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Biomedical subjects

T Abekawa

Publications and source records attributed to T Abekawa.

At least 19 recordsLinked to original sources
PubMed2005

Effect of the protein kinase C inhibitor, staurosporine, on the high dose of methamphetamine-induced behavioral sensitization to dizocilpine (MK-801).

RATIONALE: In our preliminary study, methamphetamine (METH) at 2.5 mg/kg, but not at 1.0 mg/kg, induced a delayed increase in glutamate levels in the nucleus accumbens (NAc). We hypothesize that repeated increases in glutamate levels produces behavioral sensitization to a selective uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801), and that an activation of protein kinase C (PKC) plays an important role for this sensitization. OBJECTIVES: This study was conducted to confirm delayed increases in glutamate levels induced by a higher dose of METH (2.5 mg/kg), and to examine the effect of straurosporine, a PKC inhibitor, on the higher dose of METH-induced sensitization to dizocilpine. METHODS: The effects of METH on extracellular glutamate levels in the NAc were studied using in vivo microdialysis. Locomotor activity was measured by using an infrared sensor. RESULTS: METH at 2.5 mg/kg, but not at 1.0 mg/kg, induced delayed increases in glutamate levels. The acute administration of staurosporine did not affect the locomotor activity by a single injection of METH (2.5 mg/kg). Repeated METH administrations (2.5 mg/kg, once in every other day, for five times) developed behavioral sensitization to the locomotion-inducing effect of dizocilpine (0.2 mg/kg), a selective uncompetitive NMDA receptor antagonist. Staurosporine (0.1 mg/kg), given 120 min later for every METH treatment, inhibited the development of behavioral sensitization to dizocilpine. CONCLUSIONS: These results suggest the involvement of increased glutamate levels and an activation of PKC in delayed-induced synaptic and cellular plasticity underlying the higher dose of METH-induced behavioral sensitization to dizocilpine.

Animals↗
PubMed2003

Effects of NRA0045, a novel potent antagonist at dopamine D4, 5-HT2A, and alpha1 adrenaline receptors, and NRA0160, a selective D4 receptor antagonist, on phencyclidine-induced behavior and glutamate release in rats.

RATIONALE: Administration of phencyclidine (PCP) to animals produces abnormal behavior such as hyperlocomotion, stereotyped behavior, and ataxia; this abnormal behavior is only weakly blocked by dopamine D(2) receptor antagonists. This study examined the effects of a novel thiazole derivative, NRA0045 which potently antagonizes not only dopamine D(4) receptors but also 5-HT(2A) and alpha(1) adrenaline receptors, and NRA0160, a selective dopamine D(4) receptor antagonist, on PCP-induced abnormal behavior, and accompanying increases in extracellular levels of glutamate in the medial prefrontal cortex. Furthermore, this study compared the effects of these drugs with those of clozapine and haloperidol. METHODS: To study the effects of NRA-drugs, atypical and typical antipsychotics, we measured locomotor activity with an infra-red sensor, and stereotypy and ataxia on a rating scale. Extracellular glutamate levels were measured by in vivo microdialysis. RESULTS: NRA0045 (1 or 3 mg/kg) or clozapine (1 mg/kg) attenuated hyperlocomotion, stereotypy, and ataxia induced by PCP (7.5 mg/kg) without affecting behavior after saline injection. Although haloperidol (0.1 or 1 mg/kg) attenuated or inhibited PCP-induced behavior, this drug also affected behavior after saline injection. NRA0160 (0.1, 1, or 3 mg/kg) had no effect on behavior induced by PCP or saline. NRA0045 (3 mg/kg), but not NRA0160, inhibited PCP-induced increases in glutamate levels in the medial prefrontal cortex. PCP-induced hyperlocomotion correlated with the PCP-induced increases in glutamate levels in this brain region. CONCLUSIONS: These results suggest that the effects of NRA0045 on PCP-induced abnormal behavior are similar to those of the atypical antipsychotic clozapine. NRA0045 probably attenuates PCP-induced abnormal behavior by inhibiting the PCP-induced increase in glutamate levels in the medial prefrontal cortex; this inhibition may be mediated via the blockade of 5-HT(2A) receptors.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2002

Effect of MS-153 on the development of behavioral sensitization to locomotion- and ataxia-inducing effects of phencyclidine.

