A retrospective observational study on characteristics, treatment patterns, and healthcare resource use of patients with myasthenia gravis in England.

Background: There are limited data on the real-world healthcare resource use (HCRU) and management costs of myasthenia gravis (MG) in England. Objective: This study aims to assess the burden of disease for patients with MG in England. Design: A retrospective, observational cohort study of adult patients diagnosed with MG, using data from the Hospital Episode Statistics data warehouse. Methods: Patients with a first-ever recorded diagnosis of MG between 30 June 2015 and 30 June 2020 were followed up until 30 June 2021 or death, whichever occurred first. Post-diagnosis patient characteristics, treatment patterns, HCRU, and costs were described. Costs were evaluated using National Health Service reference costs. Results: A total of 9087 patients with a median follow-up time of 2.9 years (range, 1.7-4.3 years) were included. The mean age at diagnosis was 66.5 years and 53% of the patients were male. A large proportion of patients (72.8%) were admitted as inpatients during follow-up with a mean number of 1.3 admissions. Patients hospitalized for MG-related complications spent a mean of 9.7 days per patient-year in the hospital. During follow-up, 599 (6.6% of the total cohort) and 163 (1.8%) patients had a record of rescue therapy with intravenous immunoglobulin (IVIg) and plasma exchange (PLEX), respectively. Rituximab was administered to 81 (0.9%) patients and 268 (2.9%) patients underwent thymectomy. In those patients receiving rescue therapy or rituximab, >10% received at least three cycles of the same treatment. The average annual cost of hospital admissions across all patients treated with IVIg, PLEX, and rituximab were £907,072, £689,979, and £146,726, respectively. Conclusion: A majority of MG patients required hospitalization or accident and emergency attendance, resulting in high HCRU and costs. A subset of patients required rescue therapy (including IVIg and PLEX), rituximab administration, ventilation, or thymectomy.

Chronic antipsychotic treatment exerts limited effects on the mania-like behavior of dopamine transporter knockdown mice.

BACKGROUND: Bipolar disorder is a life-threatening disorder linked to dopamine transporter (DAT) polymorphisms, with reduced DAT levels seen in positron emission tomography and postmortem brains. AIMS: The purpose of this study was to examine the effects of approved antipsychotics on DAT dysfunction-mediated mania behavior in mice. METHODS: DAT knockdown mice received either D2-family receptor antagonist risperidone or asenapine and mania-related behaviors were assessed in the clinically-relevant behavioral pattern monitor to assess spontaneous exploration. RESULTS: Chronic risperidone did not reverse mania-like behavior in DAT knockdown mice. Chronic asenapine reduced mania behavior but this effect was more pronounced in wild-type littermates than in DAT knockdown mice. CONCLUSION: Taken together, these findings suggest that while acute antipsychotic treatment may be beneficial in management of bipolar mania, more targeted therapeutics may be necessary for long-term treatment. Specific investigation into DAT-targeting drugs could improve future treatment of bipolar mania.

Chronic nicotine, but not suramin or resveratrol, partially remediates the mania-like profile of dopamine transporter knockdown mice.

Bipolar disorder (BD) is a severe mental illness affecting 2% of the global population. Current pharmacotherapies provide incomplete symptom remediation, highlighting the need for novel therapeutics. BD is characterized by fluctuations between mania and depression, likely driven by shifts between hyperdopaminergia and hypercholinergia, respectively. Hyperdopaminergia may result from insufficient activity of the dopamine transporter (DAT), the primary mediator of synaptic dopamine clearance. The DAT knockdown (DAT KD) mouse recreates this mechanism and exhibits a highly reproducible hyperexploratory profile in the cross-species translatable Behavioral Pattern Monitor (BPM) that is: (a) consistent with that observed in BD mania patients; and (b) partially normalized by chronic lithium and valproate treatment. The DAT KD/BPM model of mania therefore exhibits high levels of face-, construct-, and predictive-validity for the pre-clinical assessment of putative anti-mania drugs. Three different drug regimens - chronic nicotine (nicotinic acetylcholine receptor (nAChR) agonist; 40 mg/kg/d, 26 d), subchronic suramin (anti-purinergic; 20 mg/kg, 1 × /wk, 4 wks), and subchronic resveratrol (striatal DAT upregulator; 20 mg/kg/d, 4 d) - were administered to separate cohorts of male and female DAT KD- and wildtype (WT) littermate mice, and exploration was assessed in the BPM. Throughout, DAT KD mice exhibited robust hyperexploratory profiles relative to WTs. Nicotine partially normalized this behavior. Resveratrol modestly upregulated DAT expression but did not normalize DAT KD behavior. These results support the mania-like profile of DAT KD mice, which may be partially remediated by nAChR agonists via restoration of disrupted catecholaminergic/cholinergic equilibrium. Delineating the precise mechanism of action of nicotine could identify more selective therapeutic targets.

