Chronic nicotine, but not suramin or resveratrol, partially remediates the mania-like profile of dopamine transporter knockdown mice
| Autor: | Kwiatkowski, Molly A, Roberts, Benjamin Z, van Enkhuizen, Jordy, Ji, Baohu, Zhou, Xianjin, Young, Jared W |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Nicotine Bipolar Disorder Suramin Inbred C57BL Medical and Health Sciences Mice Animals Humans Psychiatry Dopamine Plasma Membrane Transport Proteins Animal Psychology and Cognitive Sciences Neurosciences Serious Mental Illness Brain Disorders Mania Mental Health Good Health and Well Being Resveratrol 5.1 Pharmaceuticals Disease Models Dopamine transporter Exploratory Behavior Female Development of treatments and therapeutic interventions |
| Popis: | 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; 40mg/kg/d, 26d), subchronic suramin (anti-purinergic; 20mg/kg, 1×/wk, 4wks), and subchronic resveratrol (striatal DAT upregulator; 20mg/kg/d, 4d) - 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. |
| Databáze: | OpenAIRE |
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