Infrared beams attached along all four walls and in each hole detect and record holepokes, rearing, and the location of the animal. Using these data, the BPM is able to quantify activity, exploration, and the structural patterns of motor activity of rodents . Previously, the rat and mouse BPM systems have proven useful to differentiate between pharmacological stimulants such as 3,4-methylenedioxy-N-methylamphetamine , scopolamine, and apomorphine . None of these stimulants recreated the abnormal exploratory profile observed in BD patients however. Furthermore, treatment with the mixed DAT / norepinephrine transporter inhibitor amphetamine, a manipulation often used to model BD in rodents, also failed to recreate this pattern in mice . When mice with selectively reduced DAT functioning were tested in the mouse BPM however, both constitutive knockdown of the DAT and pharmacological inhibition with the selective DAT inhibitor GBR12909 induced a behavioral profile similar to that of BD patients . These test animals were hyperactive, exhibited increased exploration as indicated by increased rearing and holepoking, and moved in straighter, more direct patterns compared to wild-type mice. This hyperexploratory profile was attenuated with environmental familiarity, but was reinstated with environmental novelty . Such observations are consistent with environmental familiarity aiding the transition from patients in a manic to a euthymic state . Moreover, the hypersensitivity of these mice to psychostimulants is consistent with the sensitivity of BD patients to stimulants . Besides the selective DAT inhibitor GBR12909,chinese vertical farming mice treated with the atypical stimulant modafinil also exhibited a similar mania-like profile in the BPM .
These data are consistent with evidence that modafinil exerts its primary effects by blocking the DAT . Modafinil may also exert downstream effects on the DA D1 and D4 receptors , although a wide array of other receptors may also be involved in the effects of modafinil . Studies investigating whether modafinil in healthy humans mimics the exploratory profile of BD patients are currently ongoing. Complete knockout of the DAT gene also results in hyperactivity and similar movement disorganization, characterized by predominantly straight path patterns . Since these DAT KO mice were tested using a video-tracker system, no information on specific exploration was assessed. Another study did investigate exploratory behavior and observed no difference in rearing and less object interactions exhibited by DAT KO compared to WT mice . Interestingly, treatment with the DA D1 antagonist SCH23390 attenuated the animals’ hyperactivity and altered their movement into more meandering behavior similar to control mice . Stimulant treatment attenuates the hyperactive profile of DAT KO mice however , mimicking treatment effects of ADHD, not BD . In fact, stimulants often exacerbate symptoms of BD mania and therefore complete KO of the DAT gene may not be suitable as a model for BD mania. Another mouse model of BD mania, created with a mutation in the Clock gene, exhibited similarities with the behavioral phenotype of patients in the BPM, but failed to mimic the pattern completely . In contrast to patients with BD, these ClockΔ19 mice exhibited more circumscribed, small-scale movements instead of direct, more linear paths . Hence, while circadian machinery linked to BD, although not this particular gene, and ClockΔ19 mice exhibiting altered sleep patterns , these mice do not recreate the pattern of altered exploration observed in BD mania patients . Furthermore, these mice have yet to be tested in domains of neurocognition relevant to BD. Similarly to ClockΔ19 mice, a mouse model of schizophrenia, the chakragati strain, also exhibited hyperactivity combined with more meandering, small-scale movements in the BPM .
The increased small scale movements of these mice are likely due to unilateral increases of DA in the brains of these mice. Other mechanisms involved could include the serotonin system as psilocin and the non-selective serotonin receptor agonist 5-methoxyN,N-dimethyltryptamine also induced circumscribed behavior in mice, an effect mediated by the 5-HT2C and 5-HT1A receptors respectively . Importantly however, these hallucinogens reduced activity and exploration in mice, resulting in a profile different from that of BD patients. It therefore seems that selectively reducing DAT functioning in mice specifically recreates the behavioral phenotype of BD mania patients in the BPM. Thus, while the mouse BPM has face validity for the human BPM, the prediction that reduced, but not completely lost, DAT functioning in mice recreates the hyper-exploratory profile of mania patients further supports the translational validity of the BPM. Going beyond these face and predictive validities, the effects of pharmacological treatments on the exploratory profile of these models were also investigated. Acute treatment with the mood-stabilizing agent valproate attenuated hyperactivity of DAT KD mice but not that of GBR12909-induced activity . Chronic treatment is needed before the Young Mania Rating Scale score of patients drop to the point they are considered euthymic , as does their degree of hyperactivity , supporting the premise that the pharmacological predictive validity of a model of mania may be more suitably assessed using chronic treatments . Encouragingly, chronic valproate treatment via the rodents’ chow at 15 g/kg resulted in serum concentrations within the human therapeutic range for BD .The hyperexploration and abnormal behavioral organization were unaffected in these models however, supporting the premise that valproate does not fully treat every aspect of mania, and that measurements beyond hyperactivity alone are required for the development of fully efficacious treatments . Interestingly, mania patients treated largely with valproate also exhibited a reduced effect size difference of hyperactivity compared with healthy subjects, yet their hyper-exploratory or abnormal behavioral organization was unaffected consistent with animal studies . The positive effects of chronic valproate treatment on models involving reduced DAT functioning may be explained by chronic valproate increasing neuronal DAT levels . Hence, reducing synaptic DA levels by increasing DAT expression may be a viable treatment for BD mania. This possibility is consistent with evidence of hyperdopaminergic states of manic BD patients , which are also seen in the DAT KD animal model . Another putative treatment would therefore include directly reducing DA availability, which was also studied in these models. In humans, treatment with alpha-methyl-p-tyrosine , a competitive inhibitor of tyrosine hydroxylase, the rate-limiting enzyme in the biosynthesis of catecholamines, reduced symptoms in manic patients and increased depression in BD depressed subjects . In another study however, AMPT did not affect mood during treatment of euthymic subjects, but resulted in hypomanic relapses post-treatment . When administered to DAT KD mice, AMPT attenuated the mania-like activity levels and disordered movement organization, without affecting control mice , consistent with reduced symptoms in mania patients . Exploration however, was not attenuated by AMPT in DAT KD mice, but was instead increased. Hence, consistent with BD mania patients, chronic valproate treatment lowered hyperactivity in reduced DAT function models but not other aspects of exploratory behavior. Furthermore, AMPT treatment reduced hyperactivity, but increased exploration, in these mice and reduced mania symptoms in mania patients. To a certain extent, these data therefore support the pharmacological predictive validity of reduced DAT functioning as a model for BD mania. In summary, abnormal exploration of patients with BD was characterized using a translational paradigm that enabled comparison with the locomotor profile of potential animal models for BD . Based on putative etiological mechanisms of reduced DAT functioning,commercial vertical farming we identified that selectively reducing DAT functioning induced an abnormal exploratory profile similar to that of patients with BD mania patients, supporting the construct and predictive validity of these models. Additionally, these DAT models meet the pharmacological predictive validity criterion since their hyperactive profiles were attenuated by treatment with valproate or AMPT. Similarities of behaviors observed between the reduced DAT functioning animal models and ClockΔ19 mice may provide important future directions. Because ClockΔ19 mice have increased DA release and turnover , the relationship between the DA system and aberrant circadian rhythms may be fundamentally important in the biological mechanisms of BD.
