Norepinephrine noradrenergic receptors

Capuano CA, Leibowitz SF, Barr GA. 1992. The pharmaco-ontogeny of the paraventricular alpha 2-noradrenergic receptor system mediating norepinephrine-induced feeding in the rat. Brain Res Dev Brain Res 68(1) 67-74. 

Dextroamphetamine is a powerful stimulant of the nervous system that manifests its effects by releasing dopamine and norepinephrine from presynaptic nerve endings, thus stimulating central dopaminergic and noradrenergic receptors. In certain doses it strengthens the excitatory process in the CNS, reduces fatigue, elevates mood and the capacity to work, reduces the need for sleep, and decreases appetite. 

Norepinephrine is released into the synapse from vesicles [(1) in Fig. 2.7] amphetamine facilitates this release. Norepinephrine acts in the CNS at two different types of noradrenergic receptors, the a and the P [see (2a), (2b) and (3) in Fig. 2.7]. a-Adrenergic receptors can be subdivided into receptors (coupled to phospholipase and located postsynaptically) and tt2 receptors (coupled to Gj and located primarily presynapti-cally) (Insel, 1996). P-Adrenergic receptors in the CNS are predominantly of the P subtype (3 in Fig. 2.7). P receptors are coupled to and lead to an increase in cAMP. Cyclic AMP triggers a variety of events mediated by protein kinases, including phosphorylation of the P receptor itself and regulation of gene expression via phosphorylation of transcription factors. 

Although the density of fibers innervating various sites differs considerably, most regions of the CNS receive diffuse noradrenergic input. All noradrenergic receptor subtypes are metabotropic. When applied to neurons, norepinephrine can hyperpolarize them by increasing potassium conductance. This effect is mediated by ct2 receptors and has been characterized... 

In terms of antidepressant actions, evidence points to the projection of noradrenergic neurons from the locus coeruleus to the frontal cortex as the substrate of this therapeutic action (Fig. 5-24). The noradrenergic receptor subtype that may mediate norepinephrine s antidepressant actions there is the beta 1 postsynaptic receptor. Therapeutic actions in cognition are not yet established but could theoretically be mediated by norepinephrine s pathway from the locus coeruleus to other areas of the frontal cortex (Fig. 5-25). Postsynaptic receptors thought to mediate cognitive actions of norepinephrine in animal models are especially the alpha 2 noradrenergic... 

Overactivity of noradrenergic neurons creates too much postsynaptic norepinephrine at noradrenergic receptors, particularly beta receptors (Fig. 8-14). As is consistent with the hypothesis of a state of norepinephrine excess in anxiety, it is possible to reduce symptoms of anxiety in some cases by blocking beta receptors with beta... 

The principle of negative feedback control is also found at the presynaptic level of autonomic function. Important presynaptic feedback inhibitory control mechanisms have been shown to exist at most nerve endings. A well-documented mechanism involves an 2 receptor located on noradrenergic nerve terminals. This receptor is activated by norepinephrine and similar molecules activation diminishes further release of norepinephrine from these nerve endings (Table 6-4). Conversely, a presynaptic Breceptor appears to facilitate the release of norepinephrine. Presynaptic receptors that respond to the transmitter substances released by the nerve ending are called autoreceptors. Autoreceptors are usually inhibitory, but many cholinergic fibers, especially somatic motor fibers, have excitatory nicotinic autoreceptors. 

Norepinephrine Noradrenergic neuron cell bodies are mainly located in the brain stem and the lateral tegmental area of the pons. These neurons fan out broadly to provide most regions of the CNS with diffuse noradrenergic input. Excitatory effects are produced by activation of alpha and beta, receptors. Inhibitory effects are caused by activation of alphaj and beta, receptors. CNS stimulants, monoamine oxidase inhibitors, and tricyclic antidepressants affect the activity of noradrenergic pathways. 

Extractions are also sometimes necessary to remove unwanted ligands that may interfere with the binding assay. To measure the content of norepinephrine in adrenal tissue it is essential first to separate the desired ligand from the epinephrine present in this tissue, since both catecholamines will interact with the noradrenergic receptor binding sites (Enna, 1978). 

Ethanol also reduces the activity of the noradrenergic system in the locus coeruleus, and alterations in norepinephrine activity may account for some aspects of intoxication and the abstinence syndrome. The 0.2 antagonist clon-idine and the P-receptor antagonist propranolol reduce some symptoms of alcohol withdrawal (Bailly et al. 1992 Carlsson and Fasth 1976 Dobrydnjov et al. 2004 Kahkonen 2003 Petty et al. 1997 Wong et al. 2003). 

The postsynaptic receptors on any given neuron receive information from transmitters released from another neuron. Typically, postsynaptic receptors are located on dendrites or cell bodies of neurons, but may also occur on axons or nerve terminals in the latter case, an axoaxonic synaptic relationship may cause increases or decreases in transmitter release. In contrast, autoreceptors are found on certain neurons and respond to transmitter molecules released from the same neuron. Autoreceptors may be widely distributed on the surface of the neuron. At the nerve terminal, they respond to transmitter molecules released into the synaptic cleft on the cell body, they may respond to transmitter molecules released by dendrites. Functionally, most autoreceptors appear to decrease further transmitter release in a kind of negative feedback loop. Autoreceptors have been identified for all the catecholamines, as well as for several other neurotransmitters. a2-adrenergic receptors are often found on noradrenergic nerve terminals of postganglionic sympathetic nerves, as well as on noradrenergic neurons in the CNS [36], and activation of these receptors decreases further norepinephrine release. Dopamine autoreceptors,... 

More direct evidence of noradrenergic effects comes from studies using the a2 antagonist, yohimbine. a2 adrenergic receptors are known to be present on the cell bodies and terminals of norepinephrine neurons,... 

The inhibitory presynaptic a-adrenoceptors found on noradrenergic neurons are of the aj-subtype. Adrenoceptors of the Pj subclass also occur presynap-tically, and activation of these receptors leads to enhanced norepinephrine release. The physiological and pharmacological importance of these presynaptic P2-receptors is less certain than it is for presynaptic aj-receptors. 

Angiotensin II, acting at presynaptic receptors on noradrenergic nerve terminals, potentiates the release of norepinephrine during low-frequency sympathetic nerve stimulation. Aside from its action on the nerve terminals of postganglionic sympathetic neurons, angiotensin II can directly stimulate sympathetic neurons in the central nervous system, in peripheral autonomic ganglia, and at the adrenal medulla. 

FIGURE 2.7 Noradrenergic synapse. The release of norepinephrine (1) can be enhanced by compounds such as amphetamine. Once released, norepinephrine binds to a2 receptors (2a), al receptors (2b), and pi receptors (3). Norepinephrine is removed from the synapse via cleavage by catechol-O-methyl-transferase (COMT) or via reuptake by the norepinephrine transporter (4). 

Other available antidepressants have unique mechanisms of action that may have an impact on norepinephrine, serotonin, or dopamine indirectly through other mechanisms. For example, mirtazapine s direct antagonism of presynaptic a2-adrenergic receptors results in an indirect increase in central noradrenergic and serotonergic activity. 

One can simply classify a drug as noradrenergic on the basis of interaction with the transporter or specific receptor subtypes. But this does not really address the functional consequences, such as the extent to which, for instance, a drug affects the intrasynaptic concentration of norepinephrine. The latter requires some knowledge of the pathway followed by norepinephrine from synthesis, storage, release, and clearance. This pathway is depicted in Figure 15-1. 

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