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M Misawa

Publications and source records attributed to M Misawa.

At least 55 records · Page 3Linked to original sources
PubMed1998

Conditioned fear stress induces ethanol-associated place preference in rats.

The purpose of the present study was to establish ethanol-induced place preference under conditioned fear stress (exposure to an environment paired previously with electric foot shock) in rats by using the conditioned place preference paradigm. The administration of ethanol (300 mg/kg, i.p.) with conditioned fear stress, but not without conditioned fear stress, induced a marked and significant place preference. Furthermore, additional exposure to conditioned fear stress immediately before the post-conditioning test further enhanced the development of ethanol-induced place preference. These results suggest that psychological stress may play an important role in the development of ethanol-induced place preference, and the present method may be useful for studying the mechanism of the rewarding effect of ethanol.

Animals↗
PubMed1998

Upregulation of NMDA receptor subunit proteins in the cerebral cortex during diazepam withdrawal.

The present study investigated the changes in NMDA receptor subunit proteins in diazepam-withdrawn rat cerebral cortex, using Western blotting analysis. The protein levels of the NR1 and NR2B, but not NR2A, subunits were significantly increased in diazepam-withdrawn rats compared to those in control rats. Therefore, an increase in the NR1 and NR2B subunit proteins may be responsible for both the previously observed upregulation of [3H]dizocilpine binding in the cerebral cortex and the appearance of diazepam withdrawal signs.

Animals↗
PubMed1998

Region-specific changes in [3H]dizocilpine binding in diazepam-withdrawn rats.

In the present study, to clarify the role of the N-methyl-D-aspartate (NMDA) receptor in the appearance of diazepam withdrawal signs, the changes in [3H]dizocilpine binding in several brain regions from diazepam-withdrawn rats were investigated. Brain membranes were prepared 42-45 h after termination of diazepam treatment when maximal withdrawal signs were shown. The Bmax value for [3H]dizocilpine binding was significantly increased in cerebrocortical, but not hippocampal and cerebellar, tissues from diazepam-withdrawn rats, while the Kd value did not change in any group. Together with our previous finding that NMDA receptor antagonists potently suppress diazepam withdrawal signs, these results suggest that the upregulation of the NMDA receptor in the cerebral cortex may play an important role in the appearance of spontaneous withdrawal signs caused by discontinuation of chronic diazepam treatment.

Animals↗
PubMed1998

Hypersusceptibility to DMCM-induced seizures during diazepam withdrawal in mice: evidence for upregulation of NMDA receptors.

The present study investigated the role of NMDA (N-methyl-D-aspartate) receptors in the hypersusceptibility to seizures induced by the benzodiazepine inverse agonist DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) during diazepam withdrawal in mice, using behavioral and biochemical approaches. The seizure threshold of DMCM was markedly decreased during diazepam withdrawal, reflecting withdrawal hyperexcitability in response to physical dependence. The decrease in the seizure threshold of DMCM in diazepam-withdrawn mice was inhibited by the non-competitive NMDA receptor antagonists MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate; 50 microg/kg, s.c.) and ifenprodil (20 mg/kg, i.p.). The effective doses of these compounds were lower than those required to prevent DMCM-induced seizures in chronically vehicle-treated mice. Since MK-801 and ifenprodil do not only bind to NMDA receptors but also to sigma receptors, the present study also investigated the effects of sigma receptor ligands. The decrease in the seizure threshold of DMCM in diazepam-withdrawn mice was not modified by the sigma receptor agonist, (+)-pentazocine (5 mg/kg, s.c.), or the sigma receptor antagonist, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride; 5 mg/kg, i.p.). Furthermore, the latency to the expression of wild running induced by intracerebroventricular administration of NMDA (60 ng/mouse) was also significantly lower in diazepam-withdrawn mice than in vehicle-treated control mice. On the other hand, there was no difference in the spermidine concentration between vehicle-treated control and diazepam-withdrawn mice. In a receptor binding experiment, the Bmax value for [3H]-MK-801 binding was significantly increased in cerebrocortical tissues from diazepam-withdrawn mice, while the Kd value did not change in either group. However, the acute addition of a high concentration of diazepam (10 and 100 microM) in vitro did not alter [3H]-MK-801 binding in cerebrocortical membrane preparations. The behavioral experiments suggest that NMDA receptor antagonists may suppress benzodiazepine withdrawal responses, while the biochemical study reveals upregulation of the NMDA receptor, which may play an important role in the hypersusceptibility to DMCM-induced seizure in diazepam-withdrawn mice.

