[Role of intracellular Ca2+ dynamics in the development of drug dependence--Participation of Inositol 1,4,5-trisphosphate receptors].

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are classified to a multigene family of channel proteins that mediate Ca2+ release from endoplasmic reticulum, and are one of regulators to modify intracellular Ca2+ concentration. Little is known about functional relationship between rewarding effects due to drugs of abuse and IP3Rs. This report reviews the roles and regulatory mechanisms of intracellular Ca2+ channels, especially type 1 IP3Rs (IP3Rs-1), in brain of animals with rewarding effects produced by drugs of abuse.

Nicotinic acetylcholine receptors regulate type 1 inositol 1,4,5-trisphosphate receptor expression via calmodulin kinase IV activation.

Type 1 inositol 1,4,5-trisphosphate receptors (IP3 R-1) are among the important calcium channels regulating intracellular Ca(2+) concentration in the central nervous system. In a previous study, we showed that drugs of abuse, such as cocaine, methamphetamine, and ethanol, induced IP3 R-1 upregulation via the calcium signal transduction pathway in psychological dependence. Although nicotine, a major component in tobacco smoke, participates in psychological and/or physical dependence, it has not yet been clarified how nicotine alters IP3 R-1 expression.

Increase of type 2 ryanodine receptors in mouse nucleus accumbens in the development and expression of morphine-induced place preference.

The present study investigated the effect of ryanodine receptors (RyRs) in the development and expression of morphine-induced conditioned place preference (CPP). Type 2 RyRs (RyRs-2) in the nucleus accumbens (NAcc) significantly increased in morphine-conditioned mice, whereas type 1, 2, and 3 RyRs in the frontal cortex and ventral tegmental area showed no changes. Intracerebroventricular pretreatment with dantrolene, a RyRs antagonist, during the conditioning phase of CPP, dose-dependently inhibited morphine-induced CPP.

[Role of alteration in intracellular Ca2+ dynamics in the development of drug dependence].

Ca2+ influx into neuron through L-type voltage-gated Ca2+ channels (VDCCs) plays an important role in psychostimulant-induced behaviroal and neuronal plasticity. On the other hand, Ca2+ release from ryanodine receptors in the endoplasmic reticulum is one mechanism altering the intracellular Ca2+ concentration. Little is known about functional relationship between psychological dependence due to drugs of abuse and L-type VDCCs or ryanodine receptors.

Sensitization of ethanol-induced place preference as a result of up-regulation of type 1 inositol 1,4,5-trisphosphate receptors in mouse nucleus accumbens.

This study involved mice that received 4 days of ethanol (EtOH) vapor inhalation and then were assessed for type 1 inositol 1,4,5-trisphosphate receptor (IP3 Rs-1) expression and the development of EtOH-induced place preference at various time points in withdrawal. IP3 R-1 protein was found to be significantly increased in the nucleus accumbens (NAcc) of mice immediately after 4-day EtOH vapor inhalation, while it significantly reduced to the control level during the next 3 days of withdrawal from EtOH inhalation. EtOH (2 g/kg, i.

[Mechanisms of ethanol-induced type I IP3 receptor expression].

Ethanol has a variety of action on neuronal functions, though its mechanism of action remains uncertain. Previous investigations have demonstrated functional alteration of neurotransmitter receptors and ion channels by ethanol at its concentration observed in the blood of alcoholics. Our recent studies have shown that chronic ethanol treatment up-regulates high voltage-gated L-type calcium channels and ryanodine receptors, both of which regulate intracellular Ca2+ concentration, and that the up-regulation of these calcium channels participates in behavioral changes including the rewarding effect.

Regulatory mechanisms and pathophysiological significance of IP3 receptors and ryanodine receptors in drug dependence.

Calcium is a ubiquitous intracellular signaling molecule required for initiating and regulating neuronal functions. Ca(2+) release from intracellular stores in the endoplasmic reticulum into intracellular spaces via intracellular Ca(2+)-releasing channels, inositol 1,4,5-trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs), is one mechanism altering the intracellular Ca(2+) concentration. Functional abnormalities in endoplasmic calcium channels can disturb cellular calcium homeostasis and, in turn, produce pathological conditions.

Acamprosate suppresses ethanol-induced place preference in mice with ethanol physical dependence.

The present study investigated the effect of acamprosate on ethanol (EtOH)-induced place preference in mice with EtOH physical dependence. The expression of EtOH (2 g/kg, intraperitoneally)-induced place preference in mice without EtOH treatment before the experiment was dose-dependently suppressed by acamprosate. The levels of protein kinase A (PKA) and phospho-cAMP response element binding protein (p-CREB) in the limbic forebrain after EtOH-conditioning in naïve mice was unchanged.

