Acute SAK3, however, not ST101, (0.5 mg/kg, p.o., each) administration improved acetylcholine (ACh) launch in the hippocampus, enhancing memory space impairments observed in olfactory bulbectomized mice [18] thereby. in the naive mouse hippocampal CA1 area however, not in the medial prefrontal cortex (mPFC), while SAK3 didn’t affect NA launch in either mind area. The T-type calcium mineral channel-specific inhibitor, NNC 55C0396 (1 M) considerably antagonized SAK3-improved DA and 5-HT produces in the hippocampus. Oddly enough, the 7 nicotinic ACh receptor (nAChR) antagonist, methyllycaconitine (1 nM) considerably inhibited DA launch, as well as the 4 nAChR antagonist, dihydro–erythroidine (100 M) considerably clogged both DA and 5-HT produces pursuing SAK3 (0.5 mg/kg, p.o.) administration in the hippocampus. SAK3 didn’t alter basal monoamine material both in the hippocampus and mPFC. SAK3 (0.5 mg/kg, p.o.) administration also considerably raised DA and 5-HT produces in the hippocampal CA1 area of amyloid-precursor proteins (APP)NL-GF knock-in (KI) mice. Furthermore, hippocampal DA and 5-HT material had been decreased in APPNL-GF KI mice considerably. Taken collectively, our data claim that SAK3 promotes monoamine DA and 5-HT produces by improving the T-type calcium mineral route and nAChR in the mouse hippocampus. Intro Monoamines including dopamine (DA), serotonin (5-HT), and noradrenaline (NA) mediate different central nerve program functions such as for example motivation, engine function, and cognition [1,2]. Dysregulation of monoamine systems is connected with various neurodegenerative and psychiatric disorders [3]. In individuals with schizophrenia, mesocorticolimbic DA dysfunction makes up about both cognitive and psychotic disturbances. Anti-psychotics with DA receptor blockers, such as for example risperidone, are utilized for therapy [4 generally,5]. Furthermore, blockade of 5-HT and NA reuptake may be the most common focus on of therapeutics for unhappiness and behavioral and emotional symptoms of dementia (BPSD) in sufferers with Alzheimers disease (Advertisement) [6,7]. Furthermore, 5-HT amounts are markedly low in the cerebral limbic and basal ganglia areas in sufferers with Advertisement compared to healthful topics [8,9]. These reviews indicated that dysregulation of monoamine amounts has a vital function in psychomotor disruption in both psychiatry illnesses and Advertisement. T-type calcium mineral channels, referred to as transient and low voltage-activated calcium mineral stations, are characterized as electrophysiological kinetics by fast inactivation and gradual deactivation [10,11]. All Cav3.1, Cav3.2, and Cav3.3 T-type calcium stations are portrayed in the mind and keep maintaining the pathological and physiological systems [12C16]. Previously, we created the cognitive enhancer, ST101 (spiro [imidazole [1.2-a] pyridine-3, 2-indan]-2(3H)-1), which enhances Cav3.1 T-type calcium route current in Cav3.1-transfected neuro2A cells [17]. ST101 considerably enhanced calcium mineral/calmodulin-dependent proteins kinase II and subsequently marketed long-term potentiation in rat somatosensory cortical pieces; these effects had been blocked with the T-type calcium mineral route inhibitor, mibefradil [17]. We produced a far more powerful T-type calcium mineral route enhancer also, 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) [18]. SAK3 potentiates Cav3.1 and Cav3.3 currents, which screen a far more potent impact than ST101 [18]. Acute SAK3, however, not ST101, (0.5 mg/kg, p.o., each) administration elevated acetylcholine (ACh) discharge in the hippocampus, thus improving storage impairments observed in olfactory bulbectomized mice [18]. Furthermore, SAK3 prevents neuronal cell loss of life in hippocampal CA1 pyramidal neurons accompanied by transient human brain ischemia through nicotinic ACh receptor (nAChR) arousal [18,19]. As a result, SAK3 might activate nAChR signaling by promoting hippocampal ACh discharge through improving T-type calcium mineral stations. However, the consequences of SAK3 on monoamine discharge remain unclear. Within this framework, we investigated the consequences of SAK3 on monoamine discharge in the mouse medial prefrontal cortex (mPFC) and hippocampal CA1 area. We also examined the consequences of SAK3 (0.5 mg/kg, p.o.) on monoamine discharge in the hippocampus in amyloid precursor proteins (APP)NL-GF knock-in (KI) mice as an pet model of Advertisement [20]. Our outcomes provide evidence that T-type calcium mineral route