Autoreceptors norepinephrine

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,... 

Clonidine (Catapres). Clonidine is largely used to treat high blood pressure. Although we don t fully understand how clonidine acts, it appears to reduce norepinephrine activity by stimulating a norepinephrine receptor known as the alpha-2 receptor. When clonidine binds to alpha-2 receptors on norepinephrine neurons, so-called autoreceptors, the cells are tricked into believing that there is already sufficient norepinephrine released and thus decrease any additional release of norepinephrine. As one might anticipate, clonidine is somewhat effective at reducing the hyperactivity and impulsivity of ADHD. It does not, however, provide nearly as much benefit for the inattention of ADHD. 

H3-receptors have been identified in the central nervous system. They are located on presynaptic membranes and serve as inhibitory autoreceptors at histaminergic neurons. They are also found on certain human autonomic nerve endings and in atrial tissue where they may inhibit norepinephrine release during ischemia. 

Imipramine Tertiary Blockade of norepinephrine reuptake at 0.2 autoreceptor and blockade of serotonin reuptake at 5-HTi autoreceptor 13 2 42 2 Enuresis, age 6+ years... 

It is thought that some problems with brain functioning might be due to breakdowns in this autoreceptor feedback system. Both norepinephrine and serotonin have autoreceptor feedback systems in the nuclei in which the cells originate. These systems appear to be affected in some models of anxiety. 

Mirtazapine has a complex pharmacology. It is an antagonist of the presynaptic k2 autoreceptor and enhances the release of both norepinephrine and 5-HT. In addition, mirtazapine is an antagonist of 5-HT and 5-HT receptors. Finally,... 

FIGURE 5—44. This figure shows how norepinephrine can function as a brake for serotonin release. When norepinephrine is released from nearby noradrenergic neurons, it can diffuse to alpha 2 receptors, not only to those on noradrenergic neurons but as shown here, also to these same receptors on serotonin neurons. Like its actions on noradrenergic neurons, norepinephrine occupancy of alpha 2 receptors on serotonin neurons will turn off serotonin release. Thus, serotonin release can be inhibited not only by serotonin but, as shown here, also by norepinephrine. Alpha 2 receptors on a norepinephrine neuron are called autoreceptors, but alpha 2 receptors on serotonin neurons are called heteroreceptors. 

FIGURE 8—13. If an alpha 2 agonist such as clonidine, is administered, it will have much the same action as norepinephrine (NE) itself both at somatodendritic alpha 2 autoreceptors and at terminal alpha 2 autoreceptors. This action is that of reducing both neuronal impulse in NE neurons and release of NE from noradrenergic axon terminals. Thus, alpha 2 agonists will decrease the symptoms associated with anxiety, especially the autonomic symptoms of dilated pupils, tachycardia, tremor, and sweating. 

Norepinephrine One theory about the biological basis of panic disorder is that there is an initial excess of norepinephrine (Fig. 9—3). This theory is supported by evidence that panic disorder patients are hypersensitive to alpha-2 antagonists and hyposensitive to alpha-2 agonists. Thus, yohimbine, an alpha-2 antagonist, acts as a promoter of norepinephrine release by cutting the brake cable of the presyn-aptic norepinephrine autoreceptor, as shown earlier in Figure 7—6. The consequence... 

Hallucinogens have rather complex interactions at neurotransmitter systems, but one of the most prominent is a common action as agonists at serotonin 2A (5HT2A) receptor sites (Fig. 13—10). Hallucinogens certainly have additional effects at other 5HT receptors (especially 3HT1A somatodendritic autoreceptors) and also at other neurotransmitter systems, especially norepinephrine and dopamine, but the relative importance of these other actions are less well known. Also, MDMA appears to be a powerful releaser of serotonin and it and several drugs structurally related to it... 

On the other hand, it has been suggested that the primary problem in depression is an increased sensitivity to receptors that are located on the presynaptic terminals of amine synapses.54 These presynaptic autoreceptors normally regulate and limit the release of amine transmitters, such as norepinephrine or serotonin, from the presynaptic terminal. Increasing their sensitivity could result in a relative lack of adequate neurotransmitter release at these synapses. By causing overstimulation of these presynaptic receptors, antidepressant drugs could eventually normalize their sensitivity and help reestablish proper control and regulation of these amine synapses.54... 