Convergent neural substrates of inattention in bipolar disorder patients and dopamine transporter-deficient mice using the 5-choice CPT.

OBJECTIVES: Bipolar disorder (BD) is a debilitating psychiatric illness affecting 2%-5% of the population. Although mania is the cardinal feature of BD, inattention and related cognitive dysfunction are observed across all stages. Since cognitive dysfunction confers poor functional outcome in patients, understanding the relevant neural mechanisms remains key to developing novel-targeted therapeutics. METHODS: The 5-choice continuous performance test (5C-CPT) is a mouse and fMRI-compatible human attentional task, requiring responding to target stimuli while inhibiting responding to nontarget stimuli, as in clinical CPTs. This task was used to delineate systems-level neural deficits in BD contributing to inattentive performance in human subjects with BD as well as mouse models with either parietal cortex (PC) lesions or reduced dopamine transporter (DAT) expression. RESULTS: Mania BD participants exhibited severe 5C-CPT impairment. Euthymic BD patients exhibited modestly impaired 5C-CPT. High impulsivity BD subjects exhibited reduced PC activation during target and nontarget responding compared with healthy participants. In mice, bilateral PC lesions impaired both target and nontarget responding. In the DAT knockdown mouse model of BD mania, knockdown mice exhibited severely impaired 5C-CPT performance versus wildtype littermates. CONCLUSIONS: These data support the role of the PC in inattention in BD-specifically regarding identifying the appropriate response to target vs nontarget stimuli. Moreover, the findings indicate that severely reduced DAT function/hyperdopaminergia recreates the attentional deficits observed in BD mania patients. Determining the contribution of DAT in the PC to attention may provide a future target for treatment development.

Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder.

Developing novel therapeutics for bipolar disorder (BD) has been hampered by limited mechanistic knowledge how sufferers switch between mania and depression-how the same brain can switch between extreme states-described as the "holy grail" of BD research. Strong evidence implicates seasonally-induced switching between states, with mania associated with summer-onset, depression with winter-onset. Determining mechanisms of and sensitivity to such switching is required. C57BL/6J and dopamine transporter hypomorphic (DAT-HY 50% expression) mice performed a battery of psychiatry-relevant behavioral tasks following 2-week housing in chambers under seasonally relevant photoperiod extremes. Summer-like and winter-like photoperiod exposure induced mania-relevant and depression-relevant behaviors respectively in mice. This behavioral switch paralleled neurotransmitter switching from dopamine to somatostatin in hypothalamic neurons (receiving direct input from the photoperiod-processing center, the suprachiasmatic nucleus). Mice with reduced DAT expression exhibited hypersensitivity to these summer-like and winter-like photoperiods, including more extreme mania-relevant (including reward sensitivity during reinforcement learning), and depression-relevant (including punishment-sensitivity and loss-sensitivity during reinforcement learning) behaviors. DAT mRNA levels switched in wildtype littermate mice across photoperiods, an effect not replicated in DAT hypomorphic mice. This inability to adjust DAT levels to match photoperiod-induced neurotransmitter switching as a homeostatic control likely contributes to the susceptibility of DAT hypormophic mice to these switching photoperiods. These data reveal the potential contribution of photoperiod-induced neuroplasticity within an identified circuit of the hypothalamus, linked with reduced DAT function, underlying switching between states in BD. Further investigations of the circuit will likely identify novel therapeutic targets to block switching between states.

The effects of reduced dopamine transporter function and chronic lithium on motivation, probabilistic learning, and neurochemistry in mice: Modeling bipolar mania.

