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.
Shen
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Millhauser Laboratories, Department of Psychiatry, New York University School of Medicine, 550 First Avenue MLH HN 511, New York, NY 10016, USA.
Li
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Meller
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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