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At least 955 records · Page 53Linked to original sources
PubMed1993

NMDA receptors have a dominant role in population spike-paired pulse facilitation in the dentate gyrus of urethane-anesthetized rats.

Paired-pulse facilitation was studied at the perforant path-granule cell synapses in the dentate gyrus of urethane-anesthetized rats. Extracellular field potentials comprising excitatory postsynaptic potentials (EPSPs) and population spikes (PSs) were used to compare facilitation of both responses at interpulse intervals between 10 and 1000 ms. In this model system EPSPs, produced at stimulus intensities well below the PS threshold, exhibited paired-pulse facilitation (PPF) at intervals less than 40 ms. Between 40 and 100 ms both responses were of equal size and from 200 to 1000 ms the second response exhibited paired-pulse depression (PPD). With higher stimulus intensities, PSs exhibited early (10-30 ms) and late (400-1000 ms) PPD and intermediate interval (40-200 ms) PPF. The enhanced PS amplitude during facilitation was accompanied by a modest decrease in EPSP slope and increase in PS latencies to onset and to peak. If PS amplitude was increased to the same extent by simply increasing stimulus intensity, an increase in EPSP slope and decrease in PS latencies to onset and peak were observed. Current source-density analysis revealed that the current sink generated by synaptic activation of granule cell dendrites was indistinguishable between control and facilitated responses up to the onset of the PS. However, the facilitated response exhibited a marked increase in the duration and amplitude of current flowing into the dendrites during the late phase of the EPSP. PPF of the PS was attenuated or blocked by the administration of the known NMDA receptor-ion channel blockers, MK-801, dextromethorphan and ketamine. The depressant effects of these pharmacological agents on facilitation shared the same time course as facilitation itself, peaking at 60 ms and lasting approximately 200 ms. These data suggest that facilitation in this situation is due to postsynaptic rather than presynaptic modulations, and is based upon an increase in the NMDA-mediated component of the evoked response. No increase in transmitter release, per se, could be demonstrated.

Analysis of Variance↗
PubMed1995

Sigma receptor-mediated neuroprotection against glutamate toxicity in primary rat neuronal cultures.

The role of the putative sigma receptor in mediating neuroprotection against glutamate-induced neuronal injury was examined in mature cultured rat cortical neurons. With the exception of the selective sigma 1 ligand (+)-3-PPP, all of the sigma ligands tested were neuroprotective, preventing glutamate-induced morphological changes and increases in LDH release. Their rank order of neuroprotective potency (and EC50 values) was as follows: (+)-SKF 10,047 (0.81 microM) > (+)- cyclazocine (2.3 microM) > dextromethorphan (3.1 microM) = haloperidol (3.7 microM) > (+)-pentazocine (8.5 microM) > DTG (42.7 microM) = carbetapentane (46.3 microM). When corrected for relative sigma versus PCP binding affinity, it appears that a positive correlation exists between neuroprotective potency and sigma 1 site affinity. However, there does not appear to be a significant correlation between neuroprotective potency and the sigma 2 site. Critically, none of the sigma ligands were neurotoxic when tested alone at concentrations at least 5-30 times their respective neuroprotective EC50 values. Results from preliminary experiments with the selective sigma 1 ligand (+)-pentazocine indicated that sigma-mediated neuroprotection may involve the buffering of glutamate-induced calcium flux. Collectively, the results of these in vitro experiments demonstrate that sigma ligands are neuroprotective and therefore deserve further exploration as potential therapeutic agents in in vivo models of CNS injury and neurodegenerative disorders.

Animals↗
PubMed1995

Comparison of the prevalence of the poor metabolizer phenotype for CYP2D6 between 203 Hmong subjects and 280 white subjects residing in Minnesota.

Genetic polymorphism of the P450IID6 (CYP2D6) enzyme system can be an important component of the variability in response to drug therapy. Interpopulation differences in the prevalence of deficiencies of drug-metabolizing enzymes may be clinically important in the selection and dosage of drug therapies for patients. Since 1980, the State of Minnesota has had more than a 1000% increase in population of Hmong refugees from Laos. The Hmong are frequently treated in our institution's international clinic with virtually no systematically acquired knowledge about the ability of this relatively ethnically pure population to metabolize commonly used Western medications. To further our knowledge of drug metabolism in this population, we identified the prevalence of the poor metabolizer phenotype for CYP2D6 in a sample population of Hmong subjects and compared this prevalence to that in a sample population of white subjects. Urine collected after ingestion of dextromethorphan in 237 healthy Hmong and 280 healthy white volunteers was analyzed by HPLC. Based on probit plots of the metabolic ratios (dextro-methorphan/dextrorphan), 8.9% of Hmong subjects and 6.1% of white subjects were assigned the poor metabolizer phenotype (difference not significant). Weak associations were found between body surface area and metabolic ratio for both Hmong and white men and between smoking status and metabolic ratio for white subjects only. We conclude that the prevalence of poor metabolizers for the CYP2D6 enzyme system is similar between Hmong subjects and white subjects residing in Minnesota and that an antimode of 0.3 for metabolic ratio appears to be reasonable for the populations studied.