Mirtazapine [Remeron] Exact mechanism unclear may increase norepinephrine and serotonin activity by blocking inhibitory presynaptic autoreceptors Low incidence of sedative, anticholinergic, and cardiovascular side effects May cause agitation, anxiety, other mood changes... 

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. 

Gainetdinov RR, Caron MG (2003) Monoamine transporters from genes to behavior. Annu Rev Pharmacol Toxicol 43 261-284. Epub %2002 Sep 17 Garcia AS, Barrera G, Burke TF, Ma S, Hensler JG, Moiilak DA (2004) Autoreceptor-mediated inhibition of norepinephrine release in rat medial prefrontal cortex is maintained after chronic desipramine treatment. J Neurochem 91 683-693 Gelb DJ, Oliver E, Gilman S (1999) Diagnostic criteria for Parkinson disease. Arch Neurol 56 33-39... 

Figure 4.4 Remeron blocks alpha-2 receptors on neurons that make serotonin and norepinephrine (noradrenaline). Alpha-2 autoreceptors are found on neurons that make norepinephrine. When norepinephrine is released in the synapse, some of it binds to autoreceptors, which tells the neuron to stop releasing neurotransmitters. Alpha-2 heteroreceptors are receptors found on neurons that do not make norepinephrine. Heteroreceptors also provide negative feedback to the neuron releasing a neurotransmitter (serotonin in this diagram).

Autoreceptors appear to regulate transmitter synthesis and/or release. The mechanisms by which these receptors exert their activity in the nerve terminal is unknown, although processes involving protein phosphorylation, calmodulin, and protein carboxymethylation have been proposed. Released transmitter is believed to feed back to the terminal from which it was released and inhibit further release by binding to the autoreceptor. Although autoreceptors have been identified to dopamine, norepinephrine, serotonin, and GABA, the most detailed information to date concerns the norepinephrine autoreceptor, which shares properties with the a-receptor. 

Heteroreceptors (HRs), like autoreceptors, can either suppress (inhibitory autoreceptors such as the tt2-adrenergic) or enhance the release of neurotransmitters. They are termed heteroreceptors since they are activated by neurotransmitters (e.g. norepinephrine) different from those produced by the nerve on which they are located (e.g. serotonergic). There might be numerous different heteroreceptors that bind various neurotransmitters on a single nerve. Table 1.2 summarizes some of the main modulating mechanisms relevant to intact functioning of the presynaptic nerve. Psychotropic medications can either enhance or suppress many of the major processes or modulatory events listed in this chapter. - ... 

Figure 6-3. Lcx al integration of ANS control via modulation of transmitter release. In the example shown, release of norepinephrine from a sympathetic nerve ending is modulated by norepinephrine itself, acting on presynaptic autoreceptors, and by acetylcholine and angiotensin II. Many other modulators (see text) influence the release process.

Figure 30-2. Possible sites of action of antidepressant drugs. Inhibition of neuronal reuptake of norepinephrine and serotonin increases the synaptic activities of these neurotransmitters. Inhibition of MAO increases the presynaptic stores of both norepinephrine and serotonin, which leads to increased neurotransmitter effects. Blockade of the presynaptic alphag autoreceptor prevents feedback inhibition of the release of norepinephrine. Note These are acute actions of antidepressants.

CNS Autoreceotors for Norepinephrine (NE) - Though the concept of autoinhibition of NE release is not universally accepted,the consensus is that release of NE from sympathetic nerves is modulated through inhibitory a2 autoreceptors. By contrast, somadendritic a2-adreno-ceptors of central noradrenergic neurons inhibit firing.Release of H-amezinium from rat cortical noradrenergic axons has been advanced as a model for the study of the a2-autoreceptor hypothesis. There are a number of mechanisms possible for the link between presynaptic a2 adrenoceptor activation and transmitter release, in which a pivotal role for Ca2+ has been established.3.8 (tore recent data implicates inhibition of adenylate cyclase with receptor activation and subsequent attenuation of transmitter release. 

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