Repeated treatment with antidepressants differentially alters 5-HT1A agonist-stimulated [35S]GTP gamma S binding in rat brain regions.
Electrophysiological studies have led to the proposal that the neurobiological mechanism(s) underlying drug therapy of anxiety and depression involve(s) regionally specific adaptations in 5-HT(1A) receptor sensitivity. Depending on the drug utilized, a decrease in sensitivity of inhibitory somatodendritic autoreceptors, an increase in sensitivity of postsynaptic receptors, or both alterations, occur after several weeks of treatment. This hypothesis was tested using N,N-dipropyl-5-carboxamidotryptamine-stimulated guanosine-5'-O-(3-thio)triphosphate ([(35)S]GTPgammaS) binding assessed by autoradiography. Rats were treated for 21 days with one of four different anxiolytic/antidepressant drugs (in mg/kg): fluoxetine (10), imipramine (10), clorgyline (1), ipsapirone (2 x 20) or saline. Three brain regions rich in 5-HT(1A) receptors were examined: the dorsal raphe (somatodendritic), the dorsal hippocampus (postsynaptic) and the lateral septum (postsynaptic). Only imipramine (+17%) and fluoxetine (+54%) significantly increased agonist-stimulated binding in the dorsal hippocampus; all drugs except imipramine significantly decreased binding in the dorsal raphe (-19 to -41%). These results generally support the concept of a net enhancement of hippocampal 5-HT neurotransmission via one or more 5-HT receptor subtypes. The most consistent effect, however, was a significant decrease in stimulated [(35)S]GTPgammaS binding in the lateral septum after all four treatments (-14 to -23%), suggesting that this may be a heretofore unrecognized common outcome of antidepressant treatment deserving further study.
Millhauser Laboratories, Department of Psychiatry, New York University School of Medicine, 550 First Avenue MLH HN 511, New York, NY 10016, USA.
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D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage; D000928:Antidepressive Agents / Q000008:administration & dosage*; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003010:Clorgyline / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005473:Fluoxetine / Q000008:administration & dosage; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism*; D007099:Imipramine / Q000008:administration & dosage; D008297:Male; D011743:Pyrimidines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013462:Sulfur Radioisotopes / Q000378:metabolism
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D011743:Pyrimidines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D013462:Sulfur Radioisotopes; D005473:Fluoxetine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C043077:ipsapirone; D003010:Clorgyline; D007099:Imipramine