A Preliminary Study of the Effects of Treatment with Lithium Versus Quetiapine on Attention of Adolescents with Bipolar Disorder.

Objectives: Despite attentional deficits being a prominent feature of bipolar disorder, there are limited data on the effects of common treatments for bipolar disorder on attention. Thus, we sought to compare the effects of lithium versus quetiapine on attention in adolescents with bipolar disorder. Methods: Adolescents ages 10-17 with bipolar disorder, type I, who were experiencing a manic or mixed episode, were recruited from outpatient settings and the inpatient psychiatric units at Cincinnati Children's Hospital Medical Center during their first manic episode. Healthy comparison subjects were recruited from outreach programs in the community. Patients were randomized to lithium or quetiapine, administered in a double-dummy, double-blinded manner for 6 weeks. Attentional deficits were assessed in all groups using the Identical Pairs Continuous Performance Task at baseline and at week 6. Results: Patients with bipolar disorder (n = 79) had impaired attention relative to the healthy group (n = 57) at both baseline and after 6 weeks of treatment. The lithium-treated group (n = 30) had poorer attentional performance than the healthy group at week 6. There was a difference in change in performance between lithium- and quetiapine-treated (n = 49) groups. Conclusion: Youth with bipolar disorder may have impaired attention relative to their healthy peers. Conclusions are limited by the high dropout rate in the lithium-treated group.

Effects of combined glucocorticoid/mineralocorticoid receptor modulation (CORT118335) on energy balance, adiposity, and lipid metabolism in male rats.

Psychological stress and excess glucocorticoids are associated with metabolic and cardiovascular diseases. Glucocorticoids act primarily through mineralocorticoid (MR) and glucocorticoid receptors (GR), and compounds modulating these receptors show promise in mitigating metabolic and cardiovascular-related phenotypes. CORT118335 (GR/MR modulator) prevents high-fat diet-induced weight gain and adiposity in mice, but the ability of this compound to reverse obesity-related symptoms is unknown. Adult male rats were subcutaneously administered CORT118335 (3, 10, or 30 mg/kg) or vehicle once daily. A 5-day treatment with CORT118335 at 30 mg/kg induced weight loss in rats fed a chow diet by decreasing food intake. However, lower doses of the compound attenuated body weight gain primarily because of decreased calorific efficiency, as there were no significant differences in food intake compared with vehicle. Notably, the body weight effects of CORT118335 persisted during a 2-wk treatment hiatus, suggesting prolonged effects of the compound. To our knowledge, we are the first to demonstrate a sustained effect of combined GR/MR modulation on body weight gain. These findings suggest that CORT118335 may have long-lasting effects, likely due to GR/MR-induced transcriptional changes. Prolonged (18 days) treatment of CORT118335 (10 mg/kg) reversed body weight gain and adiposity in animals fed a high-fat diet for 13 wk. Surprisingly, this occurred despite a worsening of the lipid profile and glucose homeostasis as well as a disrupted diurnal corticosterone rhythm, suggesting GR agonistic effects in the periphery. We conclude that species and tissue-specific targeting may result in promising leads for exploiting the metabolically beneficial aspects of GR/MR modulation.

Differential effects of imipramine and CORT118335 (Glucocorticoid receptor modulator/mineralocorticoid receptor antagonist) on brain-endocrine stress responses and depression-like behavior in female rats.

Depression is commonly associated with hypothalamic-pituitary adrenal (HPA) axis dysfunction that primarily manifests as aberrant glucocorticoid secretion. Glucocorticoids act on Type I mineralocorticoid (MR) and Type II glucocorticoid receptors (GR) to modulate mood and endocrine responses. Successful antidepressant treatment normalizes HPA axis function, in part due to modulatory effects on MR and GR in cortico-limbic structures. Although women are twice as likely to suffer from depression, little is known about how antidepressants modulate brain, endocrine, and behavioral stress responses in females. Here, we assessed the impact of CORT118335 (GR modulator/MR antagonist) and imipramine (tricyclic antidepressant) on neuroendocrine and behavioral responses to restraint or forced swim stress (FST) in female rats (n=10-12/group). Increased immobility CORT118335 in the FST is purported to reflect passive coping or depression-like behavior. CORT118335 dampened adrenocorticotropic hormone (ACTH) and corticosterone responses to the FST, but did not affect immobility. Imipramine suppressed ACTH, but had minimal effects on corticosterone responses to FST. Despite these marginal effects, imipramine decreased immobility, suggesting antidepressant efficacy. In an effort to link brain-endocrine responses with behavior, c-Fos was assessed in HPA axis and mood modulatory regions in response to the FST. CORT118335 upregulated c-Fos expression in the paraventricular nucleus of the hypothalamus. Imipramine decreased c-Fos in the basolateral amygdala and hippocampus (CA1 and CA3), but increased c-Fos in the central amygdala. These data suggest the antidepressant-like (e.g., active coping) properties of imipramine may be due to widespread effects on cortico-limbic circuits that regulate emotional and cognitive processes.