Adolescent↗
PubMed1976

Antitussive activity of some naturally occurring cannabinoids in anesthetized cats.

Experimental cough was elicited in pentobarbital-anesthetized cats by either electrical stimulation of the superior laryngeal nerve or by mechanical stimulation of the tracheal mucosa. Intravenous administration of delta9-tetrahydrocannabinol (THC) effectively reduced the amplitude of the cough response in both these models of experimentally induced cough with ED50 values (AtD50) of 1.84 and 0.78 mg/kg, respectively. This cough suppressant activity of THC was more similar to codeine-PO4 than dextromethorphan-HBr. On the other hand, both cannabinol (CBN) and cannabidiol (CBD) were devoid of antitussive activity at doses as high as 10.0 mg/kg.

Animals↗
PubMed1991

Effects of 8-hydroxy-2-(di-n-propylamino)tetralin, a selective agonist of 5-HT1A receptors, on the cough reflex in rats.

The effects of the agonist of 5-HT1A receptors, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on the capsaicin-induced cough reflex in rats were studied. I.p. injection of 8-OH-DPAT, at doses of 0.1 and 0.3 mg/kg, significantly decreased the number of coughs in a dose-dependent manner. The antitussive effect of 8-OH-DPAT (0.3 mg/kg) was blocked by prior injection of methysergide (3 mg/kg i.p.) and spiperone (0.3 mg/kg i.p.), whereas ketanserin (3 mg/kg i.p.) had no effect on the antitussive effect of 8-OH-DPAT. The antitussive effects of dihydrocodeine (1 mg/kg i.p.) and dextromethorphan (3 mg/kg i.p.) were also antagonized by methysergide and spiperone. However, these cough-depressant effects were not reduced by ketanserin. These results suggest that the antitussive action of 8-OH-DPAT may be related to the enhancement of the function of 5-HT1A receptors, and that antitussives interact with the 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Dextrorotatory opioids and phencyclidine exert anticonvulsant action in prepiriform cortex.

We have investigated the ability of an array of putative noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists to suppress convulsions induced by a unilateral, focal injection of (-)-bicuculline methiodide (118 pmol) into the rat prepiriform cortex. The anticonvulsant potency of these compounds, (+)-5-methyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) greater than dextrorphan greater than or equal to 1-(1-phenylcyclohexyl)piperidine hydrochloride (PCP) greater than dextromethorphan greater than (+)-pentazocine, upon microinjection into the prepiriform cortex, was highly correlated (r = 0.971; P less than 0.01) with their respective affinities for the [3H]dextrorphan-labelled NMDA receptors in rat forebrain membranes. These results suggest that noncompetitive antagonism of NMDA receptors underlies the anticonvulsant action of these compounds.

Animals↗
PubMed1992

Antitussive effects of Ca2+ channel antagonists.

The effects of Ca2+ channel antagonists on the capsaicin-induced cough reflex in guinea pigs were studied. Intraperitoneal injection of nifedipine, verapamil and flunarizine in doses that ranged from 0.3 to 3.0 mg/kg decreased the number of coughs in a dose-dependent manner. These Ca2+ channel antagonists exhibited antitussive effects in the following order of potency: flunarizine = verapamil greater than nifedipine. Pretreatment with a low dose of nifedipine (0.3 mg/kg), which by itself had no significant effect on the number of coughs, markedly increased the antitussive effects of morphine, dihydrocodeine and dextromethorphan. These data suggest that Ca2+ channels play an important role in the regulation of the cough reflex.

Animals↗
PubMed1992

Effect of kynurenate on functional deficits resulting from traumatic spinal cord injury.

