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, 232 (8), 1441-50

Effect of Lithium on Behavioral Disinhibition Induced by Electrolytic Lesion of the Median Raphe Nucleus

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Effect of Lithium on Behavioral Disinhibition Induced by Electrolytic Lesion of the Median Raphe Nucleus

Fernanda A Pezzato et al. Psychopharmacology (Berl).

Abstract

Rationale: 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.

Objective: The aim of this study is to assess the effect of chronic lithium treatment on behavioral disinhibition induced by MnR lesions.

Methods: 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.

Results: 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.

Conclusions: 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.

Figures

Figure 1
Figure 1
Experimental timeline for surgical procedures, lithium treatment, and behavioral testing. Prior to surgery, mice were randomly assigned to three experimental groups (MnR Lesioned, Sham Lesioned and Intact). Ten days following surgery, mice were tested in the open field test (OF1) and then half of the mice were provided chow containing 4 g/kg LiCl (lithium treated group), while the other half were provided with control chow (control group) throughout the remainder of the experiment. The OF was conducted three times on successive days (OF2, OF3 and OF4, days 31, 32 and 33 respectively), followed by the elevated plus maze test (EPM), and the light dark box test (LDB). After the LDB mice were single housed for 96h for habituation (48h, days 44 to 46) and then tested in saccharin preference (SP) and stress-induced hyperthermia (SIH)
Figure 2
Figure 2
Effect of chronic lithium treatment on the locomotor activity of mice after lesion of the MnR. Values represent the mean (± SEM) of locomotor activity (distance in meters) of groups treated with lithium (I+LiCl, S+LiCl and L+LiCl) or control chow (I+C, S+C and I+C). Mice were tested before the start of treatment (OF1-Day 10) and later three additional times on successive days following chronic lithium treatment (OF2, OF3, and OF4 on days 31, 32 and 33 respectively). *p<0.05 (Fisher LSD test) for differences in the activity of L+C and L+LiCl groups
Figure 3
Figure 3
Effects of MnR lesion and chronic lithium treatment in the elevated plus maze and light/dark box tests. (A) Percentage of entries into open arms relative to the total number of entries (open arms+closed arms) and (B) the total number of crossings between arms in EPM test. (C) Number of stereotypical circling behavior episodes during the elevated plus maze test (EPM). (D) Total number of transitions between light and dark chambers in the LDB test. ***p<0.001 (Fisher LSD test) for differences between L+C and all other groups. All data are presented as mean±SEM. MnR lesioned (L), sham lesioned (S) and intact (I) mice treated with lithium (LiCl) or control (C) chow
Figure 4
Figure 4
Effects of MnR lesion and chronic lithium treatment on saccharin preference and body weight following single housing. (A) Saccharin preference in relation to the total liquid consumption (water + saccharin consumption) over a period of 24h in the third day of the saccharin preference test. (B) Changes in body weight (in grams) after 96h of single housing. All data are presented as mean±SEM. MnR lesioned (L), sham lesioned (S) and intact (I) mice treated with lithium (LiCl) or control (C) chow
Figure 5
Figure 5
Effect of MnR lesion and chronic lithium treatment on baseline and stress induced temperature change. Baseline (BL) and post-stress (PS) body temperatures (in Celsius; mean±SEM) in the stress induced hyperthermia test (SIH) (mean±SEM) in mice from MnR lesioned (L), sham lesioned (S) and intact (I) mice treated with lithium (LiCl) or control (C) chow groups
Figure 6
Figure 6
MnR lesion analysis. (A) Coronal representation at I.A. −0.68 (Franklin and Paxinos 2007). (B) Representative photo of a Nissl method stained coronal slice of the brainstem of a MnR lesioned mouse; arrow points to gliosis at the site of the lesion (in darker blue). (C) Size of the lesioned area (in mm2) obtained from histological analysis of mice after electrolytic lesion of MnR treated with lithium (L+LiCl) or control (L+C) chow (mean±SEM). I.A.: interaural level

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