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

PLoS One. 2018 Dec 20;13(12):e0206986. doi: 10.1371/journal.pone.0206986. eCollection 2018.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Protein Precursor / genetics*
  • Animals
  • CA1 Region, Hippocampal / drug effects*
  • CA1 Region, Hippocampal / metabolism
  • CA1 Region, Hippocampal / physiology
  • Calcium Channels, T-Type / deficiency
  • Calcium Channels, T-Type / genetics
  • Calcium Channels, T-Type / metabolism*
  • Cognition / drug effects
  • Dopamine / metabolism*
  • Gene Knock-In Techniques*
  • Gene Knockout Techniques
  • Imidazoles / pharmacology*
  • Male
  • Mice
  • Serotonin / metabolism*
  • Spiro Compounds / pharmacology*

Substances

  • Amyloid beta-Protein Precursor
  • Cacna1g protein, mouse
  • Calcium Channels, T-Type
  • Imidazoles
  • SAK3 compound
  • Spiro Compounds
  • Serotonin
  • Dopamine

Grants and funding

This work was supported in part by grants-in-aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (Kakenhi 25293124 to K.F. and 17K15456 to Y.Y.), by the Project of Translational and Clinical Research Core Centers from the Japan Agency for Medical Research and Development (AMED) (to K.F.), by the Smoking Research Foundation (K.F.), by the Research Fellow of the Japan Society for the Promotion of Science (266540 to Y.Y.), and by the The Research Foundation for Pharmaceutical Sciences (to Y.Y.).