Repeated social defeat-induced depression-like behavioral and biological alterations in rats: involvement of cholecystokinin.

Cholecystokinin (CCK) involvement in depression-like disorders is poorly documented. Here, we investigated whether CCKergic neurotransmission is relevant to depressive-like symptoms and antidepressant therapy using a novel preclinical model based on repeated social defeat over 4 weeks in rats. Repeated social defeat triggers changes that could be considered as behavioral and biological correlates of depressive symptoms in humans, such as a hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis (increase of serum corticosterone levels and of adrenal gland weight), increased immobility time in the forced swimming test (FST), decrease of body weight and of sweet water consumption and reduction of hippocampal volume associated with a decreased cell proliferation in the dentate gyrus. In addition, in vivo microdialysis showed that cortical CCK release was tonically increased in defeated rats. Chronic imipramine treatment (16 mg kg(-1) per day for 25 days) prevented both the repeated social defeat-induced alterations of biological and behavioral parameters and the associated increase of cortical CCK release. Chronic blockade of CCK2 receptors by the specific antagonist CI-988 (1 mg kg(-1) per day for 25 days) also normalized immobility time in the FST and prevented HPA axis hyperactivity, reduction of hippocampal volume and cell proliferation and decreased sweet water intake normally evoked by repeated social defeat. These data showed that the repeated social-defeat paradigm can be considered as a suitable model of 'depression' in rats. The causal link between social defeat-evoked (1) increase in cortical CCKergic neurotransmission and (2) depression-like symptoms that we highlighted here strongly suggests that CCKergic systems may be a relevant target for novel antidepressant therapy.

Clinical chronopharmacology of ACTH 1-17. II. Effects on plasma testosterone, plasma aldosterone, plasma and urinary electrolytes (K, Na, Ca and Mg).

The aim of the investigation was to study the effects of ACTH 1-17 on plasma testosterone, plasma aldosterone as well as on both plasma and urinary electrolytes (K, Na, Mg and Ca) in healthy young adult males with regard to the time (clock hours) at which this polypeptide was injected. Eight healthy adults (males from 28 to 30 years) volunteered for the study. The were synchronized with a diurnal activity from 0700 to midnight and a nocturnal rest. Each week, during 6 consecutive weeks (January 19 to February 25, 1980) a 3-day test was performed on Saturday, Sunday and Monday. On Sundays 3 control-tests and the 3 ACTH-tests were programmed during which either saline or 100 microgram ACTH 1-17 were injected i.m. at respectively 0700, 1400 and 2100. During each 3 day-test period (72 h) the urinary excretion of K, Na, Mg and Ca was determined every 4 h at fixed clock hours. In addition, on Sundays, venous blood was sampled prior to control or ACTH injections at respectively 0700, 1400 and 2100 and 20, 40, 60, 90, 120, 150 and 180 min thereafter. Plasma testosterone, aldosterone (radioimmunoassays) K, Na (flame photometry), Mg and Ca (photocolorimetric methods) were determined in the collected samples. Both conventional and cosinor methods were used for statistical analyses. The injection of ACTH at 0700 was followed by a clear and statistically significant rise of plasma testosterone. No change with regard to control occurred when ACTH was injected at either 1400 or at 2100. A statistically significant rise of plasma aldosterone was observed after each of the ACTH injections. However, the highest plasma aldosterone level was reached when ACTH was administered at 1400 and the lowest level at 2100. ACTH-induced changes in plasma electrolytes were either nil (for Na and Ca) or small (for K and Mg). A more or less important increase of urinary K occurred after the ACTH injection at each of the 3 considered times. The highest values of excreted K occurred after the injection of ACTH at 0700, without shift of the acrophase. In contrast, injections of ACTH at 1400 and 2100 induced a dramatic alteration of the K rhythms. ACTH induced an important fall in the Na urinary excretion. This fall was the greatest when ACTH was injected at 1400. Na rhythm alterations also occurred, particularly after ACTH injections at 2100. However, this effect was less pronounced after ACTH injection at 0700 than at other considered time points. The urinary amount of excreted Ca did not seem to be affected by ACTH. Rhythm alterations occurred after ACTH injections at 1400 and 2100. Peaks of plasma testosterone, plasma aldosterone as well as plasma cortisol (reported in a previous paper) resulting from ACTH stimulation coincided in time with the acrophase of the physiological circadian rhythm in plasma levels of these hormones...