Neuroendocrine pharmacology of stress

Effects of Antidepressant Drugs on the Behavioral and Physiological Responses to Lipopolysaccharide (LPS) in Rodents

Regulation of 5-HT1A receptor function in brain following agonist or antidepressant administration

Regulation oftyrosine hydroxylase expres- sion byantidepressant treatments wasinvestigated inthelocus coeruleus (LC), themajor noradrenergic nucleus inbrain. Rats weretreated chronically withvarious antidepressants, and tyrosine hydroxylase levels weremeasured intheLC by inimunoblot analysis. Representatives ofallmajorclasses of antidepressant medication-including imipramine, nortripty- line, tranylcypromine, fluvoxamine, fluoxetine, bupropion, iprindole, andelectroconvulsive seizures-were found tode- crease levels oftyrosine hydroxylase immunoreactivit by 40-70%intheLC.Decreased levels ofenzyme himunoreac. tivity wereshowntobeassociated with equivalent decreases in enzyme mRNA levels. Antidepressant regulation ofLCtyro- sine hydroxylase appeared specific tothese compounds, inas- muchaschronic treatment ofrats with representatives ofother classes ofpsychotropic drugs, including haloperidol, diaze- pam,clonidine, cocaine, andmorphine, failed todecrease levels ofthis protein. Theresults demonstrate thatchronic antidepressants dramatically downregulate theexpression of tyrosine hydroxylase intheLCandraise thepossibility that suchregulation oftheenzyme represents anadaptive response ofLCneurons toantidepressants that mediates someoftheir therapeutic actions indepression and/or other psychiatric disturbances. Amongthebest studied actions ofantidepressant treatments aretheir effects onthepostsynaptic noradrenergic system. Thus,oneofthemostconsistent adaptive responses to chronic administration ofantidepressants, including electro- convulsive seizures (ECS), isadownregulation ofthep- adrenergic receptor-coupled cAMP system (1-3). These treatments havealso beenshownmorerecently toregulate additional postreceptor sites inthis signal-transduction path-

Chronic antidepressant administration decreases theexpression of tyrosine hydroxylase intheratlocus coeruleus

Numerous data showed that 5-hydroxytryptamine-1A (5-HT1A) receptors couple to Gαo/αi proteins for signal transduction. However, the α subunit isoforms really involved in 5-HT1A receptor coupling in brain remain to be identified. Moreover, regional differences in the functional characteristics of brain 5-HT1A receptors have been evidenced repeatedly. Because such differences could be due to variations in G proteins interacting with the same receptor, relevant approaches were used for identifying α subunits physically coupled to 5-HT1A receptors in different regions of the rat brain. Using immunoaffinity chromatography coupled to Western blot detection, 5-HT1A receptors were found to interact equally with Gαo and Gαi3 in the cerebral cortex, mainly with Gαo and weakly with Gαi3 in the hippocampus and exclusively with Gαi3 in the anterior raphe area. In the hypothalamus, 5-HT1A receptors seemed to be coupled to the latter two G proteins plus Gαi1 and Gαz. Complementary experiments based on an antibody capture technique coupled to both classic radioactivity and scintillation proximity assay detections showed that hippocampal 5-HT1A receptor stimulation induced 5′-O-(3-[35S]thio)triphosphate binding to immunoprecipitates with Gαi3 and Gαo antisera. In the anterior raphe, such 5-HT1A receptor-mediated effect was obtained with Gαi3 antiserum only. These results demonstrated the existence of regional differences in the coupling of 5-HT1A receptors to G proteins in the rat brain. In the anterior raphe, 5-HT1A receptors seem to interact specifically with Gαi3, whereas in the hippocampus, they are mainly coupled to Gαo proteins. Such a disparity in G-protein coupling might explain regional differences in adaptive regulations of brain 5-HT1A receptors.

https://molpharm.aspetjournals.org/content/molpharm/early/2006/06/13/mol.106.022756.full.pdf

Regional differences in the coupling of 5-hydroxytryptamine-1A receptors to G proteins in the rat brain.

The present studies examined the dose-response relationship of fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT1A receptors, as measured from the reduced neuroendocrine responses to a 5-HT1A agonist. Because hypothalamic Gz proteins mediate the ACTH and oxytocin responses to 5-HT1A receptor activation, we also determined the effect of fluoxetine on the levels of Gz proteins in the hypothalamus. Rats were injected daily for 14 days with saline or with fluoxetine doses of 0.3, 1, 3, 5, 7. 5, or 10 mg/kg/day. Fluoxetine produced a dose-dependent reduction in the oxytocin, ACTH, and corticosterone responses to the 5-HT1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT, 50 micrograms/kg, s.c.). The lowest fluoxetine dose that significantly, although incompletely, reduced the neuroendocrine responses to 8-OH-DPAT was 5 mg/kg/day. The 10 mg/kg/day dose of fluoxetine maximally inhibited all neuroendocrine responses to 8-OH-DPAT. Hypothalamic levels of Gz protein were reduced by both the 7.5 and 10 mg/kg/day doses of fluoxetine, whereas Gi1 protein levels were reduced only after the highest dose (10 mg/kg/day) of fluoxetine. Gi2, Gi3, and Go levels were not reduced by any fluoxetine dose. Cytosolic levels of Gi1 and Gz proteins were unaltered, indicating that reductions in Gz and Gi1 proteins are not caused by a redistribution of the proteins from the membrane into the cytosol. The results from the present study indicate that fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT1A receptor systems is dose-dependent and may be caused in part by reductions in the hypothalamic levels of Gz proteins.

Daily Injections of Fluoxetine Induce Dose-Dependent Desensitization of Hypothalamic 5-HT1A Receptors: Reductions in Neuroendocrine Responses to 8-OH-DPAT and in Levels of Gz and Gi Proteins

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Daily Injections of Fluoxetine Induce Dose-Dependent Desensitization of Hypothalamic 5-HT1A Receptors: Reductions in Neuroendocrine Responses to 8-OH-DPAT and in Levels of Gz and Gi Proteins