Circadian Rhythms in Adenohypophysial Hormone Levels and Hypothalamic Monoamine Turnover in Mycobacterial-Adjuvant-Injected Rats

Abstract

The effect of Freund’s adjuvant injection on 24-hour variation in circulating ACTH, prolactin, growth hormone (GH) and thyroid-stimulating hormone (TSH) levels, and of hypothalamic norepinephrine (NE) content and dopamine (DA) and serotonin (5HT) turnover was examined in adult rats. In control rats, serum ACTH and prolactin exhibited peak values at the light-dark transition while the maximum in TSH was found in the late afternoon. GH levels did not vary on a 24-hour basis. In Freund’s-adjuvant-injected rats, 24-hour variations in TSH levels became blunted while 24-hour variations in prolactin and ACTH persisted. Freund’s adjuvant treatment augmented serum ACTH and prolactin levels, and decreased GH and TSH levels. Hypothalamic NE content, and turnover of DA and 5HT varied on a 24-hour basis in rats receiving adjuvant’s vehicle. The NE content of the anterior, medial and posterior hypothalamus peaked at 04.00 h, while that of the median eminence attained its maximum at 16.00–20.00 h. Maxima in hypothalamic DA and 5HT turnover occurred at 04.00 h regardless of the region examined. In Freund’s-adjuvant-injected rats, reduced amplitude of daily variations of NE content in the median eminence and anterior and medial hypothalamus, as well as a phase advance in the 24-hour rhythm of the posterior hypothalamic NE content were seen. Mycobacterial adjuvant injection also reduced the amplitude of circadian rhythm in hypothalamic 5HT turnover, shifted the maximum in median eminence DA turnover towards light-dark transition, and decreased the amplitude of DA turnover rhythm in the anterior, medial and posterior hypothalamus. Administration of the immunosuppressant drug cyclosporine restored the augmented ACTH and prolactin levels and the depressed GH and TSH levels found in Freund’s-adjuvant-injected rats. Cyclosporine was also effective to restore 24-hour rhythmicity of serum ACTH and TSH, but not of prolactin levels. Immunosuppression restored rhythmicity of NE content and of DA and 5HT turnover in anterior, medial and posterior hypothalamic regions. Cyclosporine did not modify the effect of Freund’s adjuvant on median eminence but in was able to counteract the changes in the DA and 5HT turnover in the median eminence found after immunization. The results are in accord with a significant effect of immune-mediated inflammatory response at an early phase after Freund’s adjuvant injection on ACTH, GH, prolactin and TSH release mechanisms, which was partially sensitive to immunosuppression induced by cyclosporine.

Age-Dependent Changes in 24-Hour Rhythms of Thymic and Circulating Growth Hormone and Adrenocorticotropin in Rats Injected with Freund’s Adjuvant

“…We previously reported changes in the 24-hour rhythms of adenohypophysial hormone release and hypothalamic monoamine and neuropeptide content during Freund's adjuvant arthritis in rats. Our results were compatible with significant effects of immunemediated inflammatory response on hormone secretory processes, which were partially sensitive to immunosuppression by cyclosporine [24][25][26]. These as well as other studies indicated that significant changes in 24-hour rhythms did occur during experimental arthritis in rats [27][28][29][30][31][32][33][34][35].…”

“…Changes in cir-Esquifino/García Bonacho/Arce/Cutrera/ Cardinali cadian rhythms are apparent at an early phase of experimental arthritis in rats and persist thereafter [29][30][31][32]46]. In previous studies we reported significant effects of immune-mediated inflammation on 24-hour variations of ACTH, GH, LH, testosterone, prolactin and TSH release after Freund's adjuvant injection to young adult [24,25] and old rats [33]. In old rats, 24-hour rhythms of circulating TSH, LH and testosterone became blunted.…”

Circadian Disorganization in Experimental Arthritis

“…For example, morning-evening differences in circulating ACTH and corticosterone disappeared by days 7-21, and between days 6 and 8 after FCA injection a loss of the adrenocortical ODC circadian rhythm of activity was found [80]. In our studies conducted during the preclinical phase of arthritis (table 2), a significant effect of the immune-mediated inflammatory response on the diurnal rhythmicity of circulating ACTH, growth hormone (GH), prolactin (PRL) and thyrotropin (TSH) release was found, and was partially sensitive to immunosuppression by cyclosporine [75]. Further experiments indicated that hypothalamic levels of corticotropin-releasing hormone (CRH), TSH-releasing hormone (TRH), GH-releasing hormone (GHRH) and somatostatin were altered in the preclinical phase of arthritis [81].…”

Psychoimmune Neuroendocrine Integrative Mechanisms Revisited

“…For example, morning-evening differences in circulating ACTH and corticosterone disappeared by days 7-21, and between days 6 and 8 after Freund's adjuvant injection, a loss of the adrenocortical ornithine decarboxylase circadian rhythm of activity was also found [45]. The results of Selgas et al [44] were compatible with a significant effect of immune-mediated inflammatory response on diurnal rhythmicity of ACTH, GH, prolactin and TSH release, which was partially sensitive to immunosuppression by cyclosporine [44].…”

“…In the review by Selgas et al, published in Biological Signals and Receptors, 1998 [1], circadian rhythms in adenohypophyseal hormone levels and hypothalamic monoamine turnover were examined in mycobacterial adjuvant-injected rats at the preclinical phase of the disease [44]. In Freund's-adjuvant-injected rats, the 24-hour organization of the biologic responses is altered.…”