Neurotransmitters

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Although neurotransmitters relate to all neuroanatomical discussions, they are of particular interest in relation to the basal ganglia and their function. Much of the basic understanding of neurotransmitters in clinical medicine came from studies of human basal ganglial disorders, and most medical specialists in this area of neurology have a sound foundation in neurochemistry and neuropharmacology. Additional material related to neurotransmitters was reviewed in the discussion of Emotion, Mood, and Thought (see Chapter s.). A neurotransmitter is an endogenous chemical that relays information from one neuron to another through synaptic release and receptor activation. To qualify as a neurotransmitter, five classic criteria must be demonstrated: (1) presence within neurons, (2) synthetic pathways with identified enzymes, (3) release mechanisms from the neuron into the synapse, (4) metabolic pathways to effect the removal of the chemical, and (5) mimicry of neuronal activity by iatrogenic application of the neurochemical. Few chemicals accepted as neurotransmitters actually fulfill all criteria within the central nervous system.

DOPAMINE

This simple catecholamine is synthesized in four major central nervous system pathways, and the most important and most widely understood involves the nigrostriatal pathway of the basal ganglia. The synthetic pathway for dopamine is tyrosine--!

ardopa--2

ardopamine. The rate-limiting enzyme is tyrosine hydroxylase (enzyme 1), and the second synthesizing step involves aromatic amino acid decarboxylase (enzyme 2). Once dopamine is produced in the nigral cell, it is transported along the axon to the striatal terminals, where it is released from vesicles into the synaptic cleft. There are receptors for dopamine on the striatal cells (postsynaptic receptors) as well as presynaptic or auto-receptors on the nigral axon. Depolarization of the autoreceptor raises the resting potential of the presynaptic neuron and makes the neuron easier to depolarize; on the other hand, the gradient between resting potential and action potential has been reduced, so that the end result is a decreased release of dopamine. This important mechanism provides for self-regulation of dopamine function. Activation of the postsynaptic receptors by dopamine can lead to depolarization or hyperpolarization, depending on the receptor site. An important concept for all neurotransmitters, including dopamine, is that the final result, hyperpolarization or depolarization, is dependent on both the transmitter and its receptor. The concept of an inhibitory transmitter should be abandoned for the more accurate concept of an inhibitory interaction between neurotransmitter and receptor.

Dopamine activity can be increased by four mechanisms: (1) increased synthesis, (2) increased release, (3) prolongation of neurotransmitter activity, and (4) direct receptor stimulation. Synthesis of the neurotransmitter can be increased by giving dopa because it is the product beyond the rate-limiting enzyme and there is ordinarily an abundant amount of aromatic amino acid decarboxylase in the central nervous system. When dopa is combined with a peripherally active decarboxylase inhibitor, more dopa is delivered across the blood-brain barrier and can be used to synthesize central dopamine. Increased release can be effected by drugs such as cocaine, amphetamine, and methylphenidate, all forcing release of presynaptic catecholamines. The normal metabolism of dopamine involves reuptake of dopamine into the presynaptic cell, with subsequent metabolism by two enzymes, monoamine oxidase (MAO) and catechol O-methyltransferase (COMT). Prolongation of dopamine activity can be effected by blocking re-uptake or altering enzyme activity. Amantadine and possibly some tricyclic antidepressant medications operate on the dopaminergic system through blockade of reuptake. MAO inhibitors and COMT inhibitors for human use also increase dopaminergic activity. Finally, direct activation of the dopamine receptors on the striatal cell can be induced by agonists like bromocriptine, pergolide, and other drugs. Importantly, orally administered dopamine itself has no place in altering the central nervous system dopamine levels, because it cannot cross the blood-brain barrier.

Dopamine function can be antagonized by three basic mechanisms: (1) decreased synthesis, (2) decreased release, and (3) blockade of dopamine receptors. Alpha-methyl para-tyrosine inhibits the synthesis of dopamine by blocking the rate-limiting enzyme tyrosine hydroxylase. Because this is also the rate-limiting enzyme for the synthesis of norepinephrine, the use of this drug had widespread effects on the autonomic nervous system. Vesicular packaging

of dopamine for proper release is blocked by reserpine and tetrabenazine, which are very potent dopamine antagonists. However, these drugs are nonspecific and also inhibit vesicular storage of norepinephrine and serotonin. Finally, receptor blockade occurs with phenothiazine neuroleptics or haloperidol. These drugs are relatively specific for the dopaminergic system, but are not specific to any one dopaminergic pathway. Hence, when one tries to block dopamine function in one region, one may also block dopaminergic function in other basal ganglial and nonbasal ganglial systems. Dopaminergic pathways include the nigrostriatal, mesolimbic, mesocortical, and hypothalamic circuit involving prolactin. Many of the side effects of these potent drugs can be explained by these overlap effects.

Dopamine receptors fall into two major categories; those associated with (D1 group) or independent of (D2 group) adenyl cyclase. The D-, group includes receptor types D-, and D5 , and the D2 group includes D2 , D3 , and D4 . In relationship to the striatum and its double dopaminergic input from the substantia nigra, the direct pathway involves the D-, receptors and the indirect pathway involves D2 systems.