The potential role of excitatory amino acid (EAA) receptors in spinal cord trauma was examined in a standardized rat model of contusive injury. EAA antagonists were administered in a split-dose protocol with half given 5 min prior to and the remainder 15 min after contusion produced at the T8 vertebral level. Hindlimb function was assessed using a battery of tests of reflex and more complex behaviors at 1 day after injury and weekly thereafter through 4-8 weeks. Functional deficits were compared for groups administered intravenous MK 801 (1 mg/kg), dextromethorphan (10 mg/kg) and kynurenate (300 mg/kg) or the vehicle, saline, alone. In addition, possible effect of the drugs themselves on hindlimb function were assessed in uninjured controls. None of the drugs produced more than transient effect on uninjured rats. In contused rats, only kynurenate produced significant reductions in functional deficits as compared to saline controls. Significant improvement of hindlimb function was also observed when the thoracic cord was locally perfused with kynurenate via intrathecal cannulas and when kynurenate was directly infused into the contusive injury site by stereotaxic microinjection. Using the latter route of administration, a dose-dependent effect of kynurenate (100, 200 and 400 nmol) on the ability of contused rats to use their hindlimbs in locomotion was demonstrated. The highest dose also resulted in a significant reduction in overall functional deficits from 1 week through 1 month and at 2 months after injury. Our results support the hypothesis that EAA receptors at or near the injury site are involved in producing a proportion of the overall functional deficits stemming from traumatic injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1984

Interaction of dextrorotatory opioids with phencyclidine recognition sites in rat brain membranes.

The potencies of several dextrorotatory opioids, including four pairs of enantiomers, as inhibitors of specific [3H]PCP binding to rat brain synaptic membranes has been determined. Of the compounds tested unlabeled phencyclidine (PCP) was the most potent followed by (-)-cyclazocine greater than dextrorphan greater than (+) ketamine greater than (+) cyclazocine greater than (+)- SKF10 ,047 greater than levorphanol greater than dextromethorphan greater than (-) SKF10 ,047 greater than (-)-ketamine greater than (+/-) pentazocine and greater than (+/-) ethylketocyclazocine. The opiate mu receptor ligands, morphine, naloxone and naltrexone were virtually inactive as competitors of specific [3H]PCP binding. Unlike the stereostructural requirements for opiate mu receptors where activity resides predominantly in the levorotatory enantiomers, the present results support the contention that binding to the [3H]PCP labeled recognition site may reside in either the levorotatory or the dextrorotatory enantiomer. The specific binding of [3H]PCP which was defined as total binding minus that occurring in the presence of 10 microM dextrorphan was found to be of a high affinity, saturable, reversible and sensitive to thermal degradation. These results suggest that certain dextrorotatory morphinan derivatives may prove to be useful probes in further investigations of the molecular characteristics of the [3H]PCP binding site in brain membrane preparations.

Animals↗
PubMed1991

The role of lipophilicity in the inhibition of polymorphic cytochrome P450IID6 oxidation by beta-blocking agents in vitro.

The importance of lipophilicity as a determinant of the affinity of beta-adrenoceptor blocking agents for a specific human hepatic monooxygenase--cytochrome P450IID6 (responsible for the debrisoquine-type of oxidation polymorphism)--was investigated in vitro by estimating the inhibition constants of a series of compounds in a microsomal system with monitoring of the kinetics of dextromethorphan O-demethylation. Lipophilicity is a key predictor of the affinity of beta-blocking drugs for cytochrome P450IID6 and of their potential to cause specific competitive drug interactions, but more complex structural factors appear to be important as well. A high lipophilicity is also a necessary, but not a sufficient condition for these compounds to be metabolized by cytochrome P450IID6.

Adrenergic beta-Antagonists↗
PubMed1993

Non-opioid antitussives potentiate some behavioural and EEG effects of N-methyl-D-aspartate channel blockers.

The effects of the non-opioid oral antitussives dextromethorphan (DM) and caramiphen (CP) were tested against the behavioural and EEG effects elicited by the N-methyl-D-aspartate (NMDA) antagonists dizocilpine (MK 801) and phencyclidine (PCP) in rats and mice. PCP (1.25-10 mg/kg i.p.) induced a dose-dependent increase/decrease of the locomotor/exploratory activity of mice. DM (25-50 mg/kg i.p.) and MK 801 (0.125-0.250 mg/kg i.p.) induced an increase of the locomotor/exploratory activity of mice, while CP (25-50 mg/kg i.p.) did not produce such an effect. CP (12.5 mg/kg i.p.) and DM (12.5 mg/kg i.p.) significantly potentiated the effects of PCP (1.25 mg/kg i.p.) and MK 801 (0.062 mg/kg i.p.) in the open field test in mice. In rats, PCP (1.25-10 mg/kg i.p.) induced three dose-dependent EEG stages: 1) increase of the cortical desynchronization periods; 2) increase of the amplitude of cortical background activity; 3) appearance of cortical slow wave-spike complexes. Even though DM (up to 100 mg/kg i.p.) only induced PCP-like EEG stage 1 by itself, and CP (up to 50 mg/kg i.p.) did not affect basal cortical EEG activity, these drugs, at the doses of 30-50 mg/kg i.p., potentiated all the EEG effects induced by PCP. These data support the view of an interaction between non-opioid antitussives and non-competitive NMDA antagonists.

