Abstract
The lateral hypothalamus integrates critical physiological functions such as the sleep-wake cycle, energy expenditure, and sexual behaviors. These functions are severely dysregulated during mania. In this study, we successfully induced manic-like behavioral phenotypes in adult, male Wistar rats through bilateral lateral hypothalamic area kindling (LHK). To test the validity of the model, we studied the effect of standard antimanic medications lithium (47.5 mg/kg) or valproic acid (200 mg/kg) twice/day for 15 days in attenuating manic-like behaviors in the LHK rat. Compared with pre-kindling behaviors, LHK rats displayed significantly increased sexual self-stimulation (P = 0.034), excessive rearing (P = 0.0005), feeding (P = 0.013), and grooming (P = 0.007) during the kindling interval. LHK rats also drank more alcohol during the mania-induction days compared with baseline ethanol consumption levels (P = 0.01). Moreover, LHK rat exhibited increased total locomotor activity (P = 0.02) with reduced rest interval (P < 0.001) during the mania induction and post-mania days compared with baseline activity levels and rest intervals. Chronic administration of lithium or valproic acid significantly attenuated manic-like behaviors in the LHK rat model. Given the behavioral phenotype and the response to standard antimanic medications, the LHK rats may provide a model for studying manic psychopathology in humans.Electronic supplementary materialThe online version of this article (doi:10.1186/s40345-014-0007-8) contains supplementary material, which is available to authorized users.
Highlights
Bipolar disorder is a common, recurrent medical illness (Merikangas et al 2007) characterized by at least one manic episode or alternating episodes of mania and depression (American Psychiatric Association 2000; Goodwin and Jamison 2007; Judd et al 2002)
Within the lateral hypothalamic area kindling (LHK) group, the frequency of sexual behavior showed a significant increase during kindling and post-kindling compared with pre-kindling levels: one-way ANOVA F2,33 = 3.364, P = 0.0468, post hoc t test pre-kindling vs. kindling (t = 2.416, df = 11, P = 0.034), and pre-kindling vs. post-kindling (t = 3.493, df = 11, P = 0.005, Figure 1C)
A significant increase in the total time spent in grooming behavior was evident in the LHK compared with the kindled nucleus accumbens (NAC) or kindled infralimbic cortex (ILC) groups during kindling (F2,21 = 5.821, P = 0.009, Additional file 5: Figure S1B)
Summary
Bipolar disorder is a common, recurrent medical illness (Merikangas et al 2007) characterized by at least one manic episode (type I) or alternating episodes of mania (or hypomania in type II) and depression (American Psychiatric Association 2000; Goodwin and Jamison 2007; Judd et al 2002). Current pharmacological interventions can be divided into three groups: lithium, anticonvulsants, and atypical antipsychotics. The efficacy of these agents as monotherapies in the treatment. Despite being highly valuable in studying this complex disorder, current animal models have several limitations. Amphetamine treatment in rodents is a well-accepted mania model, while in humans, it could induce a syndrome virtually indistinguishable from paranoid schizophrenia. These observations highlight the significant need to identify new valid mania models that exhibit more phenotypic features of the illness and link certain aspects of manic-like behaviors to the underlying neural networks. We propose a novel animal model through kindling of the lateral hypothalamic area in rats
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