Animals↗
PubMed1998

Subsensitivity to mitochondrial diazepam binding inhibitor receptor agonist FGIN-1-27-induced antiseizure effect in diazepam-withdrawn mice.

We investigated the role of the mitochondrial diazepam binding inhibitor receptor (MDR) in diazepam-withdrawal seizure. In chronically vehicle-treated mice, the potent and selective MDR agonist FGIN-1-27 (N,N-di-n-hexyl 2-(4-fluorophenyl)indole-3-acetamide: 30 microg/mouse, i.c.v.) markedly increased the threshold for pentylenetetrazole (PTZ)-induced seizure. The antiseizure effect of FGIN-1-27 was blocked by pretreatment with the selective MDR antagonist PK11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxa mide). In chronically diazepam-treated mice, the seizure threshold of PTZ was decreased during diazepam withdrawal, indicating withdrawal hyperexcitability. Interestingly, FGIN-1-27 (30 microg/mouse, i.c.v.) failed to increase the seizure threshold of PTZ in diazepam-withdrawn mice, in contrast to its effect in chronically vehicle-treated mice. These findings suggest that the sensitivity of MDR-mediated pathways in the brain may be decreased during diazepam withdrawal.

Animals↗
PubMed1998

A new pharyngitis model using capsaicin in rats.

1. Application of capsaicin solution onto the rat pharyngeal mucosa caused a well-reproducible increase in vascular permeability in the pharynx. 2. Capsaicin-induced pharyngeal inflammation was unaffected by a histamine H1 blocker and non-steroidal anti-inflammatory agents, whereas dexamethasone was effective in its inhibition. 3. FK224, a dual antagonist of tachykinin NK1 and NK2 receptors, and FK888, a selective antagonist of NK1 receptor, significantly inhibited capsaicin-induced plasma exudation in the pharynx. 4. In capsaicinized animals, the application of capsaicin solution in the pharyngeal mucosa did not induce pharyngitis. 5. These results suggest that the mechanism of the capsaicin-induced pharyngitis primarily involves tachykinins.

Animals↗
PubMed1998

Relationship between fat distribution and lipid and apolipoprotein profiles in young teenagers.

The influence of obesity and fat distribution on serum levels of lipoprotein and apolipoprotein was investigated in 294 Japanese junior high school children (12-13 years of age). Serum levels of low-density lipoprotein cholesterol (LDLC) (P = 0.013), triglycerides (TG) (P = 0.0006), and apolipoprotein B (apoB) (P = 0.003), and the apoB/A-I ratio (P = 0.005) were significantly higher and serum levels of high-density lipoprotein cholesterol (HDLC) (P = 0.00003) and apoA-1(P = 0.003) were significantly lower in obese boys than in non-obese boys. The serum levels of TG (P = 0.013) and the apoB/A-I ratio (P = 0.011) were significantly higher and the serum levels of HDLC (P = 0.004) was significantly lower in obese girls than in non-obese girls. The LDLC/apoB ratio was lower in obese girls than in non-obese girls (P = 0.03). Obesity (> or = 20% of ideal weight) was strongly correlated with the serum levels of lipids and apolipoproteins in boys; this relationship was less clear in girls. The degree of obesity and the body mass index (BMI) were more strongly correlated with serum levels of lipids and apolipoproteins in boys than in girls. In boys, atherogenic lipoproteins and apolipoproteins, such as LDLC and apoB, showed a stronger correlation with the thickness of the triceps skinfold, while in girls the anti-atherogenic lipoproteins and apolipoproteins, such as HDLC and apoA-I, showed a stronger correlation with both the triceps and the subscapular skinfold thicknesses. In girls the relationships between the BMI and the degree of obesity and the thickness of the subscapular skinfold (S) thickness were similar to the relationships between those parameters and the triceps skinfold (T) thickness. In boys, these parameters showed a stronger correlation with the subscapular skinfold thickness than with the triceps skinfold thickness. The correlation coefficients for the relationships between skinfold thickness and lipid and apolipoprotein levels were similar to the coefficients for the relationships between skinfold thicknesses and the severity of obesity and the BMI. The distribution of central-type fat accumulation, which is indicated by the thickness of the subscapular skinfold, the S/T ratio and S-T value, was inversely correlated with the HDLC level in both boys and girls. The degree of obesity was strongly correlated with the atherogenic lipoprotein profile in boys, in part because the subscapular skinfold thickness was strongly correlated with the degree of obesity and the BMI. In girls, the correlations between indices of central-type obesity and atherogenic lipid and apolipoprotein profiles were stronger than in boys. These data suggest that childhood obesity may be an early cardiovascular risk factor.

