Z. Merali

Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical features.

Depression has been associated with both suppression and enhancement of various aspects of immune functioning. It was of interest to determine whether cytokine alterations associated with depression, including interleukin-1 (IL-1β) and interleukin-2 (IL-2), were related to the neurovegetative symptom profile or to the chronicity of the illness. Circulating ACTH, cortisol, norepinephrine (NE) and epinephrine levels, and production of IL-1β and IL-2 from mitogen-stimulated lymphocytes were assessed in classical major depression, atypical depression (ie, with reversed neurovegetative features), and dysthymia (chronic depression without comorbid major depression) with either typical or atypical profiles, as well as nondepressed control subjects. Among atypical depressives, plasma ACTH levels were elevated while cortisol was reduced relative to controls. Irrespective of neurovegetative profile, IL-1β production was increased in dysthymic patients, and was highly correlated with age-of-onset and duration of illness. In contrast, IL-2 production was reduced in each of the groups, although less so among atypical major depressives. Moreover, IL-2 production in the depressive groups was directly related to plasma NE levels. While neither depressed mood per se nor neurovegetative features accounted for this effect, it seemed likely that chronicity of illness or age-of-onset were associated with cytokine alterations. Given that circulating cytokines influence neuroendocrine functioning, and may affect neurovegetative features, a role for interleukins may exist with respect to the pathophysiology of certain subtypes of depression.

Nesfatin-1 increases anxiety- and fear-related behaviors in the rat

RationaleNesfatin-1, derived from the protein NEFA/nucleobindin2 (NUCB2), is a newly identified peptide that acts as a potent satiety agent. It has been reported that peptides involved in the regulation of ingestive behavior are also involved in the regulation of the stress response. However, the relation between nesfatin-1 and stressor-related behaviors like anxiety and/or fear has not yet been investigated.ObjectiveThe effects of intracerebroventricular (ICV) injection of nesfatin-1 (0, 5, and 25xa0pmol/3xa0μl) were assessed in several paradigms that are thought to reflect anxiety and/or fear in rats.ResultsConsistent with an anxiogenic effect, nesfatin-1 dose-dependently decreased the percentage of time spent on the open arms of the elevated plus maze, increased latency to approach, and decreased consumption of a palatable snack in an anxiogenic (unfamiliar) environment. Moreover, ICV nesfatin-1 increased the fear-potentiated startle response and the time spent freezing to both context and conditioned cues in a conditioned emotional response test.ConclusionsThese findings suggest that in addition to its role as a satiety peptide, nesfatin-1 may also be involved in the mediation of anxiety- and/or fear-related responses.

A prospective study of neuroendocrine and immune alterations associated with the stress of an oral academic examination among graduate students

Stressful experiences may influence neuroendocrine, immune and cytokine functioning, as well as physical and psychological well being. The present prospective investigation assessed physiological and behavioral variations in anticipation of a critical oral academic examination among graduate students (i.e. related to a dissertation or comprehensive defense). Relative to matched control subjects, plasma cortisol levels were elevated among graduate students, especially females, 1 h prior to the oral examination, but not 6-8 weeks earlier (at about the time of the submission of the written document). In contrast, mitogen-stimulated (Con-A) lymphocyte proliferation was only reduced 6-8 weeks before the examination. Neither adrenocorticotrophic hormone (ACTH), prolactin, serum interleukin-1beta (IL-1beta) nor mitogen stimulated IL-1beta production was influenced at any time. Although, graduate students did not differ from controls with respect to perceived stress and feelings of mastery, they reported more frequent malaise (e.g. headaches, sore throat, fatigue) than did controls. The present findings suggest that during the course of lengthy anticipatory periods preceding a scheduled stressor, different stress-sensitive, situation-dependent biological processes may be engendered. It is further suggested that cortisol release is most closely aligned with immediate threats, while the immune alterations are sensitive to more distal events, or are subject to adaptation in response to a protracted stressor.

The effects of chronic mild stress on male Sprague-Dawley and Long Evans rats: I. Biochemical and physiological analyses.