Estrogen signaling in the medial amygdala decreases emotional stress responses and obesity in ovariectomized rats.

Declining estradiol (E2), as occurs during menopause, increases risk for obesity and psychopathology (i.e., depression, anxiety). E2 modulates mood and energy homeostasis via binding to estrogen receptors (ER) in the brain. The often comorbid and bidirectional relationship between mood and metabolic disorders suggests shared hormonal and/or brain networks. The medial amygdala (MeA) is abundant in ERs and regulates mood, endocrine, and metabolic stress responses; therefore we tested the hypothesis that E2 in the MeA mitigates emotional and metabolic dysfunction in a rodent model of surgical menopause. Adult female rats were ovariectomized (OVX) and received bilateral implants of E2 or cholesterol micropellets aimed at the MeA. E2-MeA decreased anxiety-like (center entries, center time) and depression-like (immobility) behaviors in the open field and forced swim tests (FST), respectively in ovariectomized rats. E2-MeA also prevented hyperphagia, body weight gain, increased visceral adiposity, and glucose intolerance in ovariectomized rats. E2-MeA decreased caloric efficiency, suggestive of increased energy expenditure. E2-MeA also modulated c-Fos neural activity in amygdalar (central and medial) and hypothalamic (paraventricular and arcuate) brain regions that regulate mood and energy homeostasis in response to the FST, a physically demanding task. Given the shared neural circuitry between mood and body weight regulation, c-Fos expression in discrete brain regions in response to the FST may be due to the psychologically stressful and/or metabolic demands of the task. Together, these findings suggest that the MeA is a critical node for mediating estrogenic effects on mood and energy homeostasis.

Neuroanatomical Distribution of DEK Protein in Corticolimbic Circuits Associated with Learning and Memory in Adult Male and Female Mice.

DEK, a chromatin-remodeling gene expressed in most human tissues, is known for its role in cancer biology and autoimmune diseases. DEK depletion in vitro reduces cellular proliferation, induces DNA damage subsequently leading to apoptosis, and down-regulates canonical Wnt/ß-catenin signaling, a molecular pathway essential for learning and memory. Despite a recognized role in cancer (non-neuronal) cells, DEK expression and function is not well characterized in the central nervous system. We conducted a gene ontology analysis (ToppGene), using a cancer database to identify genes associated with DEK deficiency, which pinpointed several genes associated with cognitive-related diseases (i.e., Alzheimer's disease, presenile dementia). Based on this information, we examined DEK expression in corticolimbic structures associated with learning and memory in adult male and female mice using immunohistochemistry. DEK was expressed throughout the brain in both sexes, including the medial prefrontal cortex (prelimbic, infralimbic and dorsal peduncular). DEK was also abundant in all amygdalar subdivisions (basolateral, central and medial) and in the hippocampus including the CA1, CA2, CA3, dentate gyrus (DG), ventral subiculum and entorhinal cortex. Of note, compared to males, females had significantly higher DEK immunoreactivity in the CA1, indicating a sex difference in this region. DEK was co-expressed with neuronal and microglial markers in the CA1 and DG, whereas only a small percentage of DEK cells were in apposition to astrocytes in these areas. Given the reported inverse cellular and molecular profiles (e.g., cell survival, Wnt pathway) between cancer and Alzheimer's disease, these findings suggest a potentially important role of DEK in cognition.

A mixed glucocorticoid/mineralocorticoid receptor modulator dampens endocrine and hippocampal stress responsivity in male rats.

Aberrant glucocorticoid secretion is implicated in the pathophysiology of stress-related disorders (i.e., depression, anxiety). Glucocorticoids exert biological effects via mineralocorticoid (MR) and glucocorticoid (GR) receptors. Previous data from our laboratory indicate that GR antagonism/modulation (i.e., mifepristone, CORT 108297) regulate endocrine, behavioral, and central stress responses. Because of the dynamic interplay between MR and GR on HPA axis regulation and emotionality, compounds targeting both receptors are of interest for stress-related pathology. We investigated the effects of CORT 118335 (a dual selective GR modulator/MR antagonist) on endocrine, behavioral, and central (c-Fos) stress responses in male rats. Rats were treated for five days with CORT 118335, imipramine (positive control), or vehicle and exposed to restraint or forced swim stress (FST). CORT 118335 dampened corticosterone responses to both stressors, without a concomitant antidepressant-like effect in the FST. Imipramine decreased corticosterone responses to restraint stress; however, the antidepressant-like effect of imipramine in the FST was independent of circulating glucocorticoids. These findings indicate dissociation between endocrine and behavioral stress responses in the FST. CORT 118335 decreased c-Fos expression only in the CA1 division of the hippocampus. Imipramine decreased c-Fos expression in the basolateral amygdala and CA1 and CA3 divisions of the hippocampus. Overall, the data indicate differential effects of CORT 118335 and imipramine on stress-induced neuronal activity in various brain regions. The data also highlight a complex relationship between neuronal activation in stress and mood regulatory brain regions and the ensuing impact on endocrine and behavioral stress responses.