Adipose Tissue↗
PubMed1998

[Molecular mechanisms of the hyperresponsiveness of airway smooth muscle in bronchial asthma].

Nonspecific airway hyperresponsiveness (AHR) is a common feature of allergic bronchial asthmatics, but the underlying mechanisms of AHR have yet to be elucidated. The importance of AHR in the pathogenesis of asthma has been suggested by its relevance to the severity of this disease. There is thus a need to understand the underlying mechanisms of AHR for the sake of asthma therapy. In allergic asthmatics, airway smooth muscles (ASMs) obtained from in vivo hyperresponsive patients have in vitro hyperresponsiveness to cholinergic agonists. It is therefore possible that the mechanisms responsible for the AHR exist, at least in part, on the ASM site. Although ASM is known to contract in response to acetylcholine via muscarinic M3 receptors and this contractile response is augmented during AHR, no alteration in muscarinic receptor density in ASM has been demonstrated in various AHR models. It is thus likely that augmented intracellular signaling might be a possible reason for the AHR. In fact, recent investigations demonstrated increases in the levels of GTP binding protein, Ca2+ mobilization and inositol 1,4,5-trisphosphate generation and so on in hyperresponsive ASM.

Animals↗
PubMed1998

Characterization of muscarinic receptors in rat bronchial smooth muscle in vitro.

This study was undertaken to assess the important muscarinic receptor subtype in acetylcholine (ACh)-induced rat bronchial smooth muscle contraction. Ring smooth muscle strips of the left main bronchus were used. Isometrical contraction was measured in response to ACh in cumulative concentrations (10(-7)-10(-3) M) with and without preincubations with the muscarinic receptor antagonists, pirenzepine (an M1 antagonist), methoctramine (an M2 antagonist), and 4-diphenylacetoxy N-methylpiperidine (4-DAMP; an M1/M3 antagonist). Preincubation with these antagonists resulted in concentration-dependent rightward shifts of the concentration-response curves to ACh. pA2 values (means+/-sem) were 8.80+/-0.10 for 4-DAMP, 7.03+/-0.06 for pirenzepine and 5.91+/-0.36 for methoctramine, indicating that the most important muscarinic receptor mediating ACh-induced contraction of rat bronchial smooth muscle is of the M3 type.

Acetylcholine↗
PubMed1997

Age-related decrease in the antiseizure effect of ifenprodil against pentylenetetrazole in mice.

The developmental change in the antiseizure effect of ifenprodil against pentylenetetrazole (PTZ) was examined in mice. Ifenprodil (i.p.) significantly increased the latency to seizure induced by PTZ in 7- and 10-day-old mice, but not in 14- or 21-day-old mice. Intracerebroventricular administration of ifenprodil also failed to modify the latency to PTZ-induced seizure in 21-day-old mice. Dizocilpine produced an increase in the latency to PTZ-induced seizure in 7- and 21-day-old mice. In an NMDA receptor binding assay using [3H]dizocilpine, ifenprodil was clearly more potent in inhibiting [3H]dizocilpine binding in a forebrain membrane preparation from 7- rather than 21-day-old mice. These results suggest that the remarkable antiseizure effect of ifenprodil against PTZ in 7-day-old mice may be related to the high proportion of ifenprodil-sensitive NMDA receptors in the brain.

Aging↗
PubMed1997

The role of delta-opioid receptors in the discriminative stimulus properties of a low dose of methamphetamine.

