Autoreceptors desensitization

Le Poul E, Laaris N, Hamon M, Lanfumey L. (1997). Fluoxetine-induced desensitization of somatodendritic 5-HTlA autoreceptors is independent of glucocorticoid(s). Synapse. 27(4) 303-12. Leyel CF, ed. (1994). A Modern Herbal. NY Dorset Press. 

Froger N, Gardier AM, Moratalla R, Alberti I, Lena I, Boni C, De Felipe C, Rupniak NM, Hunt SP, Jacquot C, Hamon M, Lanfumey L (2001) 5-hydroxytryptamine (5-HT)lA autoreceptor adaptive changes in substance P (neurokinin 1) receptor knock-out mice mimic antidepressant-induced desensitization. J Neurosci 21 8188-8197 Gardier AM, Bourin M (2001) Appropriate use of knockout mice as models of depression or models of testing the efficacy of antidepressants. Psychopharmacology (Berl) 153 393-394... 

Antidepressant drugs, by contrast, require long-term administration for their therapeutic effects to become evident. Thus, it is clear that the acute actions of these drugs, which are most often to enhance synaptic levels of monoamines, are not sufficient in themselves to mediate their therapeutic effects. Neither is the effect of increased monoamines on postsynaptic second messenger systems, which occurs relatively quickly as well, adequate to account for the therapeutic actions of antidepressants. The most obvious explanation, then, is that molecular adaptations in response to chronic exposure to these drugs are what underlie their therapeutic effects. Consistent with this idea, several hypotheses as to the nature of the relevant molecular adaptations have been proposed. Two models focus on adaptations of the 5-HTia receptor. One theory proposes that desensitization of presynaptic somatodendritic 5-HTia autoreceptors is responsible for the therapeutic action... 

Wang HY, Friedman E Chronic lithium desensitization of autoreceptors mediating serotonin release. Psychopharmacology 94 312-314, 1988 Wang HY, Friedman E Lithium inhibition of protein kinase C activation-induced serotonin release. Psychopharmacology 99 213-218, 1989 Wank SA, Pisegna JR, de Weerth A Brain and gastrointestinal cholecystokinin receptor family structure and functional expression. Proc Natl Acad Sci USA 89 8691-8695, 1992... 

Over time, the increased 5HT at the somatodendritic 5HT1A autoreceptors causes them to down-regulate and become desensitized (Fig. 6—37). When the increase in serotonin is recognized by these presynaptic 5HT1A receptors, this information is sent to the cell nucleus of the serotonin neuron. The genome s reaction to this information is to issue instructions that cause these same receptors to become de-... 

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. 

FIGURE 6-37. Mechanism of action of serotonin selective reuptake inhibitors (SSRIs)—part 3. The consequence of serotonin increasing in the somatodentritic area of the serotonin neuron, as depicted in the Figure 6-36, is to cause the somatodendritic serotonin 1A autoreceptors to desensitize or down-regulate (red circle). 

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. 

If serotonin is very low or depleted from serotonergic neurons in depression, there would not be much of it released for an SSRI to block its reuptake (Fig. 7—31). Thus, there would theoretically be inadequate desensitization of somatodendritic 5HT1A autoreceptors. Unlike the SSRIs, which are all dependent for their actions on the endogenous release of serotonin, buspirone is not dependent on serotonin levels because it has direct actions on 5HT1A receptors (Fig. 7—32). Thus, buspirone may be able to kick start the desensitization process directly. Initially,... 

Presynaptic dopamine autoreceptors are rapidly desensitized by dopamine but not other agonists auch as apomorphine or roxindole (Arbilla et al. 1985 Seyfiried and Bartoszyk 1994 see also Kim et al. 2005). The reason for the difference is unknown. 

GABA synthesis, probably by inhibiting GABA transaminase activity, but the dose of drug necessary to achieve this effect is very high and not relevant to the clinical situation. One possibility is that valproate desensitizes GABA autoreceptors and thereby facilitates the release of the transmitter. 

Electroconvulsive therapy has been used as antidepressive, mood-stabilizing and antipsychotic treatments (Eitan and Lerer 2006 Shapira et al., 1991). It is reported that electroconvulsive shocks (ECS), an animal model for the ECT, affect the NE system. Thus, both acute and chronic ECS increase cortical and hippocampal NE release. Chronic ECS also desensitize a2-adrenergic autoreceptors in the PFC (Thomas et al., 1992). Paradoxically, electrophysiological studies report that chronic ECS suppress the firing activity of NE neurons in the ECS (Grant and Weiss 2001). Based on the evidences of ECS-induced increase in brain NE levels, it can be concluded that the benefitial effect of the ECT is mediated, at least in part, via NE system. 

Le Poul E, Laaris N, Doucet E, et al. Chronic alnespirone-induced desensitization of somatodendritic 5-HT1A autoreceptors in the rat dorsal raphe nucleus. Eur J Pharmacol 1999 365 165-173. 

Hcrvas I, Vilaid MT, Romero L, Scorza MC, Mengod G, Artigas F. Desensitization of 5-HT(lA) autoreceptors by a low chronic fluoxetine dose effect of the concurrent administration of WAY-100635. Neuropsychopharmacology 2001 24 11-20. 

Desensitizes serotonin receptors, especially serotonin 1A autoreceptors... 

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