Dopamine D1 receptor signaling system regulates ryanodine receptor expression in ethanol physical dependence.

Background: Ryanodine receptors (RyRs) amplifying activity-dependent calcium influx via calcium-induced calcium release play an important role in central nervous system functions including learning, memory, and drug abuse. In this study, we investigated the role and the regulatory mechanisms of RyR expression under continuous exposure of mice to ethanol (EtOH) vapor for 9 days.

Methods: The model of EtOH physical dependence was prepared as follows: 8-week-old male ddY mice were exposed to EtOH vapor for 9 days.

Activation of GABA(A) receptors suppresses ethanol-induced upregulation of type 1 IP(3) receptors.

Although Type 1 inositol 1,4,5-trisphosphate receptors (IP(3) Rs-1) are one of the major calcium channels to regulate intracellular Ca(2+) concentration, there have been few available data how their expression is modified by long-term exposure to ethanol. The present study attempted to clarify mechanisms of modification of IP(3) R-1 expression during long-term ethanol exposure by γ-aminobutyric acid (GABA)A receptors using mouse cerebral cortical neurons. Long-term exposure to ethanol induced IP(3) R-1 protein upregulation following increased expression of its mRNA.

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

Although our recent report demonstrates the essential involvement of up-regulation of a regulator of intracellular Ca(2+) concentration, type 1 inositol 1,4,5-trisphosphate receptors (IP(3) Rs-1), mediated via dopamine D1-like receptor (D1DR) stimulation in the cocaine-induced psychological dependence, the exact mechanisms of regulation of IP(3) R-1 expression by D1DRs have not yet been clarified. This study attempted to clarify these mechanisms using mouse cerebral cortical neurons. An agonist for phosphatidylinositide-linked D1DRs, SKF83959, induced dose- and time-dependently IP(3) R-1 protein up-regulation following its mRNA increase without cAMP production.

Increase of ryanodine receptors by dopamine D1 receptors is negatively regulated by γ-aminobutyric acid type B receptors in primary cultures of mouse cerebral cortical neurons.

Although upregulation of ryanodine receptor (RyR)-1 and -2 is mediated through the activation of dopamine D1 receptors (D1DRs) in the development of psychostimulant-induced place preference, little is known about how such increased expressions of RyRs are negatively regulated. This study investigated negative regulatory mechanisms of increase of RyR-1 and -2 expression by D1DR stimulation with its full agonist, SKF82958 or A 68930, using cultures of mouse cerebral cortical neurons. Sustained exposure to SKF82958 or A 68930 of the neurons increased RyR-1 and -2 proteins in a dose- and time-dependent-manner.

Actin dynamics in development of behavioral sensitization after withdrawal from long-term ethanol administration to mice.

Background And Methods: The present study investigated the role of actin depolymerizing factor (ADF) in the brain of mice after withdrawal from continuous ethanol (EtOH) vapor inhalation for 9 days using C57BL/6J and ADF mutant mice.

Results: C57BL/6J mice with withdrawal signs 10 hours after withdrawal from EtOH vapor inhalation showed transient and significant enhancement of locomotor activity by a single injection of EtOH (2 g/kg, i.p.

Effect of aripiprazole on anxiety associated with ethanol physical dependence and on ethanol-induced place preference.

In the present study, we investigated the effect of aripiprazole, a dopamine system stabilizer, on ethanol-induced psychological and physiological dependence and anxiety-like behavior. First we determined the effect of aripiprazole, a dopamine system stabilizer, on the development and expression of ethanol-induced place preference. Both the development and expression of ethanol-induced place preference was significantly suppressed by treatment of aripiprazole.

[Mechanism of withdrawal syndrome in alcohol dependence].

Pathophysiological process of ethanol physical dependence and its withdrawal syndrome is supposed to result from adaptive changes in a number of neurotransmission systems, and several reports have demonstrated functional relationship between behavioral responses and neurotransmission systems in ethanol-dependent and -withdrawn animals. However, the molecular mechanisms underlying behavioral responses observed in these animals are still controversial at present. Alterations of beta-adrenergic receptor (beta-AR) function in the brains of mice physically dependent on ethanol were examined because of few available data on functional changes of beta-ARs and its significance in ethanol withdrawal signs.

Regulation of type 1 inositol 1,4,5-triphosphate receptor by dopamine receptors in cocaine-induced place conditioning.