Animals↗
PubMed1993

Allosteric modulation of ligand binding to [3H](+)pentazocine-defined sigma recognition sites by phenytoin.

The allosteric modulation of sigma recognition sites by phenytoin (diphenylhydantoin) has been demonstrated by the ability of phenytoin to stimulate binding of various [3H] sigma ligands, as well as to slow dissociation from sigma sites and to shift sigma sites from a low- to a high-affinity state. Phenytoin stimulated the binding of the sigma 1- selective ligand [3H](+)pentazocine in a dose-dependent manner. Stimulation of binding at a final concentration of 250 microM phenytoin was associated with a decrease in the KD. The affinities of the sigma reference compounds caramiphen, dextromethorphan, dextrophan, (+)3-PPP and (+)SKF-10,047 were three- to eight-fold higher, while the affinities of benzetimide, BMY-14802, carbetapentane, DTG and haloperidol were unchanged in the presence of 250 microM phenytoin. The relative sensitivity of sigma compounds to allosteric modulation by phenytoin is not a property of all sigma ligands, and may provide an in vitro basis for distinguishing actions of sigma compounds and predicting sigma effects in vivo.

Allosteric Regulation↗
PubMed1994

Selective inhibition of major drug metabolizing cytochrome P450 isozymes in human liver microsomes by carbon monoxide.

The selectivity of carbon monoxide binding to specific human cytochrome P450 isozymes was investigated by studying its inhibition of prototype reactions for 3 major drug metabolizing P450s in liver microsomes: dextromethorphan O-demethylation and (+)-bufuralol 1'-hydroxylation (P450DB1, CYP2D6), diclofenac 4'-hydroxylation (P450TB, CYP2C subfamily), and midazolam 1'-hydroxylation (P450NF, CYP3A subfamily). The affinity of carbon monoxide is different for each P450 isozyme. Warburg partition coefficients were 0.35, 1.1 and 3.9 microM for P450DB1, P450TB and P450NF, respectively. Differential inhibition by carbon monoxide may be a useful tool to identify specific human cytochrome P450 isozymes in the early screening of drug biotransformation catalysts. Further studies involving other P450 isozymes and substrates should extend our understanding of the phenomena and their implications.

Carbon Monoxide↗
PubMed1996

Inhibition by noncompetitive NMDA receptor antagonists of apomorphine-induced climbing behavior in mice.

The N-methyl-D-aspartate (NMDA) subtype of glutamate receptors is an important mediator of several forms of neural and behavioral plasticity. In the present study, we examined the potential role of NMDA receptors in the glutamatergic modulation of dopaminergic function at the postsynaptic dopamine receptor by determining the effects of NMDA antagonists on apomorphine-induced climbing behavior in mice. The noncompetitive NMDA receptor antagonists, MK-801, ketamine, dextrorphan, and dextromethorphan attenuated the apomorphine-induced climbing behavior at does well below those that produce untoward side effects. These results suggest that the NMDA receptors play important roles in the glutamatergic modulation of dopaminergic function at the postsynaptic dopamine receptors that mediate the apomorphine-induced climbing behavior in mice.

Animals↗
PubMed1996

Solubilization and characterization of binding sites for [3H]NE-100, a novel and potent sigma 1 ligand, from guinea pig brain.

