasthenia gravis is an autoimmune disorder in which antibodies against the ACh receptor (ie, the postsynaptic receptor at the neuromuscular junction) are produced. As a result, the responsiveness of muscle to activity in motor nerves and to synaptic activation is reduced. Patients classically complain of fatigue and weakness involving the limb muscles and, in some patients, bulbar muscles such as those controlling eye movement and swallowing. Upon repetitive electrical stimulation, the involved muscles rapidly show fatigue and finally do not respond at all; excitability usually returns after a rest period.
Myasthenic syndrome (also called Lambert–Eaton syndrome), in contrast, involves the presynaptic component of the neuromuscular junction. Myasthenic syndrome is a paraneoplastic disorder and often occurs in the context of systemic neoplasms, especially those involving the lung and breast. Antibodies directed against Ca2+ channels located in presynaptic terminals at the neuromuscular junction interfere with transmitter release, causing weakness. B. Myotonia
In this class of disorders, affected muscles show a prolonged response to a single stimulus. Some of these disorders involve an abnormality of voltage-sensitive Na+ channels, which fail to close following an action potential. As a result, inappropriate, sustained muscle contraction may occur.
A metabotropic type of glutamate receptor has also been identified. When the transmitter glutamate binds to this receptor, the second messengers, IP3 and DAG, are liberated. This liberation can lead to increased levels of intracellular Ca2+, which may activate a spectrum of enzymes that alter neuronal function and structure.
It has been suggested that excessive activation of glutamatergic synapses can lead to very large influxes of Ca2+ into neurons, which can cause neuronal cell death. Because glutamate is an excitatory transmitter, excessive glutamate release might lead to further excitation of neuronal circuits by positive feedback, resulting in a damaging avalanche of depolarization and calcium influx into neurons. This excitotoxic mechanism of neuronal injury may be important in acute neurologic disorders, such as stroke and CNS trauma, and possibly in some chronic neurodegenerative diseases, such as Alzheimer's.
The catecholamines norepinephrine (noradrenaline), epinephrine (adrenaline), and dopamine are formed by hydroxylation and decarboxylation of the essential amino acid phenylalanine. Phenyl-ethanolamine-N-methyltransferase, the enzyme responsible for converting norepinephrine to epinephrine, is found in high concentration primarily in the adrenal medulla. Epinephrine is found at only a few sites in the CNS.
Six months before presentation, a 35-year-old single woman began to complain that she occasionally saw double when watching television. The double vision often disappeared after she had some bed rest. Subsequently, she felt that her eyelids tended to droop during reading, but after a good night's rest she felt normal again. Her physician referred her to a specialty clinic.
At the clinic, the woman said that she tired easily and her jaw muscles became fatigued at the end of a meal. No sensory deficits were found. A preliminary diagnosis was made and some tests were performed to confirm the diagnosis.
What is the differential diagnosis? Which diagnostic procedures, if any, would be useful? What is the most likely diagnosis?
Cases are discussed further in Chapter 25. Questions and answers pertaining to Section I (Chapters 1–3) can be found in Appendix D.
Dopamine is synthesized, via the intermediate molecule dihydroxyphenylalanine (DOPA), from the amino acid tyrosine by tyrosine hydroxylase and DOPA decarboxylase. Norepinephrine, in turn, is produced via hydroxylation of dopamine. Dopamine, like norepinephrine, is inactivated by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).
Dopaminergic neurons generally have an inhibitory effect. Dopamine-producing neurons project from the substantia nigra to the caudate nucleus and putamen (via the nigrostriatal system) and from the ventral tegmental area to the limbic system and cortex (via the mesolimbic and mesocortical projections). In Parkinson's disease, there is degeneration of the dopaminergic neurons and the substantia nigra. Thus, dopaminergic projections from the substantia nigra to the caudate nucleus and putamen are damaged, and the inhibition of neurons in the caudate nucleus and putamen is impaired. The dopaminergic projection from the ventral tegmental area to the limbic system and cortex may be involved in schizophrenia.
Dopamine-containing neurons have also been found in the retina and the olfactory system. In these areas they appear to mediate inhibition that filters sensory input.
Norepinephrine-containing neurons in the PNS are located in the sympathetic ganglia and project to all of the postganglionic sympathetic neurons except those innervating sweat glands, which are innervated by axons that use ACh as a transmitter. Norepinephrine-containing cell bodies in the CNS are located in two areas: the locus ceruleus and the lateral tegmental nuclei. Although the locus ceruleus is a relatively small nucleus containing only several hundred neurons, it projects widely into the cortex, hippocampus, thalamus, midbrain, cerebellum, pons, medulla, and spinal cord. The noradrenergic projections from these cells branch extensively and are distributed widely. Some of the axons branch and project to both the cerebral cortex and the cerebellum. Noradrenergic neurons in the lateral tegmental areas of the brain stem appear to have a complementary projection, projecting axons to regions of the CNS that are not innervated by the locus ceruleus.
The noradrenergic projections from the locus ceruleus and the lateral tegmental area appear to play a modulatory role in the sleep–wake cycle and in cortical activation and may also regulate sensitivity of sensory neurons. Some evidence suggests that abnormal paroxysmal activity in the locus ceruleus can result in panic attacks.
Serotonin (5-hydroxytryptamine) is an important regulatory amine in the CNS. Serotonin-containing neurons are present in the raphe nuclei in the pons and medulla. These cells are part of the reticular formation, and they project widely to the cortex and hippocampus, basal ganglia, thalamus, cerebellum, and spinal cord. Serotonin-containing neurons can also be found in the mammalian gastrointestinal tract.
Serotonin-containing neurons, along with norepinephrine-containing neurons, appear to play an important role in determining the level of arousal. Firing levels of neurons in the raphe nuclei, for example, are correlated with sleep level and show a striking cessation of activity during rapid eye movement sleep. Serotonin-containing neurons may also participate in the modulation of sensory input, particularly for pain. Selective serotonin reuptake inhibitors, which increase the amount of serotonin available at the postsynaptic membrane, are used clinically as antidepressants.
Gamma-aminobutyric acid (GABA) is present in relatively large amounts in the gray matter of the brain and spinal cord. It is an inhibitory substance and probably the mediator responsible for presynaptic inhibition. GABA and glutamic acid decarboxylase (GAD), the enzyme that forms GABA from L-glutamic acid, occur in the CNS and the retina. Two forms of GABA receptor, GABAA and GABAB, have been identified. Both mediate inhibition but by different ionic pathways (see Table 3–6). Inhibitory interneurons containing GABA are present in the cerebral cortex and cerebellum and in many nuclei throughout the brain and spinal cord. The drug baclofen acts as an agonist at GABAB receptors; its inhibitory actions may contribute to its efficacy as an antispasticity agent.
The general term endorphins refers to some endogenous morphine-like substances which bind to opiate receptors in the brain. Endorphins (brain polypeptides with actions like opiates) may function as synaptic transmitters or modulators. Endorphins appear to modulate the transmission of pain signals within sensory pathways.
Two closely related polypeptides (pentapeptides) found in the brain that also bind to opiate receptors are methionine enkephalin (met-enkephalin) and leucine enkephalin (leu-enkephalin). The amino acid sequence of met-enkephalin has been found in alpha-endorphin and beta-endorphin, and that of beta-endorphin has been found in beta-lipotropin, a polypeptide secreted by the anterior pituitary gland.
BOX 3-1 Essentials for the Clinical Neuroanatomist After reading and digesting this chapter, you should know and understand:
Membrane potential (resting potential and its basis in selective ionic permeability and gradients of ions inside/outside of neurons)
Action potentials: all-or-none characteristic. Ionic basis
Ion channels (Na+, K+ channels) and their roles within the neuronal cell membrane
The role of the Na+, K+ pump (Na,K ATPase) in maintaining resting potential (Fig 3-1)
Myelin and its functional role
Impulse conduction in myelinated versus unmyelinated axons
Synapses: excitatory versus inhibitory
Synaptic plasticity and LTP
The neuromuscular junction
Neurotransmitters (Table 3-6)