Chronic fluoxetine treatment selectively uncouples raphe 5-HT(1A) receptors as measured by [(35)S]-GTP gamma S autoradiography.
1. Selective Serotonin Reuptake Inhibitors (SSRIs) are thought to have a delay in therapeutic efficacy because of the need to overcome the inhibitory influence of raphe 5-HT(1A) autoreceptors. Prolonged SSRI administration has been reported to desensitize these autoreceptors. We have used [(35)S]-GTP gamma S autoradiography to determine whether this desensitization occurs at the level of receptor/G protein coupling. 2. Male mice were injected intraperitoneally once a day with saline or 20 mg kg(-1) fluoxetine for either 2 days or 14 days. 5-HT(1A) receptor binding and coupling to G proteins were assessed using [(3)H]-8-OH-DPAT and [(35)S]-GTP gamma S autoradiography, respectively. 3. The 5-HT receptor agonist 5-carboxamidotryptamine (5-CT) stimulated [(35)S]-GTP gamma S binding in the substantia nigra, as well as in hippocampus and dorsal raphe nucleus. The 5-HT(1A) receptor antagonist p-MPPF (4-fluoro-N-(2-[4-(2-methoxyphenyl)1-piperazinyl]ethyl)-N-(2-pyridinyl)benzamide) blocked this effect in the latter regions, whereas the 5-HT(1B/D) antagonist GR-127,935 (2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-l-yl)-phenyl]-amide) only decreased labelling in substantia nigra. 4. Fourteen-day fluoxetine treatment decreased 5-CT-stimulated [(35)S]-GTP gamma S binding in dorsal raphe (saline: 112 +/- 12% stimulation; fluoxetine: 66 +/- 13%), but not in substantia nigra (99 +/- 14% vs 103 +/- 7%) or hippocampus (157 +/- 3% vs 148 +/- 18%). Two-day fluoxetine treatment did not alter 5-CT-stimulated [(35)S]-GTP gamma S binding in any of the brain areas investigated. 5. Decreased [(35)S]-GTP gamma S binding was not due to receptor down-regulation, since the density of raphe [(3)H]-8-OH-DPAT binding sites was unaffected by fluoxetine treatment. 6. These results suggest that the desensitization of presynaptic 5-HT(1A) receptor function occurs at the level of receptor-G protein interaction on dorsal raphe neurons, and may underlie the therapeutic efficacy of long-term SSRI treatment.
Pejchal
Tina
T
Massachusetts General Hospital, Harvard Medical School, Neuroscience Center, Room 6403, Charlestown, MA 02129, USA.
Foley
Melissa A
MA
Kosofsky
Barry E
BE
Waeber
Christian
C
D000818:Animals; D001345:Autoradiography; D001665:Binding Sites; D005473:Fluoxetine / Q000008:administration & dosage / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism
D005473:Fluoxetine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors