Catecholamine Pathways in CNS
Norepinephrine, epinephrine, and dopamine are important CNS neurotransmit-ters, and their pathways and receptors have been mapped and localized to a large extent.
Dopamine (DA) is the major cate-cholamine neurotransmitter of the mammalian CNS, comprising at least 50% of the total CNS catecholamine content. There are four major dopaminergic pathways in the brain. The mesolimbic pathway originates in the ventral tegmental region of the midbrain, near the substantial nigra, and projects to several higher centers of the limbic system, including the amygdala, the frontal and cingulate cortex, the nucleus acumbens, the olfactory tubercle, and the septum. These areas mediate mood changes and cognitive function, and are believed to be the sites where drugs such as cocaine and amphetamines produce their stimulant effects. Other CNS drugs such as antidepressants, which block MAO, and antischizophrenia neu-roleptic drugs, which block DA receptors, may act in these regions. The nigrostriatal pathway projects from the substantia nigra to the corpus striatum, and specifically to the putamen and caudate nuclei, which are implicated in the control of fine motor function. The mesocortical pathway projects from the ventral tegmentum to the frontal cortex, and the tuberoinfun-dibular pathway is a short but important DA projection from the hypothalamic arcuate nucleus to the median eminence, where the terminals release DA into the pituitary portal blood. The released DA has an hormonal role, suppressing prolactin release.
Noradrenergic innervation of the brain is diffuse, and projections are widespread. Major noradrenergic nuclei occur in the brain stem in the locus ceruleus and the lateral tegmental nuclei, projecting to the thalamus, cerebellum, olfactory lobes,
Greenstein, Color Atlas of Neuroscience © 2000 Thieme and the neocortex. The precise functions of these projections are largely unknown, but may involve cognition, alertness, arousal and motivation. Noradrenergic innervation also appears to involve central components of autonomic and endocrine function. For example, noradrenergic pathways appear to coordinate the release of hypothalamic releasing factors such as CRF (see p. 301), which controls ACTH release from the anterior pituitary gland, and the release of GnRH (see p. 303), which controls the release of gonadotro-phins.
Adrenergic pathways in the CNS appear to be restricted mainly to the brain stem and modulate autonomic and endocrine function. Adrenergic nuclei occur principally in the dorsal and ventral teg-mentum, and ascend to terminate in the hypothalamus in the diencephalon. They descend the spinal cord to the intermedi-olateral cell column, which gives rise to the sympathetic preganglionic cell bodies.
The catecholaminergic innervation of the various CNS regions can be visualized by localizing the receptors the cate-cholamines act upon. This can be done by autoradiography, when radioactive ligands are attached to the receptors, or by using radioactive probes that hybridize with the mRNA that codes for the receptor. Thus, a and p receptors have been shown to occur very widely in the brain, and it is possible to distinguish between the localization of the various subtypes of a and p receptors. These findings are useful when attempting to discover the roles of catecholaminergic innervation in both normal and pathological brain function.
cingulate cortex neocorte:
hypothalamus lateral tegmental pathways cingulate cortex neocorte:
hypothalamus lateral tegmental pathways
noradrenergic pathway noradrenergic pathways locus ceruleus thalamus
^^ neocorte; tt|-adrenoceptors oç-adrenoceptors hippocampus —
adrenoceptors (mid-thalamic nuclei)
® hypo thalamus pons lateral tegmental nuclei adrenergic pathways pons lateral tegmental nuclei
ß2-adrenoceptors medial thalamic nuclei
dorsal tegmental nuclei
ß2-adrenoceptors medial thalamic nuclei striatu septum frontal cortex arcuate nucleus ventral tegmental area
mesocortical (1 ) mesolimbic (2) tuberoinfundibular (3) nigrostriatal (4)
dopamine main dopaminergic pathways substantia nigra mesocortical (1 ) mesolimbic (2) tuberoinfundibular (3) nigrostriatal (4)
dopamine main dopaminergic pathways substantia nigra
5-Hydroxytryptamine (5-HT; serotonin)
is an indolamine neurotransmitter, and its pathways in the CNS parallel, approximately, those of norepinephrine. 5-HT is found not only in brain cells but also in blood platelets, enterochromaffin cells in the gut, and in mast cells. It also occurs in the pineal, where it is the precursor of me-latonin.
5-HT is synthesized from the essential dietary amino acid tryptophan. In the neuron, tryptophan is hydroxylated to 5-hydroxytryptophan by the enzyme tryp-tophan hydroxylase, which resembles tyrosine, since tryptophan hydroxylase also requires molecular O2 and a tetrahydrop-teridine cofactor. Unlike tyrosine hydroxylase, whose activity is regulated by norepinephrine, 5-HT does not regulate the activity of tryptophan hydroxylase. Finally, 5-hydroxytryptophan is decarboxy-lated to 5-HT by the enzyme L-amino acid decarboxylase. Once synthesized, 5-HT is stored in granules, or vesicles, in the nerve terminal.
There are several serotonergic pathways in the CNS. These originate in the raphe nuclei in the midline region of the pons and upper brain stem. Cell bodies of the 5-HT neurons have been grouped and classified as B1 through B9 serotonergic nerve groups. Groups lying more rostrally in the brain stem (B4-B9) innervate the higher centers i.e. cerebellum, the neocor-tex, thalamus, and the limbic system. The more caudally placed serotonergic nuclei innervate lower CNS centers, such as the medulla and the spinal cord.
What is known of 5-HT function in the CNS comes mainly from studies with drugs such as p-cholorophenylalanine, which inhibits tryptophan hydroxylase, and with agonists or antagonists of the various 5-HT receptors. Midbrain 5-HT nuclei have an intrinsic pacemaker activity blocked by norepinephrine and by 5-HT
autoreceptors. Pacemaker activity is high during wakefulness, low during sleep, and cannot be recorded during REM (rapid eye movement) sleep. Various hallucinogenic drugs, such as lysergic acid diethylamide (LSD), are structurally similar to 5-HT, and may exert their effects through interactions with 5-HT receptors. 5-HT may mediate social interactions between individuals.
In the spinal cord, 5-HT neurons may be involved in a central pattern generator
(CPG), which generates patterned motor output. The CPG regulates motoneuron excitability by means of a rhythmic lowering of the motoneuron membrane potential. This produces an alternating modulation of reflex inputs and outputs to opposing muscles. The motor behaviors associated with the CPG identified so far include swimming, walking, running, chewing, licking, biting, and grooming with the tongue in animals.
Multiple forms of 5-HT receptors exist. The receptors may be ligand-gated or coupled to G proteins and second messenger systems. Receptors may be excitatory or inhibitory. 5-HT2 receptors are generally excitatory, while 5-HT] receptors are mainly inhibitory. 5-HT1A and 5-HT1D receptors are coupled to Gj transducer proteins and inhibit cyclic AMP production. 5-HT1A receptors have been localized to raphe nucleus nerve cells, and appear to act as autoreceptors, to inhibit 5-HT activity. 5-HT1D receptors have been localized to the basal ganglia, and may be involved in control of voluntary muscle. 5-HT2 receptors activate the phosphoinositol second messenger system and mediate depolarization of neocortical neurons. The 5-HT3 receptor is a ligand-gated ion channel, and has been localized to the entorhi-nal cortex, the area postrema of the medulla, and in the peripheral nervous system.
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