The chronic unpredictable mild stress (CMS) is a paradigm developed in animals to model the relatively minor and unanticipated irritants that lead to a state of anhedonia in some individuals. However, the effectiveness of CMS is sometimes difficult to establish, for which unique strain sensitivities has been attributed as one contributing factor. These considerations led us to design the present study, which was an investigation of the corticosterone response to CMS in two outbred rat strains--Sprague-Dawley and Long Evans. Animals were exposed to one of two conditions--control or CMS--for 3 weeks during which body weight and fecal count were regularly monitored. At the end of this period, blood was sampled at a variety of time intervals following induction of a brief restraint stressor. First, a significant effect of CMS on corticosterone levels was evident at time 0 (prior to the application of the acute restraint stressor) in both strains. Second, the typical quadratic pattern of stressor-elicited fluctuations in this measure was similar in both Sprague-Dawley and Long Evans rats, with consistently elevated levels for the first hour following exposure to the acute stressor; near baseline values were observed at 2 h. However, only in the Long Evans strain were CMS related values much less than that observed in the control group after restraint stress. Third, both strains showed a reduced weight gain in the CMS groups relative to control groups. Fourth, spleen and adrenal weights were similar across all groups. Fifth, fecal counts remained stable across weeks of treatment in all groups with the exception of the Long Evans rats exposed to CMS; in this group, average counts were systematically reduced over the treatment period. We conclude that a history of chronic stress significantly blunts corticosterone levels in Long Evans but not Sprague-Dawley rats following exposure to an acute stressor. Physiological indices however are less influenced by this experience, at least when the exposure is limited to 3 weeks.

Dysthymia: a review of pharmacological and behavioral factors

Although dysthymia, a chronic, low-grade form of depression, has a morbidity rate as high as that of major depression, and increases the risk for major depressive disorder, limited information is available concerning the etiology of this illness. In the present report we review literature concerning the biological and characterological features of dysthymia, the effectiveness of antidepressant treatments, the influence of stressors in the precipitation and maintenance of the disorder, and both quality of life and psychosocial correlates of the illness. We also provisionally suggest that dysthymia may stem from disturbances of neuroendocrine and neurotransmitter functioning (eg, corticotropin releasing hormone and arginine vasopressin within the hypothalamus, or alternatively monoamine variations within several extrahypothalamic sites), and may also involve cytokine activation. The central disturbances may reflect phenotypic variations of neuroendocrine processes or sensitization of such mechanisms. It is suggested that chronic stressor experiences or stressors encountered early in life lead to the phenotypic neurochemical alterations, which then favor the development of the dysthymic state. Owing to the persistence of the neurochemical disturbances, vulnerability to double depression is increased, and in this instance treatment with antidepressants may attenuate the symptoms of major depression but not those of the basal dysthymic state. Moreover, the residual features of depression following treatment may be indicative of underlying neurochemical disturbances, and may also serve to increase the probability of illness recurrence or relapse.

Persistence of Cadmium-Induced Metabolic Changes in Liver and Kidney

Daily intraperitoneal injection of cadmium chloride (1 milligram per kilogram) for 45 days enhanced gluconeogenesis as evidenced by significant increases in the activities of liver and kidney cortex pyruvate carboxylase, phosphopyruvate carboxylase, hexosediphosphatase, and glucose-6-phosphatase, the quartet of key, rate-limiting enzymes involved in the biotransformation of noncarbohydrate precursors into glucose. Whereas cadmium treatment decreased the level of hepatic glycogen, the concentration of blood glucose and urea was significantly elevated by this heavy metal. Discontinuation of the heavy metal treatment for 28 days, in rats previously injected with cadmium for 45 days, failed to restore the observed biochemical alterations in hepatic and renal carbohydrate metabolism to control values. Evidence indicates that cadmium augments the glucose-synthesizing capacity of liver and kidney cortex and that various metabolic changes persist even after a 4-week period of withdrawal from exposure to the heavy metal.

Influence of Psychogenic and Neurogenic Stressors on Endocrine and Immune Activity: Differential Effects in Fast and Slow Seizing Rat Strains

Variations of plasma ACTH and corticosterone, as well as splenic macrophage activity and mitogen-induced cell proliferation, were determined in rats following 15 min of either the neurogenic stressor of restraint or by a purely psychogenic stressor consisting of exposure to a ferret. The effects of these stressors were assessed in two strains of rats that were selectively bred for either Fast or Slow kindling epileptogenesis triggered in response to amygdala stimulation. The stressors differentially influenced behavioral responses, endocrine activity, and immune functioning, and these effects varied with the strain of rat. In response to restraint the Fast rats exhibited protracted struggling, while the Slow rats tended to be immobile. In contrast, upon ferret exposure the Fast rats showed greater immobility than the Slow rats. The stressors also induced marked elevations of plasma ACTH and corticosterone. Whereas the ACTH and corticosterone increases were more pronounced in response to the ferret in the Slow rats, restraint resulted in a markedly greater rise of plasma ACTH in the Fast strain. Proliferation of splenic lymphocytes in response to Con A and LPS were elevated in Fast seizing rats, while macrophage activity, as determined by oxygen burst following addition of PMA and luminol to splenic mononuclear cells, was greater in the Slow seizing strain. While neither stressor influenced cell proliferation in either the Fast or Slow rats, macrophage activity was greatly suppressed by ferret exposure only in the Slow rats. Taken together, it appears that while stressors influence behavior and immune and endocrine functioning, these effects may vary as a function of the interaction of the strain of rat and the specific type of stressor employed.

