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P Skolnick

Publications and source records attributed to P Skolnick.

At least 289 records · Page 16Linked to original sources
PubMed1984

Barbiturate and picrotoxin-sensitive chloride efflux in rat cerebral cortical synaptoneurosomes.

The effects of various barbiturates and picrotoxin in modifying the efflux of chloride (36Cl-) was studied in a novel subcellular preparation from rat cerebral cortex, the 'synaptoneurosome'. Dilution of synaptoneurosomes pre-loaded with 36Cl- resulted in