BACKGROUND: Bipolar disorder (BD) mania patients exhibit poor cognition and reward-seeking/hypermotivation, negatively impacting a patient's quality of life. Current treatments (e.g., lithium), do not treat such deficits. Treatment development has been limited due to a poor understanding of the neural mechanisms underlying these behaviors. Here, we investigated putative mechanisms underlying cognition and reward-seeking/motivational changes relevant to BD mania patients using two validated mouse models and neurochemical analyses. METHODS: The effects of reducing dopamine transporter (DAT) functioning via genetic (knockdown vs. wild-type littermates), or pharmacological (GBR12909- vs. vehicle-treated C57BL/6J mice) means were assessed in the probabilistic reversal learning task (PRLT), and progressive ratio breakpoint (PRB) test, during either water or chronic lithium treatment. These tasks quantify reward learning and effortful motivation, respectively. Neurochemistry was performed on brain samples of DAT mutants ± chronic lithium using high performance liquid chromatography. RESULTS: Reduced DAT functioning increased reversals in the PRLT, an effect partially attenuated by chronic lithium. Chronic lithium alone slowed PRLT acquisition. Reduced DAT functioning increased motivation (PRB), an effect attenuated by lithium in GBR12909-treated mice. Neurochemical analyses revealed that DAT knockdown mice exhibited elevated homovanillic acid levels, but that lithium had no effect on these elevated levels. CONCLUSIONS: Reducing DAT functioning recreates many aspects of BD mania including hypermotivation and improved reversal learning (switching), as well as elevated homovanillic acid levels. Chronic lithium only exerted main effects, impairing learning and elevating norepinephrine and serotonin levels of mice, not specifically treating the underlying mechanisms identified in these models.

Premature responses in the five-choice serial reaction time task reflect rodents' temporal strategies: evidence from no-light and pharmacological challenges.

RATIONALE: The five-choice serial reaction time task (5-CSRTT) is regularly used to study attention and impulsivity. In the 5-CSRTT, rodents initiate a trial, then after an inter-trial interval (ITI), a light appears in one of five holes. Responding in the lit vs. unlit hole reflects attention (accuracy), while responding prematurely before a light appears is suggested to reflect impulsivity/response disinhibition. Comparison of rat and mouse 5-CSRTT performance has raised questions on the validity of premature responses as measuring impulsivity/response inhibition. To minimize effort, rodents may use a temporal strategy, enabling their "timing" of the ITI, minimizing the need to attend during this delay. Greater reliance on this strategy could result in premature responses due to "guesses" if their timing was poor/altered. OBJECTIVES: To assess the degree to which rats and/or mice utilize a temporal strategy, we challenged performance using infrequent no-light trials during 5-CSRTT performance. RESULTS: Even when no light appeared when one was expected, rats responded ~60 % compared to ~40 % in mice, indicating a greater reliance on a temporal strategy by rats than by mice. Consistent with this hypothesis, rats made more premature responses than mice. Additional studies using a temporal discrimination task and a 5-CSRTT variant demonstrated that delta-9-tetrahydrocannabinol, the active ingredient in cannabis, slowed temporal perception and reduced premature responses. CONCLUSIONS: These data provide behavioral and pharmacological evidence indicating that premature responses are heavily influenced by temporal perception. Hence, they may reflect an aspect of waiting impulsivity, but not response disinhibition, an important distinction for translational clinical research.

Investigating the underlying mechanisms of aberrant behaviors in bipolar disorder from patients to models: Rodent and human studies.

Psychiatric patients with bipolar disorder suffer from states of depression and mania, during which a variety of symptoms are present. Current treatments are limited and neurocognitive deficits in particular often remain untreated. Targeted therapies based on the biological mechanisms of bipolar disorder could fill this gap and benefit patients and their families. Developing targeted therapies would benefit from appropriate animal models which are challenging to establish, but remain a vital tool. In this review, we summarize approaches to create a valid model relevant to bipolar disorder. We focus on studies that use translational tests of multivariate exploratory behavior, sensorimotor gating, decision-making under risk, and attentional functioning to discover profiles that are consistent between patients and rodent models. Using this battery of translational tests, similar behavior profiles in bipolar mania patients and mice with reduced dopamine transporter activity have been identified. Future investigations should combine other animal models that are biologically relevant to the neuropsychiatric disorder with translational behavioral assessment as outlined here. This methodology can be utilized to develop novel targeted therapies that relieve symptoms for more patients without common side effects caused by current treatments.

