Eva Björkstrand

Oxytocin as a possible mediator of SSRI-induced antidepressant effects

Abstract The nonapeptide oxytocin is released into systemic circulation in situations of psychosocial interaction, and has been shown to be involved in mechanisms of social bonding and social recognition in laboratory studies. In view of disturbances in psychosocial relationships being a triggering factor for depression and anxiety, it is interesting to note that experimental studies have shown oxytocin to possess antidepressant- and anxiolytic-like actions. Thus, in the present study we examined effects of the SSRI citalopram (20 mg/kg IP) on plasma oxytocin, acutely and upon repeated administration, in adult male Sprague-Dawley rats. Plasma oxytocin, and some functionally related peptides (CCK, gastrin, somatostatin and insulin), were measured by standard radioimmunoassay techniques. Acute citalopram administration produced a statistically significant increase in plasma oxytocin and CCK levels. Administration of citalopram for 14 days did not attenuate the oxytocin-releasing effect to a challenge dose of the SSRI zimeldine (20 mg/kg SC), whereas CCK levels were not increased after the subchronic citalopram treatment. Thus, the SSRI citalopram produces increased plasma oxytocin levels acutely, and there appears to be no or little tolerance to this effect upon repeated administration. There were no, or variable, effects on plasma levels of gastrin, somatostatin or insulin. It is suggested that oxytocin release is an important aspect of the pharmacological actions of SSRIs, and this could be an important contributory factor for the clinical profile of this group of antidepressants with particular efficacy in disorders of psychosocial origin.

Postnatal Oxytocin Injections Cause Sustained Weight Gain and Increased Nociceptive Thresholds in Male and Female Rats

The aim of the present study was to investigate possible long-term effects of postnatally administered oxytocin on weight gain, gastrointestinal hormone levels, and nociceptive thresholds in rats. For this purpose, s.c. daily injections of oxytocin (1 mg/kg) or saline (NaCl, 0.9%) were given to male and female rat pups on d 10-14 after birth. The animals were killed at the age of 60 or 94 d. Treatment with oxytocin resulted in higher body weight in males, 60 d after birth, and in females from d 60 and throughout the rest of the experiment, compared with controls. The higher body weight was due to an increased weight gain in oxytocin-treated rats, compared with controls, which was most pronounced between 40 and 60 d after birth. Oxytocin-treated male rats had increased circulating levels of cholecystokinin, a tendency to increased plasma levels of insulin (p = 0.066), and relatively more adipose tissue in the thigh and interscapular region, compared with controls. At the age of 60 d, oxytocin-treated female and male rats had a prolonged withdrawal latency when measured in the tail-flick test, compared with controls. This study shows that oxytocin can induce long-lasting changes in weight gain, hormone levels, and nociceptive thresholds, when administered postnatally, in female and male rats.

Evidence of a Peripheral and a Central Effect of Oxytocin on Pancreatic Hormone Release in Rats

The aim of the present study was to investigate how oxytocin given subcutaneously (SC) and intracerebroventricularly (ICV) influences the secretion of insulin, glucagon and glucose and to investigate whether the effect on these variables of suckling in lactating rats is mediated by oxytocinergic mechanisms. Male rats were given oxytocin in doses of 2 or 20 ng (SC) or 2 or 200 ng (ICV). Trunk blood was collected and hormone analysis performed by radioimmunoassay. Subcutaneous injections of oxytocin increased insulin, glucagon and glucose levels significantly. Two nanograms oxytocin given ICV had no effect on glucagon and glucose levels but caused a significant rise in insulin levels at this time point. This effect was abolished by atropine. The oxytocin antagonist 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin administered ICV increased insulin levels itself and therefore the effect on oxytocin-induced insulin secretion was difficult to evaluate. Intracerebroventricular injections of 200 ng oxytocin caused a significant rise not only of insulin but also of glucagon and glucose levels. Since this dose of oxytocin also caused a substantial rise of circulating oxytocin levels, these effects on glucose and glucagon may have been exerted at a peripheral site. Suckling in lactating rats was followed by a significant increase of glucose and glucagon levels. These effects were completely abolished by pretreatment with an oxytocin antagonist. In conclusion, oxytocin seems to influence pancreatic hormone secretion by two different mechanisms. Elevated circulating levels of oxytocin-e.g. as seen in response to suckling in lactating rats-are accompanied by a rise of glucagon and glucose levels which is blocked by the oxytocin antagonist. In contrast, nanogram amounts of oxytocin administered ICV cause a rise of insulin levels. Since this effect was blocked by atropine, it is likely to involve activation of vagal cholinergic neurons, innervating pancreatic beta-cells.