Investigating the effects of catecholamine depletion with AMPT in ClockΔ19 mice may further demonstrate the contribution of hyperdopaminergia being responsible for the animals’ mania-like behavior. A more traditional and commonly used translational test is the assessment of sensorimotor gating of the startle reflex. Across organisms, sensorimotor gating serves to filter out excessive stimuli in order to focus on the relevant features of the environment . In normal individuals, a weak prepulse before a subsequent startling stimulus will inhibit the startle response, termed prepulse inhibition . In the context of psychiatric research, PPI of the eye blink response was first assessed in patients with schizophrenia and afterwards translated to assess similar measures in animals, particularly rodents in which the startle response is measured by a whole-body flinch . Reduced sensorimotor gating as measured by lower PPI is observed in several psychiatric disorders such as Huntington’s disease , obsessive-compulsive disorder , schizophrenia , panic disorder , and is also observed in acutely manic and remitted BD patients , although other studies failed to report deficits in remitted adult and pediatric BD patients or in manic/mixed episode BD patients . A more recent study reported PPI deficits in male euthymic BD patients, but increased PPI in female BD patients . Additionally, normal PPI is observed in unipolar depressed individuals , suggesting that active manic symptoms and/or acute psychosis may be necessary to exhibit PPI deficits . Whether dysfunctional PPI is truly state-dependent is unclear, since PPI has yet to be studied in depressed bipolar patients. Since abnormal PPI has also been observed in the relatives of BD patients , impaired PPI may indicate a genetic predisposition to BD . Because PPI is observable across different species and measures a central component of information processing, it is a useful behavioral phenotype to investigate in animal models related to neuropsychiatric disorders. Since PPI deficits are most characterized and replicated in patients with schizophrenia , the majority of preclinical PPI studies focus on this disease . Nevertheless, sensorimotor gating has also been studied in animal models related to BD. The PPI paradigm in rodents has been used extensively in pharmacological studies, elucidating the mechanisms underlying PPI as well as searching for potential new antipsychotics . For instance, DA agonists impair PPI in both humans and animal models, effects that can be blocked by DA antagonists . Increased DA is often noted in the pathophysiology of BD and it is worth mentioning that elevating DA impairs PPI in rodents. For instance, the selective DAT inhibitor GBR12909 that recreates the behavioral profile of BD patients in mice in the BPM also impairs PPI of mice . Furthermore, modafinil also impaired PPI in mice, an effect that was reversed by co-treatment with the DA D2 receptor antagonist haloperidol . These data support the premise that the effect of modafinil was likely mediated by an interaction with the DA system. Hence, agents that recreate the mania-like BPM profile in mice also disrupt PPI, an effect that can be attenuated using BD mania-approved treatments. In addition to antipsychotic treatments, the effects of mood-stabilizing agents on PPI have also been investigated. In rats, lithium attenuated PPI deficits induced by amphetamine , supporting a possible interaction between lithium and the DA / noradrenergic system. We have observed that chronic lithium treatment resulting in low therapeutic serum concentrations blocked the GBR12909-induced PPI deficits in mice . Treatment with the anticonvulsant topiramate, occasionallyused off-label for BD, increased PPI in rats and potentiated the PPI-increasing effects of haloperidol and clozapine . Indeed, improvements of baseline PPI in normal animals or models with naturally low PPI are observed with certain antipsychotics and mood stabilizers. Similarly, healthy humans with low baseline PPI often exhibit increases in PPI after treatment with antipsychotics . PPI deficits induced by the DA agonist apomorphine in rats were also prevented by topiramate , asenapine , a novel antipsychotic in the treatment of SCZ and BD, and the mood stabilizers valproate, carbamazepine, and lithium , suggesting an interaction with the DA system for these treatments. Hence, pharmacological PPI studies may prove useful in elucidating putative treatments that may not obviously interact with the DA system. In search for BD animal models with greater etiological validity, the translational PPI paradigm has also been used to evaluate numerous genetic animal models. Potential susceptibility genes associated with BD or genes encoding for proteins that are likely involved in the pathogenesis of BD have been modified in rodents, after which the sensorimotor gating of these mice is tested . For instance, deletion at the 22q11 locus is associated with SCZ and BD .