ACETYLCHOLINE

Acetylcholine is synthesized from dietary choline, and acetyl coenzyme A by the enzyme choline acetyltransferase (CAT). There are two types of cholinergic receptors in basal ganglial structures, nicotinic and muscarinic. The cholinergic interneurons within the striatum are primarily muscarinic, but nicotinic receptors also populate the striatum as well as other basal ganglial nuclei. Because CAT is the rate-limiting enzyme, its function cannot easily be increased. Hence, augmentation of presynaptic acetylcholine has remained largely an unrealized dream for neuropharmacologists. The normal metabolism of acetylcholine takes place within the cholinergic synapse by the extracellular enzyme acetylcholinesterase. The centrally active acetylcholinesterase inhibitor physostigmine increases the available acetylcholine at central cholinergic receptors and increases cholinergic activity transiently. Its use in clinical medicine is limited by its short duration of action, its usual parenteral use, and its peripheral side effects. At present, cholinergic receptor agonists are being developed in order to bypass the presynaptic acetylcholine-synthesizing cells. In regard to antagonism of the cholinergic system, CAT inhibitors have not been developed and would likely be highly toxic. Cholinergic receptor antagonists are widely available for the muscarinic population and have been available since the nineteenth century. Originally called belladonna alkaloids, they block the muscarinic receptors of the pupil as well as the central nervous system and hence were used in the past by women who wanted large pupils as a sign of beauty.

GAMMA-AMINOBUTYRIC ACID

Unlike acetylcholine and dopamine, GABA is a tiny amino acid that serves both as a neurotransmitter and as an intermediate metabolite in the normal function of cells. GABA is synthesized from glutamate, another amino acid neurotransmitter, by way of the vitamin B6 -dependent enzyme, glutamate decarboxylase. The presence of this enzyme has helped investigators in deducing whether GABA is present in a cell as a neurotransmitter or as a metabolite in other cell functions. The metabolism of GABA can proceed by two paths, via GABA transaminase or via the Krebs cycle.

In basal gangliar systems, GABAergic cells have a dense representation in the striatum, co-existing in cells that also contain either substance P or enkaphalins. Striatal GABAergic cells send axons to the substantia nigra pars compacta and reticulata, and to the external and internal globus pallidi. The pathways from the external globus pallidus to the subthalamic nucleus and from the internal globus pallidus to the thalamus also use GABA. In all known systems, GABA appears to interact with its receptor systems to inhibit or hyperpolarize.

GLUTAMATE

This amino acid has high depolarization potential in many neuronal populations. Like GABA, it is an intermediate in cellular metabolism, so the presence of glutamate in a cell does not necessarily suggest neurological activity. As a neurotransmitter, however, glutamate functions with its receptors in an excitatory or depolarizing system at primary afferent nerve endings, the granule cells of the cerebellum, the dentate gyrus, and the corticostriatal pathways important to basal gangliar function. The differentiation between glutamate-containing and aspartate-containing neurons is difficult with present technology. Glutamate activates receptors sensitive to either N-methyl-D-aspartate (NMDA), kainate, or quisqualate (non-NMDA).

NOREPINEPHRINE

This catecholamine neurotransmitter has its main cell populations in the hypothalamus, the lateral tegmentum, and the locus ceruleus. It is synthesized from dopamine, and therefore shares the same enzymes, including the rate-limiting tyrosine hydroxylase. Norepinephrine, however, has a unique enzyme associated with its synthesis called dopamine beta-hydroxylase that transforms dopamine into norepinephrine. The presence of this unique enzyme is the primary way that noradrenergic cells are identified in the central nervous system. Norepinephrine is released from vesicles and activates two primary receptor systems, alpha and beta. Like dopamine, norepinephrine is removed from the synapse by active reuptake into the presynaptic cell and then is metabolized by two enzymes, MAO and COMT. The final metabolic product of norepinephrine is 3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid; VMA), although another metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), is often followed as the preferred marker of central nervous system norepinephrine metabolism. The noradrenergic system is more fully discussed in Chapters .

SEROTONIN

This indolamine neurotransmitter has its main cell bodies in the dorsal raphe nucleus of the brain stem as well as

the spinal cord, hippocampus, and cerebellum. In parallel to dopamine, it is synthesized by a two-step process, first with a rate-limiting enzyme and then a general enzyme. The first step takes tryptophan to 5-hydroxytryptophan (5-HTP) with the rate-limiting enzyme, tryptophan hydroxylase. The second step takes this intermediate to serotonin (5-hydroxytryptamine, or 5-HT) by aromatic amino acid decarboxylase, which is the same enzyme involved in dopamine synthesis. There are several types of serotonin receptors spread throughout the brain, and they are classified by their location, enzymatic linkage, and propensity for various ligands. Serotonin is metabolized like the catecholamines, by active reuptake into the presynaptic cell and then metabolism by MAO (see also Chapters ).

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