RATIONALE: Repeated administration of phencyclidine (PCP) produces behavioral sensitization to PCP. Although the precise mechanism is unknown, glutamatergic neurotransmission seems to play an important role in the development of sensitization. OBJECTIVES: The present study examined whether a novel compound, MS-153 (( R)-(-)-5-methyl-1-nicotinyl-2-pyrazoline), which has an ability to enhance glutamate uptake and inhibit glutamate release, would block the development of behavioral sensitization to PCP. METHODS: For studying effects of MS-153, locomotor activity was measured by an infrared sensor and ataxia was measured by a rating scale. RESULTS: MS-153 (10 and 100 mg/kg) enhanced locomotion and ataxia induced by a single injection of PCP (7.5 mg/kg). Repeated administration of PCP (20 mg/kg, once in every day, for 5 days) developed sensitization to locomotion- and ataxia-inducing effects of PCP (7.5 mg/kg). MS-153 given 60 min and 120 min later of every PCP treatment blocked the development of behavioral sensitization to both locomotion- and ataxia-inducing effects of PCP. Co-administration of MS-153 with repeated saline treatment did not produce hypersensitivity to PCP. CONCLUSIONS: These results suggest that the attenuation of glutamatergic neural transmission enhances acute effects of PCP, in contrast, blocks the behavioral sensitization developed by repeated PCP treatment. Therefore, glutamatergic neural transmission plays an important role in the development of behavioral sensitization to PCP.

Animals↗
PubMed2001

Effect of low doses of L-NAME on methamphetamine-induced dopaminergic depletion in the rat striatum.

The toxic dose of methamphetamine (METH) (5 mg/kg, s.c., x4, 2 hr intervals) decreased contents of dopamine, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in striatum, and decreased contents of serotonin (5-HT) in both striatum and nucleus accumbens. Administration of low doses of a non-selective endothelial and neuronal nitric oxide synthase (NOS) inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME) (5 and 10 mg/kg, i.p., x1) intensified the METH-induced decreases in contents of dopamine and its metabolites in striatum. NO substrate, L-arginine (500 mg/kg, i.p., x4) reversed these effects of L-NAME on the METH-neurotoxicity. L-NAME did not change the METH-induced hyperthermia. These findings, which are contrary to our previous study with a high dose of L-NAME, suggest that the inhibition of endothelial or neuronal NOS-mediated NO production by low doses of L-NAME enhanced the METH-induced neurotoxicity. The finding that L-NAME can have opposite effects on the METH-neurotoxicity according to the dosing is important, however, additional experiments should be performed to clarify which type of NOS is related to these effects.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

D1 dopamine receptor activation reduces extracellular glutamate and GABA concentrations in the medial prefrontal cortex.

The present study examined effect of administration of a selective D1 dopamine receptor agonist, SKF38393 on extracellular concentrations of glutamate (Glu) and gamma-aminobutyric acid (GABA) in mPFC, by using in vivo microdialysis. Perfusion with SKF38393 via a dialysis probe reduced concentrations of both Glu and GABA dose-relatedly, and these effects were prevented by co-perfusion with a D1 dopamine receptor antagonist, SCH23390 (40 microM). These results suggested that the dopaminergic hyperactivity may lead to the hypofunction of glutamatergic and GABAergic systems in mPFC via D1 dopamine receptor stimulation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2000

The role of benzodiazepine receptors in the acquisition and expression of behavioral sensitization to methamphetamine.

The GABA-benzodiazepine neurotransmission has been reported to be implicated in various forms of plasticity such as kindling and learning. In a previous study, we have shown that clonazepam (CZP), a GABA-benzodiazepine agonist, prevents the acquisition of behavioral sensitization to methamphetamine (MA). The present study was conducted to extend this finding by examining the effect of flumazenil (Flu), a GABA-benzodiazepine antagonist on the prevention by CZP. Rats (male Wistar-King rats) treated with MA (1 mg/kg, SC) for 10 days showed significantly enhanced motor activity compared to those treated with saline when tested with MA (1 mg/kg) after a 7-8-day withdrawal, indicating the acquisition of behavioral sensitization. Representing the previous finding, pretreatment with CZP (0.5 mg/kg) prior to MA administration prevented the acquisition of the phenomenon. Pretreatment with Flu (10 mg/kg) prior to MA administration has no influence on the acquisition of sensitization. However, pretreatment with Flu prior to CZP administration reversed the inhibitory effect of CZP. CZP showed no effect on the expression of sensitization in the sensitized rats when given prior to the MA readministration. These results strengthen the suggestion that stimulation of GABA-benzodiazepine receptors plays a role in the acquisition but not in the expression of behavioral sensitization to MA.

