T-type calcium channel enhancer SAK3 promotes dopamine and serotonin releases in the hippocampus in naive and amyloid precursor protein knock-in mice

• Published in: PloS one Vol. 13; no. 12; p. e0206986
• Main Authors: Wang, Shuo, Yabuki, Yasushi, Matsuo, Kazuya, Xu, Jing, Izumi, Hisanao, Sakimura, Kenji, Saito, Takashi, Saido, Takaomi C, Fukunaga, Kohji
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.12.2018; Public Library of Science (PLoS)
• Subjects: Acetylcholine receptors (nicotinic); Alzheimer's disease; Alzheimers disease; Amyloid beta-Protein Precursor - genetics; Amyloid precursor protein; Animal cognition; Animals; Biology and Life Sciences; Brain; CA1 Region, Hippocampal - drug effects; CA1 Region, Hippocampal - metabolism; CA1 Region, Hippocampal - physiology; Calcium; Calcium channels; Calcium channels (T-type); Calcium Channels, T-Type - deficiency; Calcium Channels, T-Type - genetics; Calcium Channels, T-Type - metabolism; Cognition - drug effects; Cognitive ability; Cyclopentane; Dementia; Development and progression; Dopamine; Dopamine - metabolism; Drug therapy; Epilepsy; Gene Knock-In Techniques; Gene Knockout Techniques; Genetic aspects; Hippocampus; Imidazoles - pharmacology; Kinases; Laboratories; Male; Medicine and Health Sciences; Methyllycaconitine; Mice; Monoamines; Neurosciences; Noradrenaline; Norepinephrine; Oral administration; Pain; Pathophysiology; Pharmaceutical sciences; Pharmacology; Physical Sciences; Physiological aspects; Physiology; Precursors; Prefrontal cortex; Proteins; Pyridines; Research and Analysis Methods; Saito, Takashi; Serotonin; Serotonin - metabolism; Sleep; Spiro Compounds - pharmacology; Japan; United Kingdom > UK
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0206986

T-type calcium channels in the brain mediate the pathophysiology of epilepsy, pain, and sleep. Recently, we developed a novel therapeutic candidate, SAK3 (ethyl 8'-methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo[1,2-a] pyridine]-2-ene-3-carboxylate), for Alzheimer's disease (AD). The cognitive improvement by SAK3 is closely associated with enhanced acetylcholine (ACh) release in the hippocampus. Since monoamines such as dopamine (DA), noradrenaline (NA), and serotonin (5-HT) are also involved in hippocampus-dependent learning and psychomotor behaviors in mice, we investigated the effects of SAK3 on these monoamine releases in the mouse brain. Oral administration of SAK3 (0.5 mg/kg, p.o.) significantly promoted DA and 5-HT releases in the naive mouse hippocampal CA1 region but not in the medial prefrontal cortex (mPFC), while SAK3 did not affect NA release in either brain region. The T-type calcium channel-specific inhibitor, NNC 55-0396 (1 μM) significantly antagonized SAK3-enhanced DA and 5-HT releases in the hippocampus. Interestingly, the α7 nicotinic ACh receptor (nAChR) antagonist, methyllycaconitine (1 nM) significantly inhibited DA release, and the α4 nAChR antagonist, dihydro-β-erythroidine (100 μM) significantly blocked both DA and 5-HT releases following SAK3 (0.5 mg/kg, p.o.) administration in the hippocampus. SAK3 did not alter basal monoamine contents both in the mPFC and hippocampus. SAK3 (0.5 mg/kg, p.o.) administration also significantly elevated DA and 5-HT releases in the hippocampal CA1 region of amyloid-precursor protein (APP)NL-GF knock-in (KI) mice. Moreover, hippocampal DA and 5-HT contents were significantly decreased in APPNL-GF KI mice. Taken together, our data suggest that SAK3 promotes monoamine DA and 5-HT releases by enhancing the T-type calcium channel and nAChR in the mouse hippocampus.