Modeling bipolar disorder in mice by increasing acetylcholine or dopamine: chronic lithium treats most, but not all features.

RATIONALE: Bipolar disorder (BD) is a disabling and life-threatening disease characterized by states of depression and mania. New and efficacious treatments have not been forthcoming partly due to a lack of well-validated models representing both facets of BD. OBJECTIVES: We hypothesized that cholinergic- and dopaminergic-pharmacological manipulations would model depression and mania respectively, each attenuated by lithium treatment. METHODS: C57BL/6 J mice received the acetylcholinesterase inhibitor physostigmine or saline before testing for "behavioral despair" (immobility) in the tail suspension test (TST) and forced swim test (FST). Physostigmine effects on exploration and sensorimotor gating were assessed using the cross-species behavioral pattern monitor (BPM) and prepulse inhibition (PPI) paradigms. Other C57BL/6 J mice received chronic lithium drinking water (300, 600, or 1200 mg/l) before assessing their effects alone in the BPM or with physostigmine on FST performance. Another group was tested with acute GBR12909 (dopamine transporter inhibitor) and chronic lithium (1000 mg/l) in the BPM. RESULTS: Physostigmine (0.03 mg/kg) increased immobility in the TST and FST without affecting activity, exploration, or PPI. Lithium (600 mg/l) resulted in low therapeutic serum concentrations and normalized the physostigmine-increased immobility in the FST. GBR12909 induced mania-like behavior in the BPM of which hyper-exploration was attenuated, though not reversed, after chronic lithium (1000 mg/ml). CONCLUSIONS: Increased cholinergic levels induced depression-like behavior and hyperdopaminergia induced mania-like behavior in mice, while chronic lithium treated some, but not all, facets of these effects. These data support a cholinergic-monoaminergic mechanism for modeling BD aspects and provide a way to assess novel therapeutics.

The catecholaminergic-cholinergic balance hypothesis of bipolar disorder revisited.

Bipolar disorder is a unique illness characterized by fluctuations between mood states of depression and mania. Originally, an adrenergic-cholinergic balance hypothesis was postulated to underlie these different affective states. In this review, we update this hypothesis with recent findings from human and animal studies, suggesting that a catecholaminergic-cholinergic hypothesis may be more relevant. Evidence from neuroimaging studies, neuropharmacological interventions, and genetic associations support the notion that increased cholinergic functioning underlies depression, whereas increased activations of the catecholamines (dopamine and norepinephrine) underlie mania. Elevated functional acetylcholine during depression may affect both muscarinic and nicotinic acetylcholine receptors in a compensatory fashion. Increased functional dopamine and norepinephrine during mania on the other hand may affect receptor expression and functioning of dopamine reuptake transporters. Despite increasing evidence supporting this hypothesis, a relationship between these two neurotransmitter systems that could explain cycling between states of depression and mania is missing. Future studies should focus on the influence of environmental stimuli and genetic susceptibilities that may affect the catecholaminergic-cholinergic balance underlying cycling between the affective states. Overall, observations from recent studies add important data to this revised balance theory of bipolar disorder, renewing interest in this field of research.

Reduced dopamine transporter functioning induces high-reward risk-preference consistent with bipolar disorder.

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 = 44). The BD and HC IGT performances were compared with the effects of chronic (genetic knockdown (KD; n = 31) and wild-type (n = 28) mice) and acute (C57BL/6J mice (n = 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 high-reward 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.

Dopamine depletion attenuates some behavioral abnormalities in a hyperdopaminergic mouse model of bipolar disorder.