Animals↗
PubMed2000

Context determines the type of sensitized behaviour: a brief review and a hypothesis on the role of environment in behavioural sensitization.

Behavioural sensitization to psychostimulants may develop context-dependency in certain circumstances. Animals given a stimulant repeatedly in a test cage but not in other environments may show enhanced drug-induced behaviour in the test cage. Conditioning mechanisms have been claimed to be responsible for these phenomena. However, several recent findings are not properly accounted for by conditioning. In addition, growing evidence supports the hypothesis that behavioural sensitization reflects neural changes induced by repeated exposure to psychostimulants (the pharmacological hypothesis). However, the pharmacological hypothesis itself fails to account for environmental influences. In this paper, we propose a hypothesis on the role of environment that is complementary to the pharmacological hypothesis. According to our hypothesis, environment does not have a causal role in the development of sensitization, but it modifies the mode of expression of the sensitized behaviour. Sensitization primarily reflects a neuroadaptive change induced by repeated exposure of the neural system to psychostimulants. However, psychostimulants are known to induce different behaviours in different environments. Therefore, repeated administration of a psychostimulant in different environments would result in augmentation of different behaviours. Our hypothesis potentially accommodates various previous observations. We briefly review the literature and present our hypothesis.

Adaptation, Physiological↗
PubMed1999

Psychotic relapse and maintenance therapy in paranoid schizophrenia: a 15 year follow up.

In spite of numerous reports on a 1 to 2 year maintenance neuroleptic treatment of schizophrenia, there is little systematic information on decade-long maintenance therapy. We conducted a retrospective study in fifty outpatients with paranoid schizophrenia who have been seen at our clinic for a duration of 15 years or more since their first psychotic episodes. Relapse rate within 2, 5, 10, and 15 years from remission of the first psychotic episode were 52, 60, 86, and 90%, respectively. However, the incidence of relapse decreased with time. This decrease was accounted for by the decrease of relapse observed when off drug. Conversely, the incidence of relapse occurred on drug remained unchanged. The average maintenance dose 15 years after remission of the first psychotic episode was 5.41 +/- 7.28 mg/d (haloperidol equivalents: mean +/- SD). The maintenance dose correlated significantly with the number of relapses and total duration of psychotic episodes. These results suggest that maintenance treatment remained effective for decades, although it did not ameliorate the liability to relapse itself. Repeated relapse may be associated with requirement for a higher neuroleptic dose for relapse prevention.

Antipsychotic Agents↗
PubMed1997

Tolerance to the neurotoxic effect of methamphetamine in rats behaviorally sensitized to methamphetamine or amphetamine.

A series of experiments was conducted to examine whether rats behaviorally sensitized to methamphetamine (MA) would show supersensitivity or tolerance to the MA-induced neurotoxic effects on dopaminergic and serotonergic nerve terminals in the striatum (ST), nucleus accumbens (NA) and medial frontal cortex (MFC). Moderate to high doses of MA (3, 4 and 5 mg HCl salt/kg, s.c., at 2 h intervals, four injections) dose-relatedly decreased the contents of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in ST, and the content of 5-HIAA in NA and that of 5-HT in MFC. These neurotoxic effects in ST were significantly attenuated in rats behaviorally sensitized to MA (4 mg HCl salt/kg, s.c., for 10 days). To examine the possibility that the attenuation in the toxic effects in sensitized rats was due to an accelerated metabolism from MA to amphetamine (AMPH), a high dose of MA (5 mg HCl salt/kg, s.c., at 2 h intervals, four injections) was administered to rats behaviorally sensitized to AMPH (4 mg HCl salt/kg, s.c., for 10 days). It was revealed that the MA-induced decrease in the striatal contents of DOPAC, homovanillic acid (HVA), 5-HT and 5-HIAA were attenuated in rats behaviorally sensitized to AMPH. The MA-induced decrease in the striatal DA content tended to be attenuated in AMPH-sensitized rats. These data suggest that rats behaviorally sensitized to MA or AMPH develop tolerance to MA-induced striatal dopaminergic and serotonergic neurotoxicity. It is speculated that the mechanism of tolerance might be mediated by an altered central response rather than peripheral metabolism.

