Repeated Treatment with Antidepressants Differentially Alters 5-HT_(1A) Agonist-Stimulated [~(35)S] GTPγS Binding in Rat Brain Regions

TLDR: The most consistent effect was a significant decrease in stimulated GTPγS binding in the lateral septum after all four treatments, a finding previously reported also after chronic buspirone treatment, suggesting this may be a heretofore unknown common outcome of antidepressant treatment deserving further study.

Abstract: 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-hydroxytryptamine 1A (5-HT 1A ) receptor sensitivity. Furthermore, the net effect of clinically-relevant repeated treatment with anxiolytic/antidepressant drugs, regardless of chemical class, appears to reflect an enhancement of 5-HT neurotransmission in forebrain targets, most notably in the hippocampus. Depending on the drug utilized, a decrease in sensitivity of inhibitory somatodendritic autoreceptors, an increase in sensitivity of postsynaptic receptors, or both alterations, occurs after 2-3 weeks of treatment. This hypothesis was tested using N,N-dipropyl-5-carboxamidotryptamine (N,N-DP-5-CT)-stimulated guanosine-5'-O-(3-thio)triphosphate (GTPγS) binding assessed by autoradiography. Rats were treated for 21 days with saline or drug (in mg/kg) once (fluoxetine, 10; imipramine, 10; clorgyline, 1) or twice daily (ipsapirone, 20) and 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%). Although these results generally support the concept of a net enhancement of hippocampal 5-HT neurotransmission, the pattern of changes in receptor sensitivity differed somewhat from the results of electrophysiological studies. The most consistent effect, however, was a significant decrease in stimulated GTPγS binding in the lateral septum after all four treatments (-14 to -23%), a finding previously reported also after chronic buspirone treatment, suggesting this may be a heretofore unrecognized common outcome of antidepressant treatment deserving further study.