Differential regulation of neuropeptide Y mRNA expression in the arcuate nucleus and locus coeruleus by stress and antidepressants.
In rats, circulating corticosterone and insulin are involved in regulation of the hypothalamic neuropeptide Y (NPY) system, which in turn, is involved in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Since the HPA axis and stress responsivity is altered in diseases such as depression, we investigated interactions between the effects of stress and antidepressant drug treatment on arcuate nucleus and locus coeruleus NPY mRNA expressions using in-situ hybridization histochemistry. After acute (2 h) and repeated immobilization (2 h daily, for 14 days), plasma concentrations of corticosterone increased, and those of insulin decreased. The expression of NPY mRNA was significantly increased in the arcuate nucleus, but was unchanged in the locus coeruleus following acute and repeated immobilization. Adrenalectomized rats with systemic corticosterone replacement (ADX+CORT), whose corticosterone concentration was maintained at approximately 50-100 ng/ml during repeated stress, showed a decrease in plasma insulin and an increase in arcuate nucleus NPY mRNA similar to that observed in sham rats, suggesting that changes in NPY mRNA levels are more closely tied to circulating insulin than to circulating corticosterone. In contrast, locus coeruleus NPY mRNA expressions in ADX+CORT rats were significantly higher than those in sham rats after repeated stress. Desmethylimipramine (DMI) treatment for 24 days did not affect basal plasma concentrations of corticosterone or insulin, or arcuate nucleus NPY mRNA expressions, but significantly decreased basal levels of locus coeruleus NPY mRNA compared to saline-treated rats. After repeated immobilization (2 h daily, for 4 days), DMI significantly reduced the stress-induced rise in locus coeruleus NPY mRNA levels, but potentiated the stress-induced rise in arcuate nucleus NPY mRNA expression. These results demonstrate that: (1) the increase in arcuate nucleus NPY mRNA expressions in stressed rats closely follows the decrease in plasma concentrations of insulin; (2) increases in NPY mRNA expressions occur in the absence of changes in plasma corticosterone; and (3) desipramine treatment potentiated the effect of stress on arcuate nucleus NPY mRNA expressions, but blocked the repeated stress-induced increase in locus coeruleus NPY mRNA expressions. Thus, NPY mRNA expression in the arcuate nucleus and the locus coeruleus is sensitive to the effects of stress and to the antidepressant drug desipramine, but the arcuate nucleus NPY system is regulated by different mechanisms than the locus coeruleus NPY system. The results provide further evidence for the importance of circulating insulin in the regulation of the arcuate nucleus NPY system.
Makino
S
S
Clinical Neuroendocrinology Branch; Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892-1284, USA.
Baker
R A
RA
Smith
M A
MA
Gold
P W
PW
D000315:Adrenalectomy; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism*; D003345:Corticosterone / Q000008:administration & dosage / Q000097:blood; D003891:Desipramine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D017403:In Situ Hybridization; D007328:Insulin / Q000097:blood; D008125:Locus Coeruleus / Q000378:metabolism*; D008297:Male; D009478:Neuropeptide Y / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D013312:Stress, Physiological / Q000378:metabolism*
D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D007328:Insulin; D009478:Neuropeptide Y; D012333:RNA, Messenger; D003891:Desipramine; D003345:Corticosterone