BACKGROUND: Patients with BD suffer from multifaceted symptoms, including hyperactive and psychomotor agitated behaviors. Previously, we quantified hyperactivity, increased exploration, and straighter movements of patients with BD mania in the human Behavioral Pattern Monitor (BPM). A similar BPM profile is observed in mice that are hyperdopaminergic due to reduced dopamine transporter (DAT) functioning. We hypothesized that dopamine depletion through alpha-methyl-p-tyrosine (AMPT) administration would attenuate this mania-like profile. METHODS: Male and female DAT wild-type (WT; n=26) and knockdown (KD; n=28) mice on a C57BL/6 background were repeatedly tested in the BPM to assess profile robustness and stability. The optimal AMPT dose was identified by treating male C57BL/6 mice (n=39) with vehicle or AMPT (10, 30, or 100mg/kg) at 24, 20, and 4h prior to testing in the BPM. Then, male and female DAT WT (n=40) and KD (n=37) mice were tested in the BPM after vehicle or AMPT (30mg/kg) treatment. RESULTS: Compared to WT littermates, KD mice exhibited increased activity, exploration, straighter movement, and disorganized behavior. AMPT-treatment reduced hyperactivity and increased path organization, but potentiated specific exploration in KD mice without affecting WT mice. LIMITATIONS: AMPT is not specific to dopamine and also depletes norepinephrine. CONCLUSIONS: KD mice exhibit abnormal exploration in the BPM similar to patients with BD mania. AMPT-induced dopamine depletion attenuated some, but potentiated other, aspects of this mania-like profile in mice. Future studies should extend these findings into other aspects of mania to determine the suitability of AMPT as a treatment for BD mania.

Sleep deprivation impairs performance in the 5-choice continuous performance test: similarities between humans and mice.

Several groups undergo extended periods without sleep due to working conditions or mental illness. Such sleep deprivation (SD) can deleteriously affect attentional processes and disrupt work and family functioning. Understanding the biological underpinnings of SD effects may assist in developing sleep therapies and cognitive enhancers. Utilizing cross-species tests of attentional processing in humans and rodents would aid in mechanistic studies examining SD-induced inattention. We assessed the effects of 36h of: (1) Total SD (TSD) in healthy male and female humans (n=50); and (2) REM SD (RSD) in male C57BL/6 mice (n=26) on performance in the cross-species 5-choice continuous performance test (5C-CPT). The 5C-CPT includes target trials on which subjects were required to respond and non-target trials on which subjects were required to inhibit from responding. TSD-induced effects on human psychomotor vigilance test (PVT) were also examined. Effects of SD were also examined on mice split into good and poor performance groups based on pre-deprivation scores. In the human 5C-CPT, TSD decreased hit rate and vigilance with trend-level effects on accuracy. In the PVT, TSD slowed response times and increased lapses. In the mouse 5C-CPT, RSD reduced accuracy and hit rate with trend-level effects on vigilance, primarily in good performers. In conclusion, SD induced impaired 5C-CPT performance in both humans and mice and validates the 5C-CPT as a cross-species translational task. The 5C-CPT can be used to examine mechanisms underlying SD-induced deficits in vigilance and assist in testing putative cognitive enhancers.

Further evidence for ClockΔ19 mice as a model for bipolar disorder mania using cross-species tests of exploration and sensorimotor gating.

Bipolar disorder (BD) is a pervasive neuropsychiatric disorder characterized by episodes of mania and depression. The switch between mania and depression may reflect seasonal changes and certainly can be affected by alterations in sleep and circadian control. The circadian locomotor output cycles kaput (CLOCK) protein is a key component of the cellular circadian clock. Mutation of the Clock gene encoding this protein in ClockΔ19 mutant mice leads to behavioral abnormalities reminiscent of BD mania. To date, however, these mice have not been assessed in behavioral paradigms that have cross-species translational validity. In the present studies of ClockΔ19 and wildtype (WT) littermate mice, we quantified exploratory behavior and sensorimotor gating, which are abnormal in BD manic patients. We also examined the saccharin preference of these mice and their circadian control in different photoperiods. ClockΔ19 mice exhibited behavioral alterations that are consistent with BD manic patients tested in comparable tasks, including hyperactivity, increased specific exploration, and reduced sensorimotor gating. Moreover, compared to WT mice, ClockΔ19 mice exhibited a greater preference for sweetened solutions and greater sensitivity to altered photoperiod. In contrast with BD manic patients however, ClockΔ19 mice exhibited more circumscribed movements during exploration. Future studies will extend the characterization of these mice in measures with cross-species translational relevance to human testing.

Differential effects of dopamine transporter inhibitors in the rodent Iowa gambling task: relevance to mania.

