Cross-Species Studies on the Mechanisms Underlying Abnormal Behavior in Bipolar Disorder: A Dopaminergic Focus

Abstract

Bipolar disorder (BD) is a severe neuropsychiatric disorder, affecting approximately 2% of the worldwide population. It is characterized by euphoric states of mania and opposite mood states of depression, which are devastating to the patients’ quality of life. Current treatment options are poor and may contribute to 1 in 3 patients attempting suicide. This shortage of efficacious therapeutics may be due to their serendipitous origin. Hence, neurocognitive symptoms often go untreated, while being highly associated with one’s functional outcome. Novel medication targeted at the disease is therefore urgently required. To better understand BD and develop targeted treatments, better animal models for BD with etiological and pharmacological validity are needed. This thesis describes a combination of approaches, investigating the putative underlying mechanisms of BD and providing novel targets to aid treatment development. Dysfunctional dopamine (DA) neurotransmission caused by reduced DA transporter (DAT) functioning likely plays a central role in the pathophysiology. Previously, BD patients exhibited a characteristic pattern in a human behavioral pattern monitor (BPM). Here, we observed that DAT knockdown (KD) mice exhibited the same hyperactive and hyper-explorative pattern in the mouse BPM. Catecholamine depletion with alpha-methyl-p-tyrosine (AMPT) attenuated some of these abnormalities. Selective DAT inhibition with GBR12909 also induced this BPM pattern and resulted in prepulse inhibition (PPI) deficits. Chronic valproate (mood-stabilizer) partly attenuated this BPM pattern in both DAT models. Chronic lithium however, exaggerated abnormal BPM behavior in the GBR12909 model, but normalized PPI deficits. Besides abnormal exploratory behavior, novel BD treatments should also target neurocognitive deficits. Both DAT models exhibited impaired decision-making in a mouse Iowa gambling task (IGT) consistent with BD patients. Moreover, increased motivation and motor impulsivity indicative of increased hedonia in BD were observed. DAT KD mice also exhibited reduced vigilance in an attentional task consistent with poor vigilance of BD patients. Finally, sleep deprivation impaired attention similarly in normal mice and healthy humans. Hence, these data highlight that reduced DAT functioning can reproduce abnormal exploration, PPI deficits, and cognitive deficits associated with BD mania. To investigate factors contributing to BD depression, we assessed the effects of acetylcholine-esterase (AChE) inhibition in mice. Physostigmine induced depressive-like behavior which was attenuated by chronic lithium. Because abnormal circadian rhythms are also present in patients, we tested mice with disrupted circadian rhythms (Clock∆19) and observed hyperactivity and hyper-exploration in the BPM, PPI deficits in the acoustic startle test, and increased saccharine preference. Further assessment of these mice as model animals for BD is warranted. Ultimately, these studies highlight the need to look beyond DATs and mania alone in investigating and treating BD. In conclusion, this thesis provides further information on the underlying mechanisms of different phases of BD and offers a way to test novel therapeutics. Dysfunctional DATs and disrupted circadian rhythms mediate mania-like behavior, while cholinergic systems are likely more important in depression. Utilizing extensively validated animal models with etiological and predictive validity as described in this thesis may ultimately yield therapeutics that specifically target the underlying circuitry of BD and improve the lives of patients