Context Bipolar mania and schizophrenia are recognized as separate disorders but share many commonalities, raising the question of whether they are in fact the same disorder on different ends of a continuum. The lack of distinct endophenotypes of bipolar mania and schizophrenia has complicated the development of animal models that are specific to these disorders. Exploration is fundamental to survival and is dysregulated in these two disorders. Although exploratory behavior in rodents has been widely studied, surprisingly little work has examined this critical function in humans. Objective We used a novel human open field paradigm, the human Behavioral Pattern Monitor (BPM), to quantify exploratory behavior of individuals with bipolar mania and schizophrenia and to identify distinctive phenotypes of these illnesses. Design Static group comparison. Setting Psychiatric hospital. Participants 15 bipolar mania and 16 schizophrenia subjects were compared to 26 healthy volunteers in the human BPM. The effects of amphetamine, the selective dopamine transporter (DAT) inhibitor GBR12909, and genetic knockdown of the DAT were compared to controls in the mouse BPM. Measures The amount of motor activity, spatial patterns of activity, and exploration of novel stimuli were quantified in both the human and mouse BPMs. Results Bipolar manic subjects demonstrated a unique exploratory pattern, characterized by high motor activity and increased object exploration. Schizophrenia subjects did not show the expected habituation of motor activity. Selective genetic or pharmacological inhibition of the DAT matched the mania phenotype better than the “gold standard” model of mania (amphetamine). Conclusion These findings validate the human open field paradigm and identify defining characteristics of bipolar mania that are distinct from schizophrenia. This cross-species study of exploration calls into question an accepted animal model of mania and should help to develop more accurate human and animal models, which are essential to identify neurobiological underpinnings of neuropsychiatric disorders.

Background-Autonomic nervous system (ANS) dysfunction and reduced heart rate variability (HRV) have been reported in a wide variety of psychiatric disorders, but have not been well characterized in bipolar mania. We recorded cardiac activity and assessed HRV in acutely hospitalized manic bipolar (BD) and schizophrenia (SCZ) patients compared to age-and gendermatched healthy comparison (HC) subjects.Method-HRV was assessed using time domain, frequency domain, and nonlinear analyses in 23 manic BD, 14 SCZ, and 23 HC subjects during a 5 minute rest period. Psychiatric symptoms were assessed by administration of the Brief Psychiatric Rating Scale (BPRS) and the Young Mania Rating Scale (YMRS).Results-Manic BD patients demonstrated a significant reduction in HRV, parasympathetic activity, and cardiac entropy compared to HC subjects, while SCZ patients demonstrated a similar, but non-significant, trend towards lower HRV and entropy. Reduction in parasympathetic tone was significantly correlated with higher YMRS scores and the unusual thought content subscale on the BPRS. Decreased entropy was associated with increased aggression and diminished personal hygiene on the YMRS scale. Conclusion-Cardiac function in manic BD individuals is characterized by decreased HRV,

Mania has long been recognized as aberrant behaviour indicative of mental illness. Manic states include a variety of complex and multifaceted symptoms that challenge clear clinical distinctions. Symptoms include over-activity, hypersexuality, irritability and reduced need for sleep, with cognitive deficits recently linked to functional outcome. Current treatments have arisen through serendipity or from other disorders. Hence, treatments are not efficacious for all patients, and there is an urgent need to develop targeted therapeutics. Part of the drug discovery process is the assessment of therapeutics in animal models. Here we review pharmacological, environmental and genetic manipulations developed to test the efficacy of therapeutics in animal models of mania. The merits of these models are discussed in terms of the manipulation used and the facet of mania measured. Moreover, the predictive validity of these models is discussed in the context of differentiating drugs that succeed or fail to meet criteria as approved mania treatments. The multifaceted symptomatology of mania has not been reflected in the majority of animal models, where locomotor activity remains the primary measure. This approach has resulted in numerous false positives for putative treatments. Recent work highlights the need to utilize multivariate strategies to enable comprehensive assessment of affective and cognitive dysfunction. Advances in therapeutic treatment may depend on novel models developed with an integrated approach that includes: (i) a comprehensive battery of tests for different aspects of mania, (ii) utilization of genetic information to establish aetiological validity and (iii) objective quantification of patient behaviour with translational cross-species paradigms. LINKED ARTICLESThis article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi. org/10.1111/bph.2011.164.issue-4 Abbreviations ADHD, attention deficit hyperactivity disorder; AMP, amphetamine; BPRS, Brief Psychiatric Rating Scale; cAMP, cyclic adenosine monophosphate; CDP, chlordiazepoxide; CGI, Clinical Global Impression; CPT, Continuous Performance Task; CVLT, California Verbal Learning Task; DAT, dopamine transporter; DBP, D-box binding protein; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders IV; ERK, extracellular-related signal kinase; FDA, Food and Drug Administration; GABA, gamma-aminobutyric acid; GluR6, glutamate 6 receptor; GSK-3, glycogen synthase kinase 3; IGT, Iowa Gambling Task; IMPase, inositol monophosphatase; MARCKS, myristoylated alanine-rich C kinase substrate, MDMA, 3,4-methylenedioxymethamphetamine; NMDA, N-methyl-D-aspartic acid; PKC, protein kinase C, PPI, prepulse inhibition; SADS-C, Schedule for Affective Disorders and Schizophrenia; YMRS, Young Mania Rating Scale Mania: from clinical presentation to the challenges of validating animal modelsMania is typically defined as a distinct period characterized by elevated, expansive or irritable mood (APA, 1...

