Functional classification of antidepressants based on antagonism of swim stress-induced fos-like immunoreactivity.
Autoradiographic analysis of 14C-2-deoxyglucose (2-DG) uptake and immunocytochemical assessment of Fos-like immunoreactivity (Fos-LI) were used to assess swim stress-induced changes in metabolic activity in brain and to define the effect of chronic treatment with antidepressants from different pharmacological classes. Saline-treated rats processed in the forced swim test exhibited marked increases in Fos-LI in limbic cortical regions, lateral septum, medial amygdala and paraventricular nucleus of the hypothalamus (PVN). Uptake of 2-DG was increased by swim stress in some of the same brain regions where Fos-LI was induced, with the notable exception of a lack of a change in the PVN. Rats received injections for 3 wk with imipramine, desipramine, fluoxetine, nisoxetine, tranylcypromine or mianserin before being processed in the forced swim test. Chronic treatment with imipramine and desipramine alone induced Fos-LI in the central nucleus of the amygdala and the dorsolateral bed nucleus of the stria terminalis. After tranylcypromine treatment, Fos-LI was induced in many brain regions including limbic cortex, amygdala and paraventricular nucleus of the hypothalamus. None of the other antidepressants induced Fos-LI in any brain region examined. Chronic administration of imipramine, desipramine and nisoxetine antagonized the swim induced expression of Fos-LI in the PVN and in limbic cortical regions, including the medial prefrontal ventrolateral orbital and cingulate cortices. Chronic treatment with fluoxetine, tranylcypromine and mianserin did not alter swim stress-induced Fos-LI in any brain region. Thus, only antidepressant drugs that affect norepinephrine uptake (i.e., imipramine, desipramine and nisoxetine) antagonized swim stress-induced Fos-LI. In contrast to the action of chronic imipramine on Fos-LI induced by swim, chronic administration of imipramine did not antagonize the stress-induced changes in 2-DG uptake in limbic cortical regions. Acute administration of propranolol, which blocks beta-adrenergic receptors, reduced the number of cells staining for Fos-LI in limbic cortical regions, resembling the effects produced by chronic imipramine, desipramine and nisoxetine. In the PVN, neither propranolol nor prazosin (an alpha 1 antagonist) blocked the swim-induced Fos-LI, suggesting that swim-induced Fos-LI in the PVN is not under control of beta- or alpha 1-adrenergic receptors. These latter results imply that adaptation of noradrenergic receptors by chronic imipramine may not be related to the antagonism of stress-induced Fos-LI. The clear functional differences of the various antidepressant agents on swim stress-induced Fos-LI after chronic administration provide a functional classification of antidepressant drug action not previously identified.
Duncan
G E
GE
Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, USA.
Knapp
D J
DJ
Johnson
K B
KB
Breese
G R
GR
D000818:Animals; D000928:Antidepressive Agents / Q000145:classification* / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D003847:Deoxyglucose / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D011224:Prazosin / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis* / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000378:metabolism*; D013550:Swimming
D000928:Antidepressive Agents; D016760:Proto-Oncogene Proteins c-fos; D003847:Deoxyglucose; D011433:Propranolol; D007099:Imipramine; D011224:Prazosin