Abstract
An imbalance between serotonin-2A (5-HT2A) and 5-HT1A receptors may underlie several mood disorders. The present studies determined whether 5-HT2A receptors interact with 5-HT1A receptors in the rat hypothalamic paraventricular nucleus (PVN). The sensitivity of the hypothalamic 5-HT1A receptors was measured as oxytocin and adrenocorticotropic hormone (ACTH) responses to the 5-HT1A receptor agonist (+)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide [(+)8-OH-DPAT] (40 μg/kg s.c.). The 5-HT2A/2C receptor agonist (-)DOI [(-)-1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane HCl] (1 mg/kg s.c.) injected 2 h prior to (+)8-OH-DPAT significantly reduced the oxytocin and ACTH responses to (+)8-OH-DPAT, producing a heterologous desensitization of the 5-HT1A receptors. Microinjection of the 5-HT2A receptor antagonist MDL100,907 [(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol; 0, 10, or 20 nmol, 15 min prior to (-)DOI] into the PVN dose-dependently prevented the desensitization of 5-HT1A receptors induced by the 5-HT2A receptor agonist (-)DOI. Double-label immunocytochemistry revealed a high degree of colocalization of 5-HT1A and 5-HT2A receptors in the oxytocin and corticotropin-releasing factor neurons of the PVN. Thus, activation of 5-HT2A receptors in the PVN may directly induce a heterologous desensitization of 5-HT1A receptors within individual neuroendocrine cells. These findings may provide insight into the long-term adaptation of 5-HT1A receptor signaling after changes in function of 5-HT2A receptors; for example, during pharmacotherapy of mood disorders.
Footnotes
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This study was supported in part by U.S. Public Health Service Grants RO1 NS 34153, RO1 MH 58448, and RO1 DA13669 (to L.D.V.d.K.), RO1 NS38059 (to N.A.M.), and RO1 MH60687 (to G.B.)
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DOI: 10.1124/jpet.103.062224.
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ABBREVIATIONS: 5-HT, 5-hydroxytryptamine; PVN, paraventricular nucleus; ACTH, adrenocorticotropic hormone; (+)8-OH-DPAT, (+)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide; CRF, corticotropin-releasing factor; MDL100,907, (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol; (-)DOI, (-)-1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane HCl; PBS, phosphate-buffered saline; DAB, 3,3′-diaminobenzidine tetrahydrochloride; Emax, maximal response; WAY100635, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl); NAN190, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine.
- Received January 8, 2004.
- Accepted April 2, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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