The ascending noradrenergic system originates in the locus coeruleus
The NE-containing neurons within the brain are located in the parts of the brain stem called the pons and medulla. Of particular interest is a structure known as the locus coeruleus (LC), a small area of the pons that contains a dense collection of noradrenergic neurons corresponding roughly to the A6 cell group (using the numbering system described previously). At first glance, the LC might not seem to be a very impressive structure, as the rat LC only contains a little more than 3000 nerve cells out of the millions of neurons present in the entire rat brain. Nevertheless, these cells send fibers into almost all areas of the forebrain, thereby providing nearly all of the NE in the cortex, limbic system, thalamus, and hypothalamus. The LC also provides noradrenergic input to the cerebellum and the spinal cord.
Norepinephrine also plays an important role in the peripheral nervous system. Many neurons that have their cell bodies in the ganglia of the sympathetic branch of the autonomic nervous system use NE as their transmitter. These cells, which send out their fibers to various target organs throughout the body, are responsible for the autonomic actions of NE that are described later. We also mentioned earlier in the post that NE (as well as EPI) functions as a hormone secreted by the adrenal glands directly into the bloodstream. In this way, there are actually two routes by which NE can reach an organ such as the heart: it can be released from sympathetic noradrenergic neurons at synapse-like contacts with cardiac cells, and it can be released from the adrenal glands and travel to the heart through the circulatory system. On the other hand, blood-borne NE does not reach the brain, because it is effectively excluded by the blood- brain barrier.
Modern techniques of neurophysiology make it possible to record the electrical firing of nerve cells in unanesthetized, freely moving animals. Aston-Jones and Bloom (1981a, 1981b) used this approach to determine how the activity of noradrenergic neurons in the LC of rats changed in relation to the behavior of the animals. The cells showed a low rate of firing (and sometimes even stopped altogether) when the rats were asleep. In contrast, presentation of novel sensory stimuli to the animals led to a short burst of LC cell firing. These and many other findings have led to the idea that the noradrenergic neurons of the LC play an important role in vigilance (that is, being alert to important stimuli in the environment).
The cellular effects of norepinephrine and epinephrine are mediated by α and β-adrenergic receptors
The receptors for NE and EPI are called adrenergic receptors (an alternate term is adrenoceptors). Like DA receptors, the adrenergic receptors all belong to the general family of metabotropic receptors. However, they serve a broader role by having to mediate both neurotransmitter (mainly NE) and hormonal (mainly EPI) actions of the catecholamines.
Early studies by Ahlquist (1948, 1979) and other investigators suggested the existence of two adrenoceptor subtypes, which were designated alpha (α) and beta (β). Since Ahlquist’s pioneering research, many experiments have shown that the α and β-adrenoceptors actually represent two families, each composed of several receptor subtypes. For present purposes, we will distinguish between α1 and α2-receptors, and also between β1 and β2. Postsynaptic adrenoceptors are found at high densities in many brain areas, including the cerebral cortex, thalamus, hypothalamus, cerebellum, and various limbic system structures such as the hippocampus and amygdala. In addition, α2-autoreceptors are located on noradrenergic nerve terminals and on the cell bodies of noradrenergic neurons in the LC and elsewhere. These autoreceptors cause an inhibition of noradrenergic cell firing and a reduction in NE release from the terminals.
Like DA D1 receptors, the β1 and β2-adrenoceptors both stimulate adenylyl cyclase and enhance the formation of cAMP. In contrast, a2-receptors operate in a similar manner as D2 receptors. That is, α2-receptors reduce the rate of cAMP synthesis by inhibiting adenylyl cyclase, and they can also cause a hyperpolarization of the cell membrane by increasing K+ channel opening. Yet another kind of mechanism is used by receptors of the α1 subtype. These receptors operate through the phosphoinositide second-messenger system, which, leads to an increased concentration of free calcium (Ca2+) ions within the postsynaptic cell.
Adrenergic agonists can stimulate arousal and eating behavior
Neurochemical and pharmacological studies in experimental animals indicate that NE is involved in many behavioral functions, including hunger and eating behavior, sexual behavior, fear and anxiety, pain, and sleep and arousal. We will provide a few pharmacological examples relevant to some of these functions.
We saw earlier that the firing of noradrenergic neurons of the LC is correlated with arousal and vigilance. The behavioral-activating functions of NE have also been investigated using pharmacological approaches. For example, Craig Berridge and his colleagues performed microinjections of the α1-receptor against phenylephrine and/or the general β receptor agonist isoproterenol into the rat medial septum, one of the brain areas believed to be important for NE’s arousing effects (Berridge et al., 2003). The animals were then monitored to determine the amount of time they spent awake or asleep. Each drug individually increased the amount of time spent awake, and at the low doses used in the study, the combination of the treatments produced the strongest effect. These results show that both α and β-receptors are involved in NE-mediated arousal.
In both humans and animals, systemically administered α2-receptor agonists have several behavioral effects related to activation of both autoreceptors and postsynaptic α2-receptors. This can be seen in the properties of dexmedetomidine (Precedex), a recently introduced α2-agonist with combined sedative, anxiolytic (antianxiety), and-analgesic (pain-reducing) effects that is particularly useful for surgical patients in the intensive care unit. The sedative and anxiolytic effects of dexmedetomidine are believed to be mediated by α2-autoreceptors in the LC, whereas the analgesic effect probably occurs at the level of the spinal cord.
Another behavioral function of NE concerns the regulation of hunger and eating behavior. The neural mechanisms underlying eating behavior are centered largely in the hypothalamus. One of the key areas within the hypothalamus is the paraventricular nucleus (PVN), a small paired structure that lies on either side of the third cerebral ventricle. The PVN receives noradrenergic input from the LC, and when NE is injected in small quantities directly into the PVN of awake rats, it elicits a robust eating response even if the animals were not previously food-deprived. This response to NE appears to be due to activation of α2-receptors located within the PVN, because the response is blocked by administration of an α2-antagonist and is mimicked when the α2-agonist clonidine, instead of NE, is injected into the PVN (Wellman et al., 1993). Although we previously discussed the α2 subtype as an autoreceptor, the PVN α2-receptors responsible for triggering eating behavior are thought to lie on postsynaptic neurons that receive noradrenergic synapses.
A number of medications work by stimulating or inhibiting peripheral adrenergic receptors
Adrenergic agonists or antagonists are frequently used in the treatment of nonpsychiatric medical conditions. This is because of the widespread distribution and important functional role of adrenergic receptors in various peripheral organs (Table 1). For example, general adrenergic agonists that activate both α and βreceptors have sometimes been used in the treatment of bronchial asthma. Stimulating the a-receptors causes constriction of the blood vessels in the bronchial lining, thus reducing congestion and edema (tissue swelling) by restricting blood flow to the tissue. On the other hand, β receptor stimulation leads to relaxation of the bronchial muscles, thereby providing a wider airway. Although general adrenergic agonists can be effective antiasthma medications, they also cause a number of adverse side effects. For this reason, asthma is more commonly treated with a selective β-adrenoceptor agonist such as albuterol. Such drugs are packaged in an inhaler that delivers the compound directly to the respiratory system. The β-receptors found in the airways are of the β2 subtype, in contrast to the heart, which contains mainly β1-receptors. Consequently, albuterol is effective in alleviating the bronchial congestion of asthmatics without producing undesirable cardiovascular side effects.
TABLE 1 Location and Physiological Actions of Peripheral α and β-Adrenergic Receptors
|Heart||Increased rate and force of contraction||
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|Smooth muscle of the trachea and bronchi||Relaxation||
|Uterine smooth muscle||Contraction||
|Adipose (fat) tissue||Increased fat breakdown and release||
Even over-the-counter cold medications are based on the properties of peripheral adrenergic receptors. Thus, the α1 receptor agonist phenylephrine is the key ingredient in Neosynephrine. This drug is used as a nasal spray to constrict the blood vessels and reduce inflamed and swollen nasal membranes resulting from colds and allergies. In the form of eye drops, it is also used to stimulate a-receptors of the iris to dilate the pupil during eye examinations or before surgery of the eyes.
Alpha2-receptor agonists such as clonidine are commonly used in the treatment of hypertension (high blood pressure). The therapeutic benefit of these drugs is due to their ability to inhibit activity of the sympathetic nervous system while stimulating the parasympathetic system. The combined effect of these actions is to reduce the patient’s heart rate and blood pressure. As would be expected from our previous discussion of α2-agonists, the typical side effects of clonidine treatment are sedation and feelings of sleepiness.
