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Notes: Summary Male rats were exposed to severe 14 day immobilization stress. Body weight, body temperature, food and water intake, behavioral parameters, and serum corticosterone levels were measured during and after the stress period. On the 7th day after cessation of stress the experimental animals together with the control rats were taken to immunocytochemical analysis involving morphometry and microdensitometry of tyrosine hydroxylase (TH), 5-hydroxytryptamine (5-HT), various neuropeptide, and glucocorticoid receptor (GR) immunoreactivities (IRs) in a large number of regions of the central nervous system. In addition, adrenocorticotropic hormone (ACTH) IR was analyzed in the pituitary gland. Seven days following cessation of the chronic stress food intake, total locomotion and forward locomotion had been restored to normal. Serum corticosterone levels appeared to remain increased even 6 days following cessation of the chronic immobilization stress, probably caused by increased release of ACTH. Paraventricular corticotropin releasing hormone (CRF) IR was negatively correlated with the pituitary ACTH IR, indicating that the increase in ACTH release was produced by an increased release of CRF from the hypothalamus. The major immunocytochemical change observed 7 days after cessation of stress was a disappearance of 5-HT IR in the 5-HT cell groups B 1, B 2, B 3, and B 7. 5-HT IR in nerve terminals was only affected in the dorsal horn, where 5-HT IR was increased in the substantia gelatinosa. GR IR was found to be significantly increaed in monoaminergic cell groups: serotoninergic B 7, dopaminergic A 12, and noradrenergic A 1, A 2, and A 6. A trend for a reduction of TH IR was observed in nigral DA cells associated with significant reductions in TH IR in striatal DA nerve terminals. Finally, increases in 5-HT and substance P (SP) IR were found in the nerve terminals of the substantia gelatinosa of the cervical spinal cord in the stress group. In the present experimental model evidence has been obtained for a maintained activation of the hypothalamic-pituitary-adrenal axis as evaluated 7 days after cessation of severe chronic immobilization stress. The reduction of 5-HT IR in various 5-HT cell groups indicates a reduction of 5-HT synthesis, which may also be associated with reduced 5-HT release from the nerve terminals, since no depletion was observed in terminal regions and in one case an increase in 5-HT IR was noted (substantia gelatinosa). The increase in GR IR, demonstrated in the NA and 5-HT cell groups in the presence of a maintained hypersecretion of corticosterone may represent signs of an upregulation of GR synthesis and/or increased translocation, which take place in the presence of maintained hypersecretion of corticosterone. Thus, 5-HT and NA neurons may respond more effectively to circulating glucocorticoids after severe chronic stress. In this way glucocorticoids may protect against stress-induced exhaustion of neurons leading to impairment of transmission. Studies on TH IR suggest a deficit in the DA transmission line of the nigrostriatal DA neurons, but of no other CA neurons studied. Such effects may contribute to behavioral suppression. Finally, the stress-induced increases in 5-HT and SP IR in the substantia gelatinosa may in part underlie the phenomenon of stress-induced analgesia.

Notes: Summary Glucocorticoid receptor (GR) immunoreactivity (IR) was analyzed semi-automatically in the forebrain and in the lower brain stem of male rats treated for two weeks with imipramine (10 μmol/kg). Serum corticosterone and aldosterone levels were determined by means of radioimmunoassay procedures. The microdensitometric analysis demonstrated a selective increase in the GR IR in the nerve cell nuclei of the locus coeruleus (A6), of the ventral part of the reticular gigantocellular nucleus (B3L) and of the nucleus raphae magnus (B3M), whereas a small reduction of GR IR was found in the nucleus raphe obscurus (B2). In the morphometric analysis significant increases in the mean profile area of nuclear GR IR, which may be secondary to the increase in GR IR, were observed in the B3M. The serum corticosterone and aldosterone levels were not found to be significantly altered. The selective changes of GR IR may reflect the presence of an altered number of GR in these nerve cell groups and/ or an altered translocation of GR to the nuclei. It is of substantial interest that these changes were observed in the presence of unchanged serum levels of corticosterone and aldosterone. It seems possible that adaptive changes in monoamine synapses induced by the chronic imipramine treatment may be responsible for the changes in GR IR found in the noradrenaline (NA) and 5-hydroxytryptamine (5-HT) cell bodies, respectively. The present results open up the possibility that chronic imipramine treatment may help to maintain the glucocorticoid receptor function in the locus coeruleus and in the 5-HT cell groups of the rostral ventromedial medulla of depressed patients.