Nature Of The Catecholaminergic Systems

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Catecholamines are relativity small organic molecules that function in the brain and elsewhere in the body, primarily in a regulatory or modulating role, to keep various systems functioning smoothly in response to demands of the internal and external environment. The most familiar of the three natural catecholamines is adrenaline, or epinephrine (Fig. 1). Its effects have been experienced by all of us, for example, in response to a frightening experience. Its release into the bloodstream from the neuronal cell bodies located in the medulla of the adrenal gland regulates heart rate and blood pressure and helps to put us into a readiness state for fight or flight. Norepinephrine, the closest chemical relative of epinephrine, is more prominently localized in the brain than epinephrine, but it is also found in so-called peripheral neurons (those neurons found outside of the brain). In the brain norepinephrine regulates mood and level of emotional arousal and

Figure 1 Pathway for biosynthesis of the major catecholamines (reproduced with permission from Friedhoff and Silva, 1993).

alertness. Dopamine, the third catecholamine, is prominently involved in regulating motor or movement functions and also in the coordination of associative thinking and integration of sensory motor function. Thus, key volitional acts such as movement and thinking are fine-tuned, integrated, and given emotional coloration through the actions of the three catecholamines.

A. Neurotransmission

Information transfer in the brain is carried out mainly by synaptic transmission, or the passage of a message across synapses or gaps between communicating cells. This occurs through a combination of electrical transmission that takes place within a neuron and the release of a chemical or neurotransmitter that crosses the synaptic gap and then acts on a postsynaptic neuron via specialized detection sites called receptors. However, there are some exceptions to this general model. For example, some neurons (not catecholami-nergic) relate to each other entirely by change in electrical potential. In many cases involving the catecholaminergic system, other substances are cor-eleased with the neurotransmitter and modify or modulate its effect. The nature of the effector response can vary depending on the type of receptor, location of the membrane, and the nature of the neuromodula-tors. For example, the stimulation of b3-adrenergic receptors located in adipose tissues will stimulate the breakdown of fats (lipolysis). This can be contrasted with the stimulation of different a2-adrenergic receptors, one of which may inhibit the release of certain neurotransmitters at the presynaptic level of adrener-gic nerve cells, thereby causing inhibition of norepi-nephrine release. Stimulation of another a2-adrenergic receptor located on the membranes of the b cells of the pancreas will cause a decrease in insulin secretion.

The synapse is an important locus for the action of drugs that modify behavior. By blocking reuptake of transmitters, the effect of the transmitter can be enhanced or exaggerated. Conversely, by blocking receptors on postsynaptic cells, transmitter effect can be reduced. A third possibility, which has been exploited pharmacologically, is the modification of the ion exchange involved in electrical transmission. This too can have effects on motor and mental activity.

It should also be kept in mind that neurotransmission in the catecholaminergic system can be altered by impingement of other transmitter systems. One example is the glutamatergic system. Neural projections from this system can modulate dopamine release in the cortex. Pharmacologic antagonists of this system, such as phenylcyclidine, can increase dopamine outflow at the level of the striatum. Strikingly, in the behavioral realm, the administration of this agent produces a clinical picture that mimics the psychotic processes that have been associated with abnormalities in the dopaminergic system.

Finally, when discussing neurotransmission the termination of the signal is of paramount importance. If the transmitter is not removed from the synaptic cleft, a desensitization of the postsynaptic receptor will occur as a result of continued catecholamine exposure. Reuptake of neurotransmitters is a common mechanism for inactivation. This process facilitates the removal of the transmitter and affords the ability to reuse the molecule. There are transporter molecules located on the membranes of terminals that produce high-affinity bonds and facilitate these mechanisms. Theoretically, these molecules are also capable of releasing bonded substances and thus producing postsynaptic activation. Nonetheless, the catecholamine transporter is an exciting area of research.

B. Biosynthesis of Catecholamines

The starting point for the synthesis of all the catecho-lamines is l-tyrosine, which is a nonessential amino acid that can be found in the diet. Synthesis of these neurotransmitters may vary, depending on dietary consumption of tyrosine-containing products. l-Tyr-osine is hydroxylated (it gains an OH group) to form dihydroxy-l-phenylalanine, which is also known as levodopa or l-dopa. The enzyme responsible for this transformation is tyrosine hydroxylase. In dopami-nergic neurons, l-dopa is metabolized to dopamine by means of the enzyme dopa decarboxylase. This enzymatic process occurs in the cytoplasmic component of neurons. In noradrenergic nerve cells and in the adrenal medulla, dopamine is transformed to norepi-nephrine. This is facilitated by the enzyme dopamine b-hydoxylase. It has been estimated that approximately 50% of the dopamine synthesized in neuronal cytoplasm of noradrenergic cells is metabolized to norepinephrine. Norepinephrine can then be transformed to epinephrine by the addition of a methyl group (CH3) to its amino group through the action of the enzyme phenethanolamine-N-methyltransferase. This last step occurs in certain neurons of the brain and in the adrenal medulla (graphic and schematic representations of the biosynthesis and breakdown of catecho-lamines can be found in many of the references listed in Suggested Reading). In general, the enzymes described in this section are produced in the neuronal cell bodies and are then transported and stored in nerve endings. Therefore, the process of catecholamine biosynthesis takes place within these terminals. The catecholamines that are synthesized are then taken up and stored in vesicles (chromaffin granules) of the nerve terminals, which are located near the cell membrane. During neural transmission, catecholamines are released from these vesicles into the synaptic cleft. Although certain precursors of catecholamines (such as l-dopa) penetrate the blood-brain barrier, the catecholamines do not. Thus, all the catecholamines found in the brain are produced there.

The amount of catecholamines within the adrenal medulla and the sympathetic nervous system is generally constant; however, there are times when cate-cholamine levels in the body change dramatically. Initial changes that occur in the synthesis of these substances, in response to changes in demand, occur in minutes, whereas slower adaptational changes occur over much longer periods, even days in some cases. Catecholamines in the body are maintained at constant levels by a highly efficient process that modulates their biosynthesis, release, and subsequent inactiva-tion. One example of a state with abnormal catecho-lamine levels is the condition known as pheochromocytoma, in which there is a tumor of the chromaffin cells of the medulla in the adrenal glands. It is characterized by hypersecretion of epinephrine, norepinephrine, dopamine, or dopa. In this condition urinary excretion of free catecholamines is also increased. The major clinical manifestations of this illness are high blood pressure, increased heart rate, sweating, rapid breathing, headaches, and the sensation of impending doom.

When an appropriate signal is received by a catecholaminergic neuron, it is transmitted down the axon to the presynaptic terminal, where it initiates the release of quanta of neurotransmitter into the synaptic cleft. The transmitter acts on receptors in postsynaptic neurons, resulting in the activation or inhibition of these cells.

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