arousal may boost monoamine discharge in both pathological and physiological circumstances. Strategies and Components Pets Man 6-week-old Rocuronium Rocuronium ddY mice had been bought from Clea Japan, Inc. (Tokyo, Japan). APPNL-GF KI mice had been extracted from Dr. Takashi Dr and Saito. Takaomi C Saido (Riken, Saitama, Japan). Cav3.1 knock-out (KO) mice were generated by Dr. Kenji Sakimura [21]. Wild-type (WT) C57BL/6J mice had been also bought from Clea Japan, Inc. (Tokyo, Japan). Pets had been housed under circumstances of constant heat range (23 2C) and dampness (55 5%) on the 12-h light-dark routine (light from 9 amC9 pm) and given with regular forage. Animals had been euthanized by isoflurane overdose or cervical dislocation after tests. All HDAC4 animal techniques had been accepted by the Committee on Pet Tests of Tohoku School. Reagents SAK3 was synthesized by Shiratori pharmaceutical Ltd (Chiba, Japan; Fig 1A) regarding to a prior research [18]. As SAK3 (0.5 mg/kg, p.o.) displays maximal ramifications of ACh discharge and significant cognitive improvement in several pet versions including APPNL-F KI mice [18,19,22], we chose dosage of SAK3 at 0.5 mg/kg to judge monoamine discharge. SAK3 was dissolved in distilled drinking water. T-type calcium mineral route inhibitor, NNC 55C0396 (1 M: Sigma-Aldrich, St-Louis, MO) [23], TTA-A2 (1 M: Alomone Labs, Jerusalem, Israel),.Nevertheless, SAK3 (0.5 mg/kg, p.o.) administration didn’t alter basal DA and 5-HT items in comparison to saline-treated mice (DA: p = 0.2604 vs. The T-type calcium mineral channel-specific inhibitor, NNC 55C0396 (1 M) considerably antagonized SAK3-improved DA and 5-HT produces in the hippocampus. Oddly enough, the 7 nicotinic ACh receptor (nAChR) antagonist, methyllycaconitine (1 nM) significantly inhibited DA release, and the 4 nAChR antagonist, dihydro–erythroidine (100 M) 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. Introduction Monoamines including dopamine (DA), serotonin (5-HT), and noradrenaline (NA) mediate numerous central nerve system functions such as motivation, motor function, and cognition [1,2]. Dysregulation of monoamine systems is usually associated with numerous psychiatric and neurodegenerative disorders [3]. In patients with schizophrenia, mesocorticolimbic DA dysfunction accounts for both psychotic and cognitive disturbances. Anti-psychotics with DA receptor blockers, such as risperidone, are generally utilized for therapy [4,5]. In addition, blockade of 5-HT and NA reuptake is the most common target of therapeutics for depressive disorder and behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimers disease (AD) [6,7]. Furthermore, 5-HT levels are markedly reduced in the cerebral limbic and basal ganglia areas in patients with AD compared to healthy subjects [8,9]. These reports indicated that dysregulation of monoamine levels has a crucial role in psychomotor disturbance in both psychiatry diseases and AD. T-type calcium channels, known as transient and low voltage-activated calcium channels, are characterized as electrophysiological kinetics by fast inactivation and slow deactivation [10,11]. All Cav3.1, Cav3.2, and Cav3.3 T-type calcium channels are expressed in the brain and maintain the physiological and pathological systems [12C16]. Previously, we developed the cognitive enhancer, ST101 (spiro [imidazole [1.2-a] pyridine-3, 2-indan]-2(3H)-one), which enhances Cav3.1 T-type calcium channel current in Cav3.1-transfected neuro2A cells [17]. ST101 significantly enhanced calcium/calmodulin-dependent protein kinase II and in turn promoted long-term potentiation in rat somatosensory cortical slices; these effects were blocked by the T-type calcium channel inhibitor, mibefradil [17]. We also generated a more potent T-type calcium channel enhancer, 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) [18]. SAK3 potentiates Cav3.1 and Cav3.3 currents, which display a more Rocuronium potent effect than ST101 [18]. Acute SAK3, but not ST101, (0.5 mg/kg, p.o., each) administration increased acetylcholine (ACh) release in the hippocampus, thereby improving memory impairments seen in olfactory bulbectomized mice [18]. Moreover, SAK3 prevents neuronal cell death in hippocampal CA1 pyramidal neurons followed by transient brain ischemia through nicotinic ACh receptor (nAChR) activation [18,19]. Therefore, SAK3 may activate nAChR signaling by promoting hippocampal ACh release through enhancing T-type calcium channels. However, the effects of SAK3 on monoamine release remain