The binding sites for [3H]NE-100, a newly defined sigma 1 ligand, was solubilized from guinea pig brain, using zwitterionic detergent 3-[(3-c holamidopropyl) dimethylamino]-1-propanesulfonate (CHAPS), and the properties of the solubilized binding sites were compared to those for [3H](+)-pentazocine, a selective sigma 1 ligand. The pharmacological selectivity of solubilized sites for both [3H]NE-100 and [3H](+)-pentazocine was identical to that obtained from membrane preparations. Stereoselectivity of benzomorphan such as pentazocine and SKF10,047 was preserved in displacing [3H]NE-100 binding in solubilized preparations as observed in membrane preparations. The inhibitory potencies of several sigma ligands on [3H]NE-100 binding were similar to those on [3H](+)-pentazocine binding, indicating that the pharmacological characteristics of the binding sites for [3H]NE-100 are retained after solubilization. Phenytoin augmented the binding of [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine hydrochloride (3-PPP) to solubilized sigma binding sites while it had no effect on the binding of [3H]NE-100. Furthermore, the inhibitory effect of putative sigma receptor agonists such as (+)-3-PPP and dextromethorphan were enhanced by phenytoin; the effects of haloperidol, a putative sigma receptor antagonist, were unaltered. Molecular weight of [3H]NE-100 binding protein was estimated to be 440KDa by Sepharose CL-6B gel filtration chromatography, and the value was identical to that of [3H](+)-pentazocine binding protein, a putative sigma 1 binding protein. These findings indicate that [3H]NE-100 binding sites are putative sigma 1 binding sites, and that NE-100 may act as an antagonist at sigma 1 binding sites.

Animals↗
PubMed1993

Anticonvulsant properties of non-competitive antagonists of the N-methyl-D-aspartate receptor in genetically epilepsy-prone rats: comparison with CPPene.

Some non-competitive antagonists of N-methyl-D-aspartate (NMDA) were evaluated for potency to antagonize audiogenic seizures in genetically epilepsy-prone rats, following intraperitoneal administration. Phencyclidine (PCP), dizocilpine (MK-801), ketamine, ifenprodil and dextromethorphan, displayed anticonvulsant activity at doses similar to those which impaired performance in the rotarod equilibrium procedure. The noncompetitive NMDA receptor antagonists, at doses which slightly overlapped with the doses required for a full anticonvulsant protection against audiogenic seizures in genetically epilepsy-prone rats, induced profound untoward behavioural effects. This behavioural syndrome was characterized by marked ataxia, hyperactivity, stereotypes and wet dog shakes. In contrast, the effective anticonvulsant dose of 3-(2-carboxypiperazin-4-yl)propenyl-1-phosphonic acid (CPPene) was less than that required to impair rotarod performance and did not produce the PCP-like syndrome. A potential use in antiepileptic therapy, of CPPene or other new selective NMDA antagonists, with fewer neurotoxic effects but not for non-competitive antagonists such as MK-801, is suggested.

Acoustic Stimulation↗
PubMed1989

Subsensitivity to the cough-depressant effects of opioid and nonopioid antitussives in morphine-dependent rats: relationship to central serotonin function.

The present study was designed to determine whether morphine-dependent rats have a decreased sensitivity to the cough-depressant effects of both opioid and nonopioid antitussives. Morphine dependence was induced by treatment with morphine-admixed food (0.5 mg/g of food) for 7 days. The cough reflex was induced by application of electrical stimulation to the tracheal mucosa by the puncture electrode-induced cough method. The cough-depressant effect was evaluated as the antitussive ED50 calculated by the method of Litchfield and Wilcoxon. The effects of both opioid (morphine and dihydrocodeine) and nonopioid (dextromethorphan and noscapine) antitussive drugs were diminished in morphine-dependent rats. The values of ED50 of these antitussive drugs in morphine-dependent rats were about 3-fold higher than those in control rats. A significantly lower number of serotonin receptors was found in the brainstem of morphine-dependent rats (Bmax: 2.88 +/- 0.32 pmoles/mg protein) than in controls (Bmax: 4.93 +/- 0.50 pmoles/mg protein). It is possible that the decreased sensitivity to both opioid and nonopioid antitussive drugs, in terms of the depression of the cough reflex, in morphine-dependent rats may be due to changes in the number of serotonin receptors.

Animals↗
PubMed1989

N-methyl-D-aspartate promotes the survival of cerebellar granule cells: pharmacological characterization.

The survival of cerebellar granule cells in culture is promoted by chronic exposure to N-methyl-D-aspartate (NMDA). The effect is due to the stimulation of 'conventional' NMDA receptor-ionophore complex: it is concentration dependent, voltage dependent and blocked by the selective antagonists D-2-amino-5-phosphonovalerate, D-2-amino-7-phosphonoheptanoate, dextromethorphan and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imin emaleate (MK 801). The most potent antagonist tested was MK-801. In contrast, non-selective antagonists, including kynurenate, were much less effective. Further, the trophic effect of NMDA is not reproduced by ibotenate or quinolinate at the concentration range tested. It could also be shown that glutamate released into the culture medium is responsible for limited cell survival in the absence of NMDA.

Animals↗