Amphetamine↗
PubMed1997

Clonazepam prevents the development of sensitization to methamphetamine.

The GABA-benzodiazepine neurotransmission has been implicated in various forms of plasticity such as kindling and learning. The present study examined the effects of clonazepam (CZP), a GABA-benzodiazepine agonist, on the development of behavioral sensitization to methamphetamine (MA). Rats treated with MA (1 mg/kg, S.C.) for 10 days displayed significantly enhanced motor activity when tested with MA (1 mg/kg) after a 7-8-day withdrawal, indicating the development of behavioral sensitization. Pretreatment with CZP (0.5 and 2.0 mg/kg) prior to MA administration prevented the development of the phenomenon. Rats treated with CZP alone showed no difference in the motor activity compared to those treated with saline. These results suggest that stimulation of GABA-benzodiazepine receptors plays a role in the development of behavioral sensitization.

Animals↗
PubMed1997

Effect of no synthesis inhibition on striatal dopamine release and stereotyped behavior induced by a single administration of methamphetamine.

1. The authors performed both microdialysis and behavioral measurement in each of rats, in order to examine effects of nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (LNAME;30 mg/kg,i.p.) on striatal dopamine (DA) release and stereotypy induced by a single administration of methamphetamine (MA)(4 mg/kg,s.c.), simultaneously. 2. LNAME administered prior to MA significantly decreased level of locomotion-stereotypy rating scores induced by MA. 3. In the same animals, LNAME had no effect on MA-induced striatal DA release. 4. The results suggest that NO synthesis inhibition attenuated MA-induced stereotypy by modulating neuronal process subsequent to activation of postsynaptic DA receptors.

Animals↗
PubMed1997

[Experimental study of methamphetamine psychosis--role of glutamate and nitric oxide in methamphetamine-induced dopaminergic and serotonergic neurotoxicity in the rat brain].

The present study examined effects of a high dose of methamphetamine (MA) (5mg/kg, s.c., x 4) on extracellular concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA) and glutamate in rat striatum (ST) and nucleus accumbens (NA) using microdialysis. The toxic dose of MA markedly increased extracellular DA, and decreased DOPAC and 5-HIAA in both ST and NA. The increase in DA release was not different in magnitude between ST and NA. Extracellular glutamate showed a delayed increase in ST, but not in NA. Tissue contents of serotonin (5-HT) and 5-HIAA significantly decreased in both ST and NA, whereas those of DA, DOPAC and HVA decreased in ST but did not change in NA. These data suggest that the marked increase of DA release is not directly related to the MA-induced dopaminergic neurotoxicity. The increase in glutamate release found only in ST may be related to the dopaminergic damage in ST. However, enhancement in glutamate release did not appear to be essential for the serotonergic neurotoxicity. Nitric oxide (NO) has recently been recognized as a novel neuronal messenger. Taking into account the relationship between NMDA receptor activation and NO formation, the present study examined effects of a NO synthesis inhibitor, N omega-nitro-L-arginine methyl ester (LNAME) on MA-induced decreases in contents of the monoamines and their metabolites, in order to clarify whether the MA-induced dopaminergic and serotonergic neurotoxicity would be mediated by NO synthesis. Coadministration with LNAME (30 mg/kg, i.p., x2), reduced the MA-induced decreases in contents of DA, DOPAC and HVA in ST, but not reduced the MA-induced decreases in contents of 5-HT in ST and NA. These findings suggest that the MA-induced dopaminergic, but not serotonergic neurotoxicity, may be related to the neural process such as NO formation caused by the activation of postsynaptic DA receptor.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

[Context-dependent sensitization: reconsideration and a hypothesis].

The repeated administration of amphetamine-like psychostimulants results in an augmentation of their behavioral responses, a phenomenon known as behavioral sensitization. One important factor associated with the process of behavioral sensitization is environmental influence. It has been reported that, when drug administration is paired with a particular environment, sensitization is observed only in that particular environment. This phenomenon has been known as context-dependent sensitization. However, considering recent reports and our own studies, the classical concept of context-dependent sensitization may not be satisfactory. We propose an alternative hypothesis. Psychostimulants are known to induce different behaviors in different environments. We believe that the repeated administration of a psychostimulant in different environments results in the augmentation of different behaviors. For instance, rats treated with a stimulant in a small cage did not locomote but were observed to sniff and rear. After repeated treatment, they showed sensitization not in locomotion but in stereotyped behaviors such as sniffing and rearing. This suggests that environment does not facilitate the development of sensitization, but rather modifies the pattern and character of a stimulant-induced behavior in the sensitized animals. In this paper, we briefly review various literature and present our hypothesis.