Recent study shows that type 1 inositol-1,4,5-triphosohate receptors (IP(3) Rs) may be involved in amphetamine-induced conditioned preference, but little is known about its role in psychological dependence on cocaine. This study investigated the role and regulation of IP(3) R-1 in mice with cocaine-induced place preference. The cocaine-induced place preference was dose-dependently inhibited by intracerebroventricular pretreatment with IP(3) R antagonists, 2-aminophenoxyethane-borate (2-APB), and xestospongin C.

Role of actin depolymerizing factor in the development of methamphetamine-induced place preference in mice.

The present study investigated role of actin depolymerizing factor (ADF) in methamphetamine-induced place preference using ADF mutant (ADFm) and wild-type mice (WT). Whereas methamphetamine developed dose-dependently place preference in wild-type mice, methamphetamine-induced place preference was significantly attenuated by ADF mutation. Moreover, the administration of phalloidin, an F-actin stabilizer, dose-dependently inhibited methamphetamine-induced place preference.

Dopamine D(1) receptors participate in cocaine-induced place preference via regulation of ryanodine receptor expression.

Ryanodine receptors (RyRs) with three different isoforms in the brain play a role to facilitate Ca(2+) release from the intracellular Ca(2+) pool. Although cocaine is a strongly addictive psychostimulant that dramatically affects the central nervous system function, the role of RyRs and regulation of their expression by cocaine-induced place preference have not yet been defined well. The present study investigated the regulation of RyR expression in mice under intermittent cocaine treatment using the place preference procedure.

β₁-adrenergic receptor up-regulation induced by nadolol is mediated via signal transduction pathway coupled to α₁-adrenergic receptors.

Although up-regulation of β-adrenergic receptors (β-ARs) occurs after long-term use of their antagonists in various tissues, the available data are little on mechanisms of β-AR up-regulation induced by their continuous blockade. The present study attempted to clarify mechanisms of β-AR up-regulation using mouse cerebral cortical neurons continuously exposed to nadolol (10 nM), a non-selective β-AR antagonist, for 24 h. Nadolol dose-dependently induced both subtypes of β-ARs, β₁- and β₂-ARs, which were not suppressed by protein A kinase inhibition with KT5720.

[Functional homology between alcohol dependence and mood disorder].

Acute and chronic consumption of alcohol (ethanol) has been reported to modify a multitude of molecular events such as membrane fluidity, neurotransmitter turnover, function of neurotransmitter receptors and intracellular signal transduction systems coupling to neurotransmitter receptors, and biochemical processes in the central nervous system. Long-term consumption of alcohol produces alcohol dependence with comorbidity such as mood disorder, schizophrenic disorder and neurotic disorder. We examined functional changes in serotonin transporter (SERT) and serotonin receptors (5-HT(1A) and 5-HT(2A) receptors) related with depression using alcohol physical dependent mice and found correlated changes between depression and alcohol dependence.

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

The present study investigated regulation of histone acetylation by L-type voltage-dependent calcium channels (VDCCs), one of the machineries to provide Ca(2+) signals. Acetylation of histone through the phosphorylation of protein kinase Cγ (PKCγ) in the development of methamphetamine (METH)-induced place preference was demonstrated in the limbic forebrain predominantly but also in the nucleus accumbens of α1C subunit knockout mice. Chronic administration of METH produced a significant place preference in mice, which was dose-dependently inhibited by both chelerythrine (a PKC inhibitor) and nifedipine (an L-type VDCC blocker).

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

Regulatory mechanisms of ryanodine receptor (RyR) expression are not well known, although methamphetamine (METH) has been reported to up-regulate RyRs in mouse brain. This study investigate regulatory mechanisms of RyR expression by dopaminergic system using the midbrain and cerebral cortical neurons in primary culture intermittently exposed to METH and dopamine receptor (DR) agonists (1 h/day, for 3 days). Intermittent METH (10 μM) exposure enhanced RyR-1 and -2 proteins and their mRNA, but not RyR-3 expression in the both types of the neurons.

Involvement of NMDA receptors in ryanodine receptor expression in dopaminergic neurons in the ventral tegmental area of mice with intermittent methamphetamine treatment.

Excitatory synapses on dopaminergic neurons of the ventral tegmental area (VTA) represent an important role in psychostimulant-induced rewarding effect. This study investigated the regulation of ryanodine receptor (RyR) and N-methyl-D-aspartate (NMDA) receptor expression in mice under intermittent methamphetamine (METH) treatment using a place preference procedure. RyR-1 and -2 significantly increased in the VTA of mice with METH-induced place preference, whereas RyR-3 showed no changes.