Terminal autoreceptors, serotonin

FIGURE 5—40. Depicted here is the consequence of the 5HT1D terminal autoreceptor being stimulated by serotonin. The terminal autoreceptor of Figure 5—39 is occupied here by 5HT, causing the blockade of 5HT release, as also shown in Fig. 5—41. 

Once the 5HT1A somatodendritic autoreceptors are desensitized, 5HT can no longer effectively inhibit its own release, and the serotonin neuron is therefore dis-inhibited. This results in a flurry of >HT release from axons due to an increase in neuronal impulse flow (Fig. 6—38). This is just another way of saying that the serotonin release is turned on at the axon terminals. The serotonin that now pours out of the various projections of serotonin pathways in the brain theoretically mediates the various therapeutic actions of the SSRls. 

Serotonin 5-HT1A Human cDNA Alzheimer s disease, anxiety, depression, schizophrenia, hypertension, inflammation, pain, migraine, spasticity ulcers, obesity glaucoma Somatodendritic autoreceptor in hippocampus and raphe nuclei, circadian rhythm, somatodendritic heteroreceptor at cholinergic terminals of myenteric plexus... 

FIGURE 6-39. Mechanism of action of serotonin selective reuptake inhibitors (SSRIs)—part 5. Finally, once the SSRIs have blocked the reuptake pump (Fig. 6-36), increased somatodendritic serotonin (Fig. 6-36), desensitized somatodendritic serotonin 1A autoreceptors (Fig. 6—37), turned on neuronal impulse flow (Fig. 6-38), and increased release of serotonin from axon terminals (Fig. 6— 38), the final step shown here may be the desensitization of postsynaptic serotonin receptors. This has also been shown in previous figures demonstrating the actions of monoamine oxidase (MAO) inhibitors (Fig. 6-4) and the actions of tricyclic antidepressants (Fig. 6—6). This desensitization may mediate the reduction of side effects of SSRIs as tolerance develops. 

On the dopamine side of the equation, one of the most promising agents in late clinical development is aripiprazole, theoretically a presynaptic D2 autoreceptor agonist. This compound is postulated to exert its antipsychotic actions in a manner far different from serotonin-dopamine antagonism that is, it may shut off the presynaptic dopamine terminal and stop dopamine release in the mesolimbic dopamine pathway by stimulating presynaptic D2 receptors. The agents Cl-1007 and DAB-... 

Histamine H3-receptors have been reported to regulate not only the release and turnover of histamine via autoreceptors on histaminerglc nerve endings [1-3], but also the releases of noradrenaline, dopamine, serotonin, and acetylcholine via heteroreceptors on non-histaminerglc axon terminals [22-26], Thioperamide increased the release of these neurotransmitters, while... 

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... 

Abstract Presynaptic receptors for dopamine, histamine and serotonin that are located on dopaminergic, histaminergic and sertonergic axon terminals, respectively, function as autoreceptors. Presynaptic receptors also occur as heteroreceptors on other axon terminals. Auto- and heteroreceptors mainly affect Ca2+-dependent exocytosis from the receptor-bearing nerve ending. Some additionally subserve other presynaptic functions. 

Our knowledge of presynaptic dopamine and serotonin receptors dates back to the 1970s (Famebo and Hamberger 1971). Presynaptic histamine receptors were discovered in 1983 (Arrang et al. 1983). Presynaptic dopamine receptors occur as autoreceptors, i.e., on dopaminergic axon terminals, and as heteroreceptors on nondopaminergic axon terminals. By analogy the same holds true for presynaptic histamine and serotonin receptors. The early days of the dopamine autoreceptors were stormy, but the controversies were finally solved (see Starke et al. 1989). The main function that presynaptic receptors affect is transmitter release, which in this article means Ca2+-dependent exocytosis. However, some receptors discussed in... 

Both mianserin and mirtazapine are antidepressant drugs which possess central 0C2 adrenoceptor blocking properties (pA2 7.3). However, mirtazapine is much more potent at histamine Hi receptors (pA2 9.1) and at 5-HT2 and 5-HT3 receptors (pA2 8.2). Blocking of Hi receptors explains the main side effects of mirtazapine, which produces marked sedation and weight gain. Blockade of presynaptic inhibitory 0C2 autoreceptors increases the release of NA, while blockade of presynaptic 0C2 inhibitory heteroreceptors on serotonin nerve terminals (Table 2) is likely to increase the release of serotonin. 

De Groote L, Olivier B, Westenberg HG. Extracellular serotonin in the prefrontal cortex is limited through terminal 5-HT(lB) autoreceptors a microdialysis study in knockout mice. Psychopharmacology (Berl) 2002 162 419-424. 

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. 

HTia autoreceptor is inhibitory in nature thus, it responds to synaptic serotonin and inhibits, through a cascade of intracellular signal transduction, the depolarization of the cell, and, finally, it inhibits the release of serotonin from nerve terminals. Hence, when pindolol is administered, it inhibits the autoinhibition caused by 5-HTia receptors and thereby causes a net increase in synaptic 5-HT concentration. There is good evidence that facilitation of serotonergic neurotransmission may act either directly or indirectly as a unifying mechanism of antidepressant treatment. 

There is, however, some preclinical basis to justify the use of 5-HT,d receptor antagonists in the treatment of depressive disorders. It has been known for some time that facilitation of 5-HT neurotransmission can be achieved by blockade of the presynaptic reuptake site by selective serotonin reuptake inhibitors such as paroxetine and fluoxetine and that such an action results in clinically useful antidepressant properties. It is now believed that the concentration of 5-HT at the terminal is controlled not only by the uptake site but also by an inhibitory terminal 5-HT autoreceptor (see Figure 1) which in higher species of animals is likely to be of the S-HTm subclass (see earlier in this chapter). This inhibitory 5-HT autoreceptor is normally activated by the endogenous release of 5-HT and antagonism of this receptor would lead to disinhibition of the neurone and a facilitation of 5-HT release. Since the net effect of this action would be to provide a rapid increase in 5-HT release, it has been postulated that a 5-HTn, receptor antagonist could have antidepressant properties. 

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