Corticotropin-releasing factor (CRF), a 41 amino acid peptide, mediates endocrine, autonomic, and behavioral responses to stress. Whereas the CRF 1 receptor appears to contribute to anxiety associated with stress, the role of the CRF 2 receptor remains unclear and may depend on drug dose, brain location, or testing environment. Results involving treatments with selective CRF 2 receptor agonists or antagonists and the behavior of CRF 2 receptor knock-out mice suggest both anxiogenic and anxiolytic effects of CRF 2 receptor activation. The present study tested the hypothesis that the effect of CRF 2 receptor activation on anxiety depends on the stress level of the animal. The selective CRF 2 receptor agonist urocortin 2 was infused into the lateral septum of mice under low-or high-stress (30 min of immobilization) testing conditions, and then behavior in the light-dark box, open-field, and novel-object tests was assessed. In the low-stress environment, 240 pmol of septal urocortin 2 increased anxiety, but lower doses (0.48, 4.8, and 48 pmol) did not have consistent effects. However, in the high-stress condition, 48 pmol of septal urocortin 2 significantly increased anxiety compared with control in wild-type but not CRF 2 receptor knock-out mice in the light-dark box. Septal administration of the relatively selective CRF 2 antagonist astressin-2B, but not the CRF 1 -selective antagonist antalarmin, blocked the anxiogenic effects of urocortin 2. Urocortin 2 infusion into the medial septum or lateral ventricle did not affect anxiety measures. These results indicate that the effect of septal CRF 2 receptor activation on anxiety is dependent on stress level.

Individuals with bipolar disorder (BD) exhibit deleterious decision making, negatively impacting their lives. Such aberrant decision making can be quantified using the Iowa Gambling Task (IGT), which requires choosing between advantageous and disadvantageous options based on different reward/punishment schedules. The mechanisms underlying this behavioral deficit are unknown, but may include the reduced dopamine transporter (DAT) functioning reported in BD patients. Using both human and mouse IGTs, we tested whether reduced DAT functioning would recreate patterns of deficient decision making of BD patients. We assessed the IGT performance of 16 BD subjects (7 female) and 17 healthy control (HC) subjects (12 female). We recorded standard IGT performance measures and novel post-reward and post-punishment decision-making strategies. We characterized a novel single-session mouse IGT using C57BL/6J mice (n ¼ 44). The BD and HC IGT performances were compared with the effects of chronic (genetic knockdown (KD; n ¼ 31) and wild-type (n ¼ 28) mice) and acute (C57BL/6J mice (n ¼ 89) treated with the DAT inhibitor GBR12909) reductions of DAT functioning in mice performing this novel IGT. BD patients exhibited impaired decision making compared with HC subjects. Both the good-performing DAT KD and GBR12909-treated mice exhibited poor decision making in the mouse IGT. The deficit of each population was driven by highreward sensitivity. The single-session mouse IGT measures dynamic risk-based decision making similar to humans. Chronic and acute reductions of DAT functioning in mice impaired decision-making consistent with poor IGT performance of BD patients. Hyperdopaminergia caused by reduced DAT may impact poor decision making in BD patients, which should be confirmed in future studies.