The effects of selective mu-, delta- and kappa-opioid receptor agonists and antagonists on the discriminative stimulus properties of methamphetamine were examined in rats that had been trained to discriminate between methamphetamine (0.4 mg/kg) and saline. Methamphetamine produced a dose-related increase in methamphetamine-appropriate responses in all of the rats. In generalization tests, neither morphine (a mu-opioid receptor agonist: 0.3-10 mg/kg) nor 3,4-dichloro-N-[2-(1-pyrrolidinyl)cyclohexo]benzeneacetamide (U50,488H: a kappa-opioid receptor agonist: 1.0-8.0 mg/kg) generalized to the discriminative stimulus properties of methamphetamine. A newly synthesized non-peptide selective delta-opioid receptor agonist 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aalpha- octahydroquinolino(2,3,3,-g)isoquinoline (TAN-67: 32 mg/kg) partially generalized (70% methamphetamine-appropriate responses) to the discriminative stimulus properties of methamphetamine. In combination tests, pretreatment with the mu- and kappa-opioid receptor antagonists, beta-funaltrexamine (9.0 mg/kg) and nor-binaltorphimine (10 mg/kg), respectively, had little or no influence on the discriminative stimulus properties of methamphetamine. In contrast, pretreatment with naltrindole (a non-selective delta-opioid receptor antagonist: 3.0 mg/kg) or naltriben (a selective delta2-opioid receptor antagonist: 1.0 mg/kg), but not with 7-benzylidenenaltrexone (a selective delta1-opioid receptor antagonist: 0.5 and 1.0 mg/kg), significantly attenuated the discriminative stimulus properties of methamphetamine. However, naltrindole (3.0 mg/kg) did not significantly attenuate the discriminative stimulus properties of methamphetamine at a higher training dose (1.0 mg/kg). Our findings may have some bearing on the relative importance of the role of delta-opioid (especially delta2-opioid) receptors in the discriminative stimulus properties of a low dose of methamphetamine.

Animals↗
PubMed1997

Differential effects of mu-, delta- and kappa-opioid receptor agonists on the discriminative stimulus properties of cocaine in rats.

The effects of selective mu-, delta- and kappa-opioid receptor agonists on the discriminative stimulus properties of cocaine were examined in rats trained to discriminate between cocaine (10 mg/kg) and saline. Cocaine produced a dose-related increase in cocaine-appropriate responses in all of the rats. In generalization tests, neither morphine (mu-opioid receptor agonist) nor N-methyl-N-7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-11-4-benzofu ranacetamide (U50,488H: kappa-opioid receptor agonist) generalized to the discriminative stimulus properties of cocaine. On the other hand, the newly synthesized non-peptide selective delta-opioid receptor agonist 2-methyl-4a alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a alpha-octahydro-quinolino(2,3,3,-g)isoquinoline (TAN-67) partially generalized (56.7% cocaine-appropriate responses) to the discriminative stimulus properties of cocaine. Intracerebroventricular (i.c.v.) administration of [D-Ala2]deltorphin II (peptide delta 2-opioid receptor agonist) completely generalized, while neither [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO: mu-opioid receptor agonist) nor [D-Pen2,D-Pen5]enkephalin (DPDPE; delta 1-opioid receptor agonist) generalized to the discriminative stimulus properties of cocaine. These results suggest that the discriminative stimulus properties of cocaine may be partially mediated by delta-opioid (especially delta 2-opioid) receptors. In combination tests, pretreatment with morphine (3.0 mg/kg) and TAN-67 (3.0 and 10 mg/kg) significantly potentiated the discriminative stimulus properties cocaine. In contrast, pretreatment with U50,488H (2.0 and 4.0 mg/kg) scarcely shifted the discriminative stimulus properties of cocaine. Furthermore, the potentiating effect of 3.0 mg/kg morphine on the discriminative stimulus properties of cocaine was attenuated by 2.0 mg/kg U50,488H. In contrast, the potentiating effect of 10 mg/kg TAN-67 on the discriminative stimulus properties of cocaine was not reversed by either 2.0 or 4.0 mg/kg U50,488H. These results suggest that mu-, delta- and kappa-opioid receptor agonists modulate the discriminative stimulus properties of cocaine through different mechanisms, perhaps through different effects on the dopaminergic system.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1997

Recovery of decreased seizure threshold for pentylenetetrazole during diazepam withdrawal by NMDA receptor antagonists.

The effects of several NMDA receptor antagonists on pentylenetetrazole-induced diazepam-withdrawal seizure were examined in mice. The decrease in the seizure threshold for pentylenetetrazole during diazepam withdrawal was inhibited by pretreatment with MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate), 7-chlorokynurenic acid and ifenprodil. Furthermore, MK-801 and ifenprodil, at doses which did not affect the threshold of pentylenetetrazole-induced seizure in control mice, also significantly suppressed the decrease in the seizure threshold during diazepam withdrawal, whereas 7-chlorokynurenic acid did not. These findings suggest that overactivity of an ion channel site and an ifenprodil binding site on the NMDA receptor may play an important role in the hypersensitivity of pentylenetetrazole-induced seizure in diazepam-withdrawn mice.