Adrenergic receptor antagonists likewise have varied clinical uses. For example, the α2-antagonist yohimbine helps in the treatment of certain types of male sexual impotence. This compound increases parasympathetic and decreases sympathetic activity, which is thought to stimulate penile blood inflow and/or inhibit blood outflow.
The α1-antagonist prazosin and the general β-adrenoceptor antagonist propranolol are both used clinically in the treatment of hypertension. Prazosin causes a dilation of blood vessels by blocking the α1 responsible for constricting these vessels. In contrast, the main function of propranolol is to block the β-receptors in the heart, thereby reducing the heart’s contractile force. The discovery that β1 is the major adrenoceptor subtype in the heart has led to the introduction of β1-selective antagonists such as metoprolol. These compounds exhibit fewer side effects than the more general β- antagonist propranolol. Beta-receptor antagonists like propranolol and metoprolol are also useful in the treatment of cardiac arrhythmia (irregular heartbeat) and angina pectoris (feelings of pain and constriction around the heart caused by deficient blood flow and oxygen delivery to the heart).
Finally, it should be mentioned that propranolol and other p-antagonists have also been applied to the treatment of generalized anxiety disorder, which is one of the most common types of anxiety disorder. Many patients with generalized anxiety disorder suffer from physical symptoms such as palpitations, flushing, and tachycardia (racing heart). Beta-blockers do not alleviate anxiety per se, but instead they may help the patient feel better by reducing some of these distressing physical symptoms of the disorder.
The most important cluster of noradrenergic neurons is the A6 cell group, which is located in a region known as the locus coeruleus. These neurons innervate almost all areas of the forebrain and mediate many of the important behavioral functions of NE. Activity of LC cells depends on the behavioral state of the organism. The cells are relatively inactive during sleep, but they fire at a rapid rate in response to novel sensory stimuli. The noradrenergic system is thus thought to be important in the maintenance of vigilance.
TABLE 2 Drugs That Affect the Noradrenergic System
|Phenelzine||Increases catecholamine levels by inhibiting MAO|
|a-Methyl-para-tyrosine (AMPT)||Depletes catecholamines by inhibiting tyrosine hydroxylase|
|Reserpine||Depletes catecholamines by inhibiting vesicular uptake|
|6-Hydroxydopamine (6-OHDA)||Damages or destroys catecholaminergic neurons|
|Cocaine and methylphenidate||Inhibit catecholajnine reuptake|
|Desipramine||Selectively inhibits NE reuptake|
|Phenylephrine||Stimulates a1-receptors (agonist)|
|Clonidine||Stimulates a2-receptors (agonist)|
|Albuterol||Stimulates β-receptors (partially selective for β2)|
|Prazosin||Blocks a1-receptors (antagonist)|
|Yohimbine||Blocks a2-receptors (antagonist)|
|Propranolol||Blocks β-receptors generally (antagonist)|
|Metoprolol||Blocks β-receptors (antagonist)|
NE and EPI activate a group of metabotropic receptors called adrenoceptors. They are divided into two broad families, α and β, which are further subdivided into α1, α2, β1 and β2. Both β-receptor subtypes enhance the synthesis of cAMP, whereas α2-receptors inhibit cAMP formation. Another mechanism of action of α2-receptors involves hyperpolarization of the cell membrane by stimulating K+ channel opening. In contrast, α1-receptors increase the intracellular concentration of Ca2+ ions by means of the phos-phoinositide second-messenger system.
Some of the drugs that affect the noradrenergic system, including adrenergic receptor agonists and antagonists. Adrenergic agonists are used therapeutically for various physiological and psychological disorders. These include the α1-agonist phenylephrine, which helps relieve nasal congestion; the α2-agonist clonidine, which is used in the treatment of hypertension and drug withdrawal symptoms; and β2-agonists such as albuterol, which is an important medication for relieving bronchial congestion in people suffering from asthma. Adrenergic receptor antagonists also have several clinical uses. The α2- antagonist yohimbine is sometimes prescribed for male impotence. The α1-antagonist prazosin, the general β-receptor antagonist propranolol, and several selective β-antagonists such as metoprolol are used in the treatment of hypertension. Beta-blockers also have a role in the treatment of generalized anxiety disorders, because these drugs reduce some of the somatic symptoms associated with strong anxiety. In general, the clinical application of adrenoceptor agonists and antagonists can be understood from the receptor subtypes in specific tissues or organs that they target and the resulting physiological effect of stimulating or blocking those receptors.