Animals↗
PubMed1996

Effects of nitric oxide synthesis inhibition on methamphetamine-induced dopaminergic and serotonergic neurotoxicity in the rat brain.

We examined effects of nitric oxide (NO.) synthesis inhibition on methamphetamine (MA)-induced dopaminergic and serotonergic neurotoxicity. The toxic dose of MA (5 mg/kg, sc, x4) significantly decreased contents of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum (ST), and significantly decreased contents of serotonin (5-HT) in the ST, nucleus accumbens (NA) and medial frontal contex (MFC). Coadministration with a NO. synthase inhibitor, N omega-nitro-L-arginine methyl ester (LNAME) (30 mg/kg, i.p., x2), reduced the MA-induced decreases in contents of DA, DOPAC and HVA in the ST, but not reduced the MA-induced decreases in contents of 5-HT in the ST, NA and MFC. These findings suggest that the MA-induced dopaminergic, but not serotonergic neurotoxicity, may be related to the neural process such as NO. formation caused by the activation of postsynaptic DA receptor.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

The role of glutamate in behavioral and neurotoxic effects of methamphetamine.

Studies on the mechanisms of behavioral and neurochemical effects of amphetamine or methamphetamine (MA) have focused on the dopaminergic system. However, recent reports suggest that the glutamatergic system may be involved in the MA effects. Our laboratory has been conducting a series of experiments to further examine the role of glutamate in both behavioral and neurotoxic effects of MA. These studies include (1) behavioral studies on the effect of N-methyl-D-aspartate (NMDA) antagonists on the development of MA-induced behavioral sensitization, (2) neurochemical studies on the effects of NMDA antagonists on MA-induced neurotoxicity, and (3) in vivo microdialysis studies on the effects of MA on glutamate release. In the present paper, the authors comment on an important role of glutamatergic systems in the behavioral and toxic effects of MA.

Animals↗
PubMed1995

Effects of nitric oxide (NO) synthesis inhibition on the development of supersensitivity to stereotypy and locomotion stimulating effects of methamphetamine.

The present study examined the effects of nitric oxide (NO) synthase inhibitor, N omega-nitro-L-arginine methyl ester (LNAME; 30 and 60 mg/kg, i.p.) on the development of supersensitivity to stereotypy as well as locomotion stimulating effects of methamphetamine (MA) (3.22 and 0.805 mg free base/kg, s.c., respectively). Rats treated with MA for 10 days showed enhancement in MA-induced stereotypy and locomotor activity. Rats pretreated with LNAME prior to MA also showed enhancement in the two types of behavior, also they showed significantly reduced stereotypy scores compared to those treated with MA alone. The results suggest that NO synthesis is not critically involved in the development of behavioral supersensitivity to stereotypy stimulating as well as locomotion stimulating effect of MA. However, No synthesis may have a modulatory role in behavioral sensitization in stereotypy.

Amino Acid Oxidoreductases↗
PubMed1995

Scopolamine prevents augmentation of stereotypy induced by chronic methamphetamine treatment.

Cholinergic neurotransmission has been implicated in various forms of neural plasticity such as kindling and learning. We have previously shown that blockade of muscarinic cholinergic receptors prevents the development of locomotor sensitization to methamphetamine. The present study was conducted to examine whether scopolamine, a muscarinic cholinergic antagonist, would also block augmentation of stereotypy induced by chronic methamphetamine (MA) treatment. Rats treated with MA (2.5 mg/kg, SC) for 10 days indicated significantly enhanced stereotyped behavior when tested with MA (2.5 mg/kg) after a 7- to 8- day withdrawal. Pretreatment with scopolamine (3 mg/kg) prior to MA administration prevented the augmentation of stereotypy. Rats treated with scopolamine alone showed no difference in MA-induced stereotypy compared to those treated with saline. Scopolamine methylbromide, a derivative of scopolamine that does not easily cross the blood-brain barrier, had no effect on the augmentation of stereotypy. These results suggest that stimulation of central muscarinic cholinergic receptors plays a role in the development of sensitization to the stereotypy stimulating effect of methamphetamine.

Animals↗