Changes in brain cyclic AMP metabolism and acetylcholine and dopamine during narcotic dependence and withdrawal

Abstract Effects of morphine administration were studied on cyclic AMP metabolism in several regions of rat brain. In the cortex, cerebellum and thalamus-hypothalamus, morphine dependence did not alter the activity of either adenylate cyclase or phosphodiesterase. However, during withdrawal from the opiate treatment, adenylate cyclase activity declined in all three regions studied. In contrast, the striatal cyclic AMP metabolism was enhanced during morphine treatment as reflected by elevated endogenous cyclic AMP and increased adenylate cyclase. Furthermore, narcotic dependence produced significant increases in acetylcholinesterase activity of rat striatum. Whereas morphine withdrawal reversed the changes in striatal acetylcholine levels and acetylcholinesterase activity, the enhanced striatal dopamine remained unaltered. Although the activity of striatal adenylate cyclase was significantly reduced when compared to the morphine-dependent rats, the drop in cyclic AMP levels was not significant. Methadone replacement did not affect the changes in striatal dopamine seen in morphine-withdrawn rats. Whereas dopamine stimulated equally well the striatal adenylate cyclase from control or morphine-dependent animals, it failed to stimulate the striatal enzyme from rats undergoing withdrawal. The crude synaptosomal fraction of the whole brain from morphine-dependent rats exhibited an increase in cyclic AMP which was accompanied by elevated adenylate cyclase and protein kinase activity. Naloxone administration suppressed this rise in cyclic AMP and reversed the morphine-stimulated increases in the activities of adenylate cyclase and protein kinase. Following the withdrawal of morphine treatment, alterations in cyclic AMP metabolism were similar to those noted in morphine-naloxone group. Furthermore, substitution of morphine with methadone antagonized the observed alterations in cyclic nucleotide metabolism during withdrawal.

Anxiety responses, plasma corticosterone and central monoamine variations elicited by stressors in reactive and nonreactive mice and their reciprocal F1 hybrids.

Stressor-provoked anxiety, plasma corticosterone, and variations of brain monoamine turnover are influenced by genetic factors, but may also be moderated by early life experiences. To evaluate the contribution of maternal influences, behavioral and neurochemical stress responses were assessed in strains of mice that were either stressor-reactive or -resilient (BALB/cByJ and C57BL/6ByJ, respectively) as well as in their reciprocal F(1) hybrids. BALB/cByJ mice demonstrated poorer maternal behaviors than did C57BL/6ByJ dams, irrespective of the pups being raised (inbred or F(1) hybrids). The BALB/cByJ mice appeared more anxious than C57BL/6ByJ mice, exhibiting greater reluctance to step-down from a platform and a greater startle response. Although the F(1) behavior generally resembled that of the C57BL/6ByJ parent strain, in the step-down test the influence of maternal factors were initially evident among the F(1) mice (particularly males) with a BALB/cByJ dam. However, over trials the C57BL/6ByJ-like behavior came to predominate. BALB/cByJ mice also exhibited greater plasma corticosterone elevations, 5-HT utilization in the central amygdala (CeA), and greater NE turnover in the paraventricular nucleus of the hypothalamus (PVN). Interestingly, among the F(1)s corticosterone and 5-HIAA in the CeA resembled that of the BALB/cByJ parent strain, whereas MHPG accumulation in the PVN was more like that of C57BL/6ByJ mice. It seems that, to some extent, maternal factors influenced anxiety responses in the hybrids, but did not influence the corticosterone or the monoamine variations. The inheritance profiles suggest that anxiety was unrelated to either the corticosterone or monoamine changes.

Effects of acute restraint stress on endogenous adrenomedullin levels

Adrenomedullin (ADM) is a 52 amino acid peptide, with a potent hypotensive/vasodilatory action. Levels of ADM are significantly elevated in patients with hypertension, and it has been postulated that such stressor-related increases may serve a regulatory or protective function. The current study assessed the effects of acute restraint stress on ADM levels in regions of the brain, plasma and peripheral tissue including heart, lung and the adrenal glands of rats. This stressor, known to stimulate sympathetic activity as well as the hypothalamic-pituitary adrenal (HPA) axis, produced a significant increase in ADM levels in the pituitary gland, plasma and adrenal glands, all of which are key components of the HPA axis. The results suggest a regulatory and/or protective role for ADM in countering HPA activation following a variety of physiological and psychological stressors.