unclear. In this context, we investigated the effects of SAK3 on monoamine release in the mouse medial prefrontal cortex (mPFC) and hippocampal CA1 region. We also evaluated the effects of SAK3 (0.5 mg/kg, p.o.) on monoamine release in the hippocampus in amyloid precursor protein (APP)NL-GF knock-in (KI) mice as an animal model of AD [20]. Our results provide evidence that T-type calcium channel activation can increase monoamine release in both physiological and pathological conditions. Materials and methods Animals Male 6-week-old ddY mice were purchased from Clea Japan, Inc. (Tokyo, Japan). APPNL-GF KI mice were obtained from Dr. Takashi Saito and Dr. Takaomi C Saido (Riken, Saitama, Japan). Cav3.1 knock-out (KO) mice were generated by Dr. Kenji Sakimura [21]. Wild-type (WT) C57BL/6J mice were also purchased from Clea Japan, Inc. (Tokyo, Japan). Animals were housed under conditions of constant heat (23 2C) and humidity (55 5%) on a 12-h light-dark cycle (light from 9 amC9 pm) and fed with standard forage. Animals were euthanized by isoflurane overdose or cervical dislocation after experiments. All animal procedures were approved by the Committee on Animal Experiments of Tohoku University or college. Reagents SAK3 was synthesized by Shiratori pharmaceutical Ltd (Chiba, Japan; Fig 1A) according to a previous study [18]. As SAK3 (0.5 mg/kg, p.o.) shows maximal effects of ACh release and significant cognitive enhancement in several animal models including APPNL-F KI mice [18,19,22], we chose dose of SAK3 at 0.5 mg/kg to evaluate monoamine release. SAK3 was dissolved in distilled water. T-type calcium channel inhibitor, NNC 55C0396 (1 M: Sigma-Aldrich, St-Louis, MO) [23], TTA-A2 (1 M: Alomone Labs, Jerusalem, Israel), 7 nAChR antagonist MLA (1 nM: Sigma-Aldrich), and 42.Error bars represent the SEM. 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 55C0396 (1 M) significantly antagonized SAK3-enhanced DA and 5-HT releases in the hippocampus. Interestingly, the 7 nicotinic ACh receptor (nAChR) antagonist, methyllycaconitine (1 nM) significantly inhibited DA release, and the 4 nAChR antagonist, dihydro–erythroidine (100 M) 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. Introduction Monoamines including dopamine (DA), serotonin (5-HT), and noradrenaline (NA) mediate various central nerve system functions such as motivation, motor function, and cognition [1,2]. Dysregulation of monoamine systems is associated with various psychiatric and neurodegenerative disorders [3]. In patients with schizophrenia, mesocorticolimbic DA dysfunction accounts for both psychotic and cognitive disturbances. Anti-psychotics with DA receptor blockers, such as risperidone, are generally used for therapy [4,5]. In addition, blockade of 5-HT and NA reuptake is the most common target of therapeutics for depression and behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimers disease (AD) [6,7]. Furthermore, 5-HT levels are markedly reduced in the cerebral limbic and basal ganglia areas in patients with AD compared to healthy subjects [8,9]. These reports indicated that dysregulation of monoamine levels has a critical role in psychomotor disturbance in both psychiatry diseases and AD. T-type calcium channels, known as transient and low voltage-activated calcium channels, are characterized as electrophysiological kinetics by fast inactivation and slow deactivation [10,11]. All Cav3.1, Cav3.2, and Cav3.3 T-type calcium channels are expressed in the brain and maintain the physiological and pathological systems [12C16]. Previously, we developed the cognitive enhancer, ST101 (spiro [imidazole [1.2-a] pyridine-3, 2-indan]-2(3H)-one), which enhances Cav3.1 T-type calcium channel current in Cav3.1-transfected neuro2A cells [17]. ST101 significantly enhanced calcium/calmodulin-dependent protein kinase II and in turn promoted long-term potentiation in rat somatosensory cortical slices; these effects were blocked by the T-type calcium channel inhibitor, mibefradil [17]. We also generated a more potent T-type calcium channel enhancer, 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) [18]. SAK3 potentiates Cav3.1 and Cav3.3 currents, which display a more potent effect than ST101 [18]. Acute SAK3, but not ST101, (0.5 mg/kg, p.o., each) administration increased acetylcholine (ACh) release in the hippocampus, thereby improving memory impairments seen in olfactory bulbectomized mice [18]. Moreover, SAK3 prevents neuronal cell death in hippocampal CA1 pyramidal neurons followed by transient brain