Animals↗
PubMed1997

Role of the NMDA receptor complex in DMCM-induced seizure in mice.

We investigated the role of the NMDA receptor complex in DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate)-induced seizures in mice. The seizure threshold of DMCM was evaluated using an i.v. infusion technique. Pretreatment with the non-competitive NMDA receptor antagonist MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d) cycloheptan-5,10-imine maleate) or phencyclidine (PCP) significantly increased the seizure threshold for DMCM. Furthermore, the seizure threshold of DMCM was increased by intracerebroventricular (i.c.v.), but not intrathecal (i.t.), pretreatment with MK-801. Moreover, 7-chlorokynurenic acid, a glycine site antagonist, also increased the seizure threshold of DMCM, whereas ifenprodil, a non-competitive polyamine site antagonist, did not. These findings indicate that the ion-channel binding site and the glycine binding site on the NMDA receptor complex in the brain may be involved in the expression of seizures induced by DMCM.

Animals↗
PubMed1997

Involvement of dopamine-dependent and -independent mechanisms in the rewarding effects mediated by delta opioid receptor subtypes in mice.

The rewarding effects of the delta 1 opioid receptor agonist [D-Pen2, Pen5]enkephalin (DPDPE) and the delta 2 opioid receptor agonist [D-Ala2]deltorphin II (DELT) on the activity of mesolimbic and nigrostriatal dopamine (DA) neurons were examined in mice. Both DPDPE (15 nmol, i.c.v.) and DELT (5 nmol, i.c.v.) produced a significant place preference in mice. The DPDPE (15 mol, i.c.v.)-induced place preference was abolished by 7-benzylidenenaltrexone (BNTX; 0.5 mg/kg, s.c.), a delta1 opioid receptor antagonist, but not by naltriben (NTB; 0.5 mg/kg, s.c.), a delta 2 opioid receptor antagonist. In contrast, the DELT (5 nmol, i.c.v.)-induced place preference was antagonized by NTB, but not BNTX. I.c.v.. injection of DPDPE, but not DELT, at a dose that produced a significant place preference produced a significant elevation of DA turnover in the mouse limbic forebrain, and this effect of DPDPE was antagonized by BNTX but not by NTB. In addition, i.c.v. injection of DPDPE or DELT not affect DA turnover in the mouse striatum. These results suggest that the rewarding effects produced by the activation of central delta 1, but not delta 2, opioid receptors may be caused through the enhancement of the mesolimbic DA neurotransmission, and confirm our previous hypothesis that the DA-dependent and -independent mechanisms may exist in the rewarding effects produced by the activation of central delta opioid receptor subtypes.

Analgesics↗
PubMed1997

Interactions between H1-antagonists and opioids: a drug discrimination study.

We previously demonstrated that combination of opioids, pentazocine and dihydrocodeine, with the histamine H1-receptor antagonists tripelennamine and chlorpheniramine could enhance their rewarding effects in rats. In the present study, the effects of combined treatment with opioids and H1-antagonists on discriminative stimulus effects were examined in rats trained to discriminate between cocaine (10 mg/kg) or morphine (3.0 mg/kg) and saline, since it is believed that discriminative stimulus effects of abused drugs are related to their rewarding effects. Tripelennamine and chlorpheniramine, but not pentazocine or dihydrocodeine, generalized to the discriminative stimulus effects of cocaine. Pentazocine (3.0 mg/kg) and dihydrocodeine (5.6 mg/kg) significantly potentiated the cocaine-like discriminative stimulus effects of low doses of tripelennamine and chlorpheniramine, respectively. On the other hand, pentazocine and dihydrocodeine, but not tripelennamine or chlorpheniramine, generalized to the discriminative stimulus effects of morphine. Neither 1.0 or 3.0 mg/kg tripelennamine nor chlorpheniramine affected the morphine-like discriminative stimulus effects of pentazocine and dihydrocodeine, respectively. These results suggest that the potentiation of the cocaine-like discriminative stimulus effects of H1-antagonists by opioids may be involved in the enhanced rewarding effects of combinations of opioids and H1-antagonists.

Analgesics, Opioid↗