Kazuhiro Kurokawa

Upregulation of L-type Cav1 channels in the development of psychological dependence

Although L‐type voltage‐dependent Ca2+ channels regulate activity‐dependent processes including synaptic plasticity and synapse formation, there are few data on the changes of Cav1 channel expression in psychological dependence. This study investigated the role of L‐type Cav1 channel expression in the brain of mouse that was psychologically dependent on methamphetamine (2 mg/kg, subcutaneous injection [s.c.]), cocaine (10 mg/kg, s.c.), and morphine (5 mg/kg, s.c.) with the conditioned place preference paradigm. Intracerebroventricular administration of nifedipine (3, 10, and 30 nmol/mouse) dose‐dependently reduced the development of methamphetamine‐, cocaine‐, and morphine‐induced rewarding effect. Under such conditions, protein levels of both Cav1.2 and Cav1.3 in the frontal cortex and the limbic forebrain were significantly increased on methamphetamine‐, cocaine‐, and morphine‐induced psychologically dependent mice. These findings suggest that the upregulation of Cav1.2 and Cav1.3 participated in the development of psychological dependence. Synapse 64:440–444, 2010.

Gabapentin blocks methamphetamine-induced sensitization and conditioned place preference via inhibition of α2/δ-1 subunits of the voltage-gated calcium channels

Our previous investigation demonstrated that repeated administration of morphine significantly enhanced α(2)/δ-1 subunit expression in the frontal cortex and limbic forebrain of mice as well as morphine-induced place preference. However, little is known about regulatory mechanisms of α(2)/δ-1 subunit expression in conditioned place preference by methamphetamine (METH). In the present study, we investigated the role of α(2)/δ-1 subunit of voltage-gated calcium channels (VGCCs) in the mouse brain under repeated treatment with METH. The level of α(2)/δ-1 subunit increased significantly in the limbic forebrain including the nucleus accumbens and the frontal cortex of mice showing METH-induced sensitization. Under these conditions, the development of behavioral sensitization induced by the intermittent administration of METH was significantly suppressed by the co-administration of gabapentin (GBP) with binding activity to an exofacial epitope of α(2)/δ-1 subunit. Furthermore, GBP administered i.c.v. caused a dose-dependent inhibition of the METH-induced place preference. Chronic GBP treatment at the dose alleviating sensitization and place preference significantly reduced the elevation of α(2)/δ-1 subunit of VGCC induced by the repeated administration of METH in the limbic forebrain and frontal cortex, whereas there were no changes in the increase of α(2)/δ-1 subunit mRNA. These findings indicate that α(2)/δ-1 subunit plays a critical role in the development of METH-induced place preference following neuronal plasticity, and that GBP, which significantly suppressed METH-induced place preference by its possible inhibitory action of α(2)/δ subunit to neuronal membrane, may possibly be used as an alternative drug to treat or prevent drug dependence.

Regulation of ryanodine receptors by dopamine D1 receptors during methamphetamine-induced place conditioning

J. Neurochem. (2010) 115, 1206–1214.

Enhancement of histone acetylation in midbrain of mice with ethanol physical dependence and its withdrawal.

Acute and chronic consumption of alcohol (ethanol) has been reported to modify a variety of molecular events such as membrane fluidity, neurotransmitter turnover, neurotransmitter receptors, and intracellular signal transduction systems coupling to neurotransmitter receptors that alter biochemical processes in the mesolimbic dopaminergic system projecting to the nucleus accumbence and prefrontal cortex from the ventral tegmental area (Spanagel, 2009). The neurochemical process of ethanol physical dependence and withdrawal syndrome is supposed to result from adaptive changes in a number of neurotransmission systems, and several reports demonstrate the functional relationship between behavioral responses observed in ethanol-dependent and -withdrawn animals and neurotransmission systems such as glutamatergic transmission (De Witte et al., 2003; Lack et al., 2007). Ethanol alters phosphorylation of cAMP response element binding protein (CREB), and phosphorylation of CREB appears to modulate ethanol selfadministration (Yang et al., 1998). Phospho-CREB (p-CREB) level and cAMP response element (CRE)mediated gene expression are substantially changed in several brain regions in response to drugs of abuse (Nestler, 2001). Especially, changes in dopaminergic and glutamatergic inputs have been shown to induce chromatin remodelling by histone modifications (Li et al., 2004; Schroeder et al., 2008) and these events are associated with drug-related behavioral sensitization and reward (Fischer et al., 2007; Kumar et al., 2005; Li et al., 2004; McClung and Nestler, 2008; Schroeder et al., 2008). Acetylation of histone lysine residues reduces the electrostatic interaction between histone proteins and DNA, which is considered to relax chromatin structure and make DNA more accessible to transcriptional regulators (Kouzarides, 2007). It is suggested that hyperacetylation of histone H3 and H4 in promoter regions is strongly associated with gene activation (Renthal and Nestler, 2008). This association also exists in the brain in vivo in response to drugs of abuse. Moreover, intermittent binge ethanol administration also induces changes in the acetylation of histone H3 and H4 in the frontal cortex, nucleus accumbens, and striatum and effects the sensitivity of adolescent brain to ethanol via dopaminergic and glutamatergic neurotransmission (Pascual et al., 2009). However, little is known about changes in acetylation of histone H3 and H4 in the ventral tegmental area of ethanol-dependent and -withdrawn mice. In the present study, we demonstrate alterations of acetylation of histone H3 and H4, which relates to genes for neural plasticity, in the ventral tegmental area of ethanol-dependent and -withdrawal mice. Male ddY strain mice (Japan SLC, Hamamatsu, Japan) were kept in a room with an ambient temperature of 228C 6 18C and a 12 h light-dark cycle (lights on 08:00–20:00 h). Food and water were available ad libitum. All animal experiments carried out in this study were approved by the Animal Research Committee of Kawasaki Medical School and conducted according to the ‘‘Guide for Care and Use