ischemia through nicotinic ACh receptor (nAChR) stimulation [18,19]. Therefore, SAK3 may activate nAChR signaling by promoting hippocampal ACh release through enhancing T-type calcium channels. However, the effects of SAK3 on monoamine release remain unclear. In this context, we investigated the effects of SAK3 on monoamine release in the mouse medial prefrontal cortex (mPFC) and hippocampal CA1 region. We also evaluated the effects of SAK3 (0.5 mg/kg, p.o.) on monoamine release in the hippocampus in amyloid precursor protein (APP)NL-GF knock-in (KI) mice as an animal model of AD [20]. Our results provide evidence that T-type calcium channel stimulation can increase monoamine release in both physiological and pathological conditions. Materials and methods Animals Male 6-week-old ddY mice were purchased from Clea Japan, Inc. (Tokyo, Japan). APPNL-GF KI mice were obtained from Dr. Takashi Saito and Dr. Takaomi C Saido (Riken, Saitama, Japan). Cav3.1 knock-out (KO) mice were generated by Dr. Kenji Sakimura [21]. Wild-type (WT) C57BL/6J mice were also purchased from Clea Japan, Inc. (Tokyo, Japan). Animals were housed under conditions of constant temperature (23 2C) and humidity (55 5%) on a 12-h light-dark cycle (light from 9 amC9 pm) and fed with standard forage. Animals were euthanized by isoflurane overdose or cervical dislocation after experiments. All animal procedures were approved by the Committee on Animal.DA and 5-HT levels in the dialysate were analyzed every 6 min (n = 10 per group). medial prefrontal cortex (mPFC), while SAK3 did not affect NA release in either brain region. The T-type calcium channel-specific inhibitor, NNC 55C0396 (1 M) significantly antagonized SAK3-enhanced DA and 5-HT releases in the hippocampus. Interestingly, the 7 nicotinic ACh receptor (nAChR) antagonist, methyllycaconitine (1 nM) significantly inhibited DA release, and the 4 nAChR antagonist, dihydro–erythroidine (100 M) significantly blocked both DA Rocuronium and 5-HT releases following SAK3 (0.5 mg/kg, p.o.) administration in the hippocampus. SAK3 did not alter basal monoamine material 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 material were significantly decreased in APPNL-GF KI mice. Taken collectively, 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. Intro Monoamines including dopamine (DA), serotonin (5-HT), and noradrenaline (NA) mediate numerous central nerve system functions such as motivation, engine function, and cognition [1,2]. Dysregulation of monoamine systems is definitely associated with numerous psychiatric and neurodegenerative disorders [3]. In individuals with schizophrenia, mesocorticolimbic DA dysfunction accounts for both psychotic and cognitive disturbances. Anti-psychotics with DA receptor blockers, such as risperidone, are generally utilized for therapy [4,5]. In addition, blockade of 5-HT and NA reuptake is the most common target of therapeutics for major depression and behavioral and mental symptoms of dementia (BPSD) in individuals with Alzheimers disease (AD) [6,7]. Furthermore, 5-HT levels are markedly reduced in the cerebral limbic and basal ganglia areas in individuals with AD compared to healthy subjects [8,9]. These reports indicated that dysregulation of monoamine levels has a essential part in psychomotor disturbance in both psychiatry diseases and AD. T-type calcium channels, known as transient and low voltage-activated calcium channels, are characterized as electrophysiological kinetics by fast inactivation and sluggish deactivation [10,11]. All Cav3.1, Cav3.2, and Cav3.3 T-type calcium channels are indicated in the brain and maintain the physiological and pathological systems [12C16]. Previously, we developed the cognitive enhancer, ST101 (spiro [imidazole [1.2-a] pyridine-3, 2-indan]-2(3H)-one), which enhances Cav3.1 T-type calcium channel current in Cav3.1-transfected neuro2A cells [17]. ST101 significantly enhanced calcium/calmodulin-dependent protein kinase II and in turn advertised long-term potentiation in rat somatosensory cortical slices; these effects were blocked from the T-type calcium channel inhibitor, mibefradil [17]. We also generated a more potent T-type calcium channel enhancer, 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) [18]. SAK3 potentiates Cav3.1 and Cav3.3 currents, which display a more potent effect than ST101 [18]. Acute SAK3, but not ST101, (0.5 mg/kg, p.o., each) administration improved acetylcholine (ACh) launch in the hippocampus, therefore improving memory space impairments seen in