RATIONALE: The Iowa Gambling Task (IGT) can be used to quantify impulsive and risky choice behaviors in psychiatric patients, e.g., bipolar disorder (BD) sufferers. Although developing treatments for these behaviors is important, few predictive animal models exist. Inhibition of the dopamine transporter (DAT) can model profiles of altered motor activity and exploration seen in patients with BD. The effect of DAT inhibition on impulsive choices related to BD has received limited study however. We used a rodent IGT to elucidate the effects of similarly acting drugs on risky choice behavior. OBJECTIVES: We hypothesized that (1) C57BL/6 mice could adopt the "safe" choice options in the IGT and (2) DAT inhibition would alter risk preference. METHODS: Mice were trained in the IGT to a stable risk-preference and then administered the norepinephrine/DAT inhibitor amphetamine, or the more selective DAT inhibitors modafinil or GBR12909. RESULTS: Mice developed a preference for the "safe" option, which was potentiated by amphetamine administration. GBR12909 or modafinil administration increased motor impulsivity, motivation significantly, and risk preference subtly. CONCLUSIONS: The rodent IGT can measure different impulse-related behaviors and differentiate similarly acting BD-related drugs. The contrasting effects of amphetamine and modafinil in mice are similar to effects in rats and humans in corresponding IGT tasks, supporting the translational validity of the task. GBR12909 and modafinil elicited similar behaviors in the IGT, likely through a shared mechanism. Future studies using a within-session IGT are warranted to confirm the suitability of DAT inhibitors to model risk-preference in BD.

Chronic valproate attenuates some, but not all, facets of mania-like behaviour in mice.

Bipolar disorder (BD) mania is a psychiatric disorder with multifaceted symptoms. Development of targeted treatments for BD mania may benefit from animal models that mimic multiple symptoms, as opposed to hyperactivity alone. Using the reverse-translated multivariate exploratory paradigm, the behavioural pattern monitor (BPM), we reported that patients with BD mania exhibit hyperactivity as well as increased specific exploration and more linear movements through space. This abnormal profile is also observed in mice with reduced function of the dopamine transporter (DAT) through either constitutive genetic [knockdown (KD)] or acute pharmacological (GBR12909) means. Here, we assessed the pharmacological predictive validity of these models by administering the BD-treatment valproic acid (VPA) for 28 d. After 1.5% VPA- or regular-chow treatment for 28 d, C57BL/6J mice received GBR12909 (9 mg/kg) or saline and were tested in the BPM. Similarly, DAT KD and wild type (WT) littermates were treated with VPA-chow and tested in the BPM. GBR12909-treated and DAT KD mice on regular chow were hyperactive, exhibited increased specific exploration and moved in straighter patterns compared to saline-treated and WT mice respectively. Chronic 1.5% VPA-chow treatment resulted in therapeutic concentrations of VPA and ameliorated hyperactivity in both models, while specific exploration and behavioural organization remained unaffected. Hence, the mania-like profile of mice with reduced functional DAT was partially attenuated by chronic VPA treatment, consistent with the incomplete symptomatic effect of VPA treatment in BD patients. Both DAT models may help to identify therapeutics that impact the full spectrum of BD mania.

Increased risk-taking behavior in dopamine transporter knockdown mice: further support for a mouse model of mania.

Reduced functioning of the dopamine transporter (DAT) has been linked to bipolar disorder (BD). Mice with reduced DAT functioning (knockdown, KD) exhibit a behavioral profile in the mouse Behavioral Pattern Monitor (BPM) consistent with patients with BD mania in the human BPM. Patients with BD also exhibit increased risk taking, which can be quantified using the Iowa Gambling Task (IGT). We hypothesized that DAT KD mice would exhibit increased risk-taking behavior in a novel mouse version of the IGT. DAT KD and wildtype (WT) littermates were trained in the mouse IGT. In session 1, KD mice initially made riskier choices, but later performed comparably to WT mice. Once trained to stable choice performance, DAT KD mice continued to exhibit a trend to choose the riskier options more than WT mice. Finally, we confirmed that these DAT KD mice also exhibited an exploratory profile in the BPM consistent with patients with BD mania, where risky choice behavior modestly correlated with specific exploration. These data demonstrate that DAT KD mice chose the riskier options more than WT mice, providing further support for the use of DAT KD mice as a model of BD mania.