Up‐regulation of L‐type high voltage‐gated calcium channel subunits by sustained exposure to 1,4‐ and 1,5‐benzodiazepines in cerebrocortical neurons

The aim of this study is to examine how sustained exposure to two 1,4‐benzodiazepines (BZDs) with different action period, diazepam and brotizolam, and a 1,5‐BZD, clobazam, affects L‐type high voltage‐gated calcium channel (HVCC) functions and its mechanisms using primary cultures of mouse cerebral cortical neurons. The sustained exposure to these three BZDs increased [45Ca2+] influx, which was due to the enhanced [45Ca2+] entry through L‐type HVCCs but not through of Cav2.1 and Cav2.2. Increase in [3H]diltiazem binding after the exposure to these three BZDs was due to the increase in the binding sites of [3H]diltiazem. Western blot analysis showed increase of Cav1.2 and Cav1.3 in association with the increased expression of α2/δ1 subunit. Similar changes in [3H]diltiazem binding and L‐type HVCC subunit expression were found in the cerebral cortex from mouse with BZD physical dependence. These results indicate that BZDs examined here have the potential to increase L‐type HVCC functions mediated via the enhanced expression of not only Cav1.2 and Cav1.3 but also α2/δ1 subunit after their sustained exposure, which may participate in the development of physical dependence by these BZDs.

Role of α2/δ subunit in the development of morphine-induced rewarding effect and behavioral sensitization

Previous data demonstrate that L-type voltage-gated calcium channel (VGCC) blockers, which bind to alpha(1) subunits of VGCC to suppress Ca(2+) entry into cells, inhibit the development of psychological dependence on drugs of abuse, suggesting the upregulation of L-type VGCC in the development of psychological dependence. However, there are few available data on changes of the auxiliary subunit alpha(2)/delta modifying L-type VGCC under such conditions. We therefore investigated here the role of alpha(2)/delta subunits of VGCCs in the brain of mouse after repeated treatment with morphine. The treatment with morphine increased alpha(2)/delta subunit expression in the frontal cortex and the limbic forebrain of mice showing rewarding effect and sensitization to hyperlocomotion by morphine. The morphine-induced behavioral sensitization and place preference were also suppressed by gabapentin, which binds to an exofacial epitope of the alpha(2)/delta auxiliary subunits of VGCCs. These findings indicate that the upregulation of alpha(2)/delta subunit as well as alpha(1) subunits of VGCC in the frontal cortex and the limbic forebrain plays a critical role in development of morphine-induced rewarding effect and behavioral sensitization following neuronal plasticity.

Dopamine D1 receptors regulate type 1 inositol 1,4,5-trisphosphate receptor expression via both AP-1- and NFATc4-mediated transcriptional processes

J. Neurochem. (2012) 122, 702–713.

L-type voltage-dependent calcium channels facilitate acetylation of histone H3 through PKCγ phosphorylation in mice with methamphetamine-induced place preference.

J. Neurochem. (2011) 118, 1056–1066.

Possible involvement of type 1 inositol 1,4,5-trisphosphate receptors up-regulated by dopamine D1 and D2 receptors in mouse nucleus accumbens neurons in the development of methamphetamine-induced place preference

Little is known about regulatory mechanisms of type 1 inositol-1,4,5-triphosphate receptor (IP(3)R-1) expression in conditioned place preference by methamphetamine (METH), though significant enhancement of IP(3)R-1 expression in the mouse frontal cortex and limbic forebrain by intermittent administration of cocaine is reported. The present study investigated the role and regulation of IP(3)R-1 in mice with METH-induced place preference. Injection of IP(3)R antagonists with different chemical structures, 2-aminophenoxyethane-borate and xestospongin C, into the mouse nucleus accumbens (NAcc) dose-dependently inhibited METH-induced place preference. The levels of IP(3)R-1 protein in the NAcc of METH-conditioned mice significantly increased, which was completely abolished by microinjection of SCH23390 and raclopride, selective dopamine D1-like and D2-like receptor (D1 and D2DR) antagonists respectively, into the mouse NAcc. Immunohistochemical assessment revealed co-localization of immunoreactivity for IP(3)R-1 and those for D1 and D2DRs in the NAcc. These findings suggest that IP(3)R-1 could be involved in the development of METH-induced place preference and that D1 and D2DRs in the NAcc of mice showing METH-induced place preference play possible regulatory roles in IP(3)R-1 expression.

Dopamine D1 receptor signaling system regulates ryanodine receptor expression after intermittent exposure to methamphetamine in primary cultures of midbrain and cerebral cortical neurons

J. Neurochem. (2011) 118, 773–783.