olfactory bulbectomized mice [18]. Moreover, SAK3 prevents neuronal cell death in hippocampal CA1 pyramidal neurons followed by transient mind ischemia through nicotinic ACh receptor (nAChR) activation [18,19]. Consequently, SAK3 may activate nAChR signaling by advertising hippocampal ACh launch through enhancing T-type calcium channels. However, the effects of SAK3 on monoamine launch remain unclear. With this context, we investigated the effects of SAK3 on monoamine launch in the mouse medial prefrontal cortex (mPFC) and hippocampal CA1 region. We also evaluated the effects of SAK3 (0.5 mg/kg, p.o.) on monoamine launch in the hippocampus in amyloid precursor protein (APP)NL-GF knock-in (KI) mice as an animal model of AD [20]. Our results provide evidence that T-type calcium channel activation can increase monoamine launch in both physiological and pathological conditions. Materials and methods Animals Male 6-week-old ddY mice were purchased from Clea Japan, Inc. (Tokyo, Japan). APPNL-GF.saline treated mice; 5-HT: p = 0.7999 vs. M) significantly clogged both DA and 5-HT releases following SAK3 (0.5 mg/kg, p.o.) administration in the hippocampus. SAK3 did not alter basal monoamine material 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 material were significantly decreased in APPNL-GF KI mice. Taken collectively, 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. Intro Monoamines including dopamine (DA), serotonin (5-HT), and noradrenaline (NA) mediate numerous central nerve system functions such as motivation, engine function, and cognition [1,2]. Dysregulation of monoamine systems is definitely associated with numerous psychiatric and neurodegenerative disorders [3]. In individuals with schizophrenia, mesocorticolimbic DA dysfunction accounts for both psychotic and cognitive disturbances. Anti-psychotics with DA receptor blockers, such as risperidone, are generally utilized for therapy [4,5]. In addition, blockade of 5-HT and NA reuptake is the most common target of therapeutics for major depression and behavioral Rocuronium and mental symptoms of dementia (BPSD) in individuals with Alzheimers disease (AD) [6,7]. Furthermore, 5-HT levels are markedly reduced in the cerebral limbic and basal ganglia areas in individuals with AD compared to healthy subjects [8,9]. These reports indicated that dysregulation of monoamine levels has a crucial role in psychomotor disturbance in both psychiatry diseases and AD. T-type calcium channels, known as transient and low voltage-activated calcium channels, are characterized as electrophysiological kinetics by fast inactivation and slow deactivation [10,11]. All Cav3.1, Cav3.2, and Cav3.3 T-type calcium channels are expressed in the brain and maintain the physiological and pathological systems [12C16]. Previously, we developed the cognitive enhancer, ST101 (spiro [imidazole [1.2-a] pyridine-3, 2-indan]-2(3H)-one), which enhances Cav3.1 T-type calcium channel current in Cav3.1-transfected neuro2A cells [17]. ST101 significantly enhanced calcium/calmodulin-dependent protein kinase II and in turn promoted long-term potentiation in rat somatosensory cortical slices; these effects were blocked by the T-type calcium channel inhibitor, mibefradil [17]. We also generated a more potent T-type calcium channel enhancer, 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) [18]. SAK3 potentiates Cav3.1 and Cav3.3 currents, which display a more potent effect than ST101 [18]. Acute SAK3, but not ST101, (0.5 mg/kg, p.o., each) administration increased acetylcholine (ACh) release in the hippocampus, thereby improving memory impairments seen in olfactory bulbectomized mice [18]. Moreover, SAK3 prevents neuronal cell death in hippocampal CA1 pyramidal neurons followed by transient brain ischemia through nicotinic ACh receptor (nAChR) activation [18,19]. Therefore, SAK3 may activate nAChR signaling by promoting hippocampal ACh release through enhancing T-type calcium channels. However, the effects of SAK3 on monoamine release remain unclear. In this context, we investigated the effects of SAK3 on monoamine release in the mouse medial prefrontal cortex (mPFC) and hippocampal CA1 region. We also evaluated the effects of SAK3 (0.5 mg/kg, p.o.) on monoamine release in the hippocampus in amyloid precursor protein (APP)NL-GF knock-in (KI) mice as an animal model of AD [20]. Our results provide evidence that T-type calcium channel activation can increase monoamine release in both physiological and pathological conditions. Materials and methods Animals.