lithium-chloride and Anxiety-Disorders

Alterations in brainstem circuits have been proposed as a possible mechanism underlying the etiology of mood disorders. Projections from the median raphe nucleus (MnR) modulate dopaminergic activity in the forebrain and are also part of a behavioral disinhibition/inhibition system that produces phenotypes resembling behavioral variations manifested during manic and depressive phases of bipolar disorder.. The aim of this study is to assess the effect of chronic lithium treatment on behavioral disinhibition induced by MnR lesions.. MnR electrolytic lesions were performed in C57BL/6J mice, with sham-operated and intact animals as control groups. Following recovery, mice were chronically treated with lithium (LiCl, added in chow) followed by behavioral testing.. MnR lesion induced manic-like behavioral alterations including hyperactivity in the open field (OF), stereotyped circling, anxiolytic/risk taking in the elevated plus maze (EPM) and light/dark box (LDB) tests, and increased basal body temperature. Lithium was specifically effective in reducing OF hyperactivity and stereotypy but did not reverse (EPM) or had a nonspecific effect (LDB) on anxiety/risk-taking measures. Additionally, lithium decreased saccharin preference and prevented weight loss during single housing.. Our data support electrolytic lesions of the MnR as an experimental model of a hyper-excitable/disinhibited phenotype consistent with some aspects of mania that are attenuated by the mood stabilizer lithium. Given lithium's relatively specific efficacy in treating mania, these data support the hypothesis that manic symptoms derive not only from the stimulation of excitatory systems but also from inactivation or decreased activity of inhibitory mechanisms.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Electrocoagulation; Hyperkinesis; Lithium Chloride; Male; Mice; Mice, Inbred C57BL; Psychomotor Agitation; Raphe Nuclei; Stereotyped Behavior; Treatment Outcome

Topics: Animals; Ankyrins; Anxiety Disorders; Bipolar Disorder; Lithium Chloride; Male; Stress, Psychological

Ankyrin 3 (ANK3) has been strongly implicated as a risk gene for bipolar disorder (BD) by recent genome-wide association studies of patient populations. However, the genetic variants of ANK3 contributing to BD risk and their pathological function are unknown.. To gain insight into the potential disease relevance of ANK3, we examined the function of mouse Ank3 in the regulation of psychiatric-related behaviors using genetic, neurobiological, pharmacological, and gene-environment interaction (G×E) approaches. Ank3 expression was reduced in mouse brain either by viral-mediated RNA interference or through disruption of brain-specific Ank3 in a heterozygous knockout mouse.. RNA interference of Ank3 in hippocampus dentate gyrus induced a highly specific and consistent phenotype marked by decreased anxiety-related behaviors and increased activity during the light phase, which were attenuated by chronic treatment with the mood stabilizer lithium. Similar behavioral alterations of reduced anxiety and increased motivation for reward were also exhibited by Ank3+/- heterozygous mice compared with wild-type Ank3+/+ mice. Remarkably, the behavioral traits of Ank3+/- mice transitioned to depression-related features after chronic stress, a trigger of mood episodes in BD. Ank3+/- mice also exhibited elevated serum corticosterone, suggesting that reduced Ank3 expression is associated with elevated stress reactivity.. This study defines a new role for Ank3 in the regulation of psychiatric-related behaviors and stress reactivity that lends support for its involvement in BD and establishes a general framework for determining the disease relevance of genes implicated by patient genome-wide association studies.

Topics: Animals; Ankyrins; Anxiety Disorders; Bipolar Disorder; Corticosterone; Dentate Gyrus; Lithium Chloride; Male; Mice; Mice, Knockout; Mice, Transgenic; Stress, Psychological