Central oxytocin increases food intake and daily weight gain in rats

Abstract The present study was performed to investigate the effects of centrally administered oxytocin on weight gain and food intake in rats. Two substrains of Sprague-Dawley rats (A and B) differing in average daily weight gain were used. Female rats of substrain A gained 2 g per day and males gained 7 g. Female rats of substrain B gained 5 g per day and males gained 8 g. Animals were implanted with a stainless steel guide cannula, allowing ICV injections into the lateral ventricle. ICV injections of 1, 5, or 10 μg of oxytocin or isotonic saline in a volume of 5 μl were given. In females, ICV treatment with either saline or 5 μg of oxytocin caused a transient loss of weight within 24 h of treatment. However, in the more slowly growing females of substrain A depression in body weight was observed after a single treatment with saline, whereas the body weight of oxytocin-treated females showed less marked depression and rapidly returned to the pretreatment weight. After a 3-day treatment period an even greater difference in daily weight gain was seen between oxytocin-treated and saline-treated female rats of substrain A. In contrast, no difference in daily weight gain or food intake was observed between oxytocin- and saline-treated male rats of substrain A, nor in females or males of the more rapidly growing substrain B. Intraperitoneal injections of 5 μg of oxytocin did not influence food intake or daily weight gain in female rats of substrain A. These data suggest that oxytocin may act centrally to influence food intake and daily weight gain in slowly growing female Sprague-Dawley rats.

Oxytocin modulates the effects of galanin in carrageenan-induced hyperalgesia in rats

In the present study we have investigated the effects of galanin and/or oxytocin on carrageenan-induced hyperalgesia, the relationship between oxytocin and galanin-containing nerve fibers in the spinal cord and the influence of galanin on oxytocin secretion. Galanin (1 microgram) given intrathecally (i.t.) decreased significantly the mechanical nociceptive threshold of the carrageenan-treated hindpaw, with no significant effect on thermal nociception. The decrease in the mechanonociceptive threshold exerted by galanin was modulated by oxytocin (1 microgram, i.t.) administered simultaneously. There was a close relationship between galanin- and oxytocin-immunoreactive fibers in the dorsal horn of the thoracic spinal cord, although there was no evidence for colocalization. Galanin 0.1 and 1 microgram given intracerebroventricularly or intraperitoneally significantly decreased the oxytocin level in plasma 60 min after injection. Taken together, these data indicate that galanin may contribute to mechanical hyperalgesia by inhibiting the release of oxytocin from nerve terminals in the spinal cord and that oxytocin may be a potential analgesic agent.

Effects of oxytocin on in vivo release of insulin and glucagon studied by microdialysis in the rat pancreas and autoradiographic evidence for [3H]oxytocin binding sites within the islets of Langerhans

In the present investigation it was studied whether oxytocin administered directly in the pancreas of the rat stimulates the release of insulin and glucagon. In order to study such effects in vivo, a new experimental model applying the microdialysis technique was developed. To test the validity of the method, glucose or arginine were infused i.v. and it was shown that perfusate concentrations of insulin and glucagon increased significantly to 344 and 292% of basal overflow, respectively. Administration of oxytocin via the dialysis probe into the splenic portion of the pancreas resulted in significant elevations of insulin and glucagon concentrations to 210 (P less than 0.05) and 528% (P less than 0.01), respectively. The present study also includes a combined autoradiographic and immunohistochemical investigation of binding sites for oxytocin in the rat pancreas. A high density of [3H]oxytocin binding was present in the periphery of the islets of Langerhans, corresponding to the localization of the glucagon-producing alpha-cells. Both oxytocin and arginine(A)-vasopressin displaced [3H]oxytocin. The IC50 values were 10 and 180 nM, respectively. In conclusion, the oxytocin-induced release of insulin and glucagon as previously demonstrated in a number of species, may be due to a stimulation exerted by the peptide directly within the pancreas.

Effect of galanin on plasma levels of oxytocin and cholecystokinin

Galanin, oxytocin and cholecystokinin (CCK) are peptides that influence feeding behaviour. Galanin has been found to stimulate food intake and oxytocin and CCK have been suggested to be satiety agents. The present study was performed in order to investigate if galanin influences the secretion of oxytocin and CCK as a possible indication of a functional relationship between these peptides with respect to their influence on feeding behaviour. Galanin (0.1 and 1 micrograms) was administered intracerebroventricularly (i.c.v.) and intraperitoneally (i.p.) to anaesthetized rats and blood samples were collected 20 and 60 min after administration. Plasma levels of oxytocin and CCK were measured with radioimmunoassay. Galanin, 0.1 and 1 microgram, caused a significant decrease in oxytocin levels after 60 min, both when administered i.c.v. and i.p. In contrast, CCK levels increased following i.c.v. and also i.p. galanin. The possible mechanisms by which galanin causes a decrease in oxytocin and an increase in CCK levels are discussed.

Evidence for a dual function of oxytocin in the control of growth hormone secretion in rats

The aim of the present study was to investigate the role of oxytocin (Oxy) in the control of growth hormone (GH) release. Oxy was administered subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) to male rats. The animals were decapitated and trunk blood was collected at 30 and 120 min after Oxy administration. GH levels were analyzed by radioimmunoassay. Oxy (100 microg, s.c) increased plasma levels of GH significantly 30 min after administration. Oxy (2 ng, i.c.v.) caused a significant rise of GH after 120 min. This effect was completely abolished by previous administration of the Oxy antagonist 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin. When 5 microg of Oxy were given i.c.v. or 1 mg s.c., an inhibition of GH secretion was seen after 120 min. This effect was also abolished by the Oxy antagonist. Thus Oxy may influence GH in opposite directions depending on the doses given.

The oxytocin receptor antagonist 1-deamino-2-d-Tyr-(OEt)-4-Thr-8-Orn-oxytocin inhibits effects of the 5-HT1A receptor agonist 8-OH-DPAT on plasma levels of insulin, cholecystokinin and somatostatin

The aim of the present study was to investigate whether the 5-HT1A receptor agonist 8-OH-DPAT, which previously has been shown to release oxytocin, also influences plasma levels of gastrointestinal and pancreatic hormones, and if so, whether such an effect is mediated by an oxytocinergic mechanism. For this purpose 8-OH-DPAT (0.5 mg/kg s.c.) was injected to male rats pretreated with the oxytocin receptor antagonist 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin (1 mg/kg s.c.), or vehicle. Thirty min after injection of 8-OH-DPAT, plasma levels of oxytocin were significantly increased. 8-OH-DPAT also increased insulin and decreased CCK and somatostatin levels, effects that were blocked by pretreatment with the oxytocin antagonist. Taken together, these data suggest that the effect of 8-OH-DPAT on plasma levels of insulin, somatostatin and CCK may be mediated by oxytocin. In previous experiments, we have shown that following i.c.v. application of oxytocin, plasma levels of insulin are increased through a cholinergic mechanism. In this study, 2 ng of oxytocin decreased plasma levels of CCK, gastrin and somatostatin, effects that were blocked by pretreatment with atropine. Since oxytocinergic fibers which originate in the PVN project to the DMX, we suggest that the effect on the release of insulin, CCK and somatostatin induced by the 5 HT1A receptor agonist 8-OH-DPAT may be mediated by an oxytocinergic activation of a vagal mechanism.

Endocrine and behavioral traits in low-avoidance performing Sprague–Dawley rats

In the present series of experiments, we have examined the endocrine profile of two stable colonies of Sprague-Dawley rats, here labeled Stock A, and Stock B, differing markedly in their ability to acquire a conditioned avoidance response. On separate occasions, the animals were subjected to five daily sessions (approximately 20 trials per 15 min session) of conditioned avoidance training, measurements of startle reactivity to an auditory stimulation and open-field spontaneous locomotor activity observations. The experiments were concluded by taking blood samples for later analysis of plasma glucose and plasma levels of the following hormones: insulin, gastrin, CCK, glucagon, somatostatin, oxytocin and corticosterone. The low-performing Stock B animals were characterized by [1] being more reactive to sensory stimulation: higher startle amplitude and shorter startle latency; [2] having higher plasma insulin and corticosterone levels, whereas plasma gastrin and oxytocin were significantly lowered and a strong tendency for a decrease also in plasma CCK. There were no differences in spontaneous locomotor activity between the two substrains. Taking total variability in avoidance performance into account, there was a statistically significant positive correlation between plasma oxytocin, as well as gastrin, levels and avoidance performance. The evidence obtained here, and in other laboratories, suggests that the Stock B animals display hormonal changes indicative of a submissive-defensive reaction pattern. Thus, the avoidance acquisition deficits displayed by the present Sprague-Dawley stocks A and B, are in all probability caused by emotional reactions when challenged with external stimuli requiring active responding.