title: Characterization of the functional heterologous desensitization of hypothalamic 5-HT(1A) receptors after 5-HT(2A) receptor activation.
abstract: Desensitization of 5-HT(1A) receptors could be involved in the long-term therapeutic effect of anxiolytic and antidepressant drugs. Pretreatment of rats with the 5-HT(2A/2C) agonist DOI induces an attenuation of hypothalamic 5-HT(1A) receptor-G(z)-protein signaling, measured as the ACTH and oxytocin responses to an injection of the 5-HT(1A) agonist 8-OH-DPAT. We characterized this functional heterologous desensitization of 5-HT(1A) receptors in rats and examined some of the mechanisms that are involved. A time course experiment revealed that DOI produces a delayed and reversible reduction of the ACTH and oxytocin responses to an 8-OH-DPAT challenge. The maximal desensitization occurred at 2 hr, and it disappeared 24 hr after DOI injection. The desensitization was dose-dependent, and it shifted the oxytocin and ACTH dose-response curves of 8-OH-DPAT to the right (increased ED(50)) with no change in their maximal responses (E(max)). The 5-HT(2A) receptor antagonist MDL 100,907 prevented the DOI-induced desensitization, indicating that 5-HT(2A) receptors mediate the effect of DOI. Analysis of the components of the 5-HT(1A) receptor-G(z)-protein signaling system showed that DOI did not alter the level of membrane-associated G(z)-proteins in the hypothalamus. Additionally, DOI did not alter the binding of [(3)H]8-OH-DPAT or the inhibition by GTPgammaS of [(3)H]8-OH-DPAT binding in the hypothalamus. In conclusion, the activation of 5-HT(2A) receptors induces a transient functional desensitization of 5-HT(1A) receptor signaling in the hypothalamus, which may occur distal to the 5-HT(1A) receptor-G(z)-protein interface.
authors.affiliation: Center for Serotonin Disorder Research and Department of Pharmacology, Loyola University of Chicago, Stritch School of Medicine, Maywood, Illinois 60153, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: D'Souza
authors.forename: D K
authors.initials: DK
authors.lastname: Raap
authors.forename: F
authors.initials: F
authors.lastname: Garcia
authors.forename: G
authors.initials: G
authors.lastname: Battaglia
authors.forename: N A
authors.initials: NA
authors.lastname: Muma
authors.forename: L D
authors.initials: LD
authors.lastname: Van de Kar
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D010121:Oxytocin / Q000097:blood; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: D000662:Amphetamines; D005464:Fluorobenzenes; D008565:Membrane Proteins; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D010121:Oxytocin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000324:Adrenocorticotropic Hormone; D019204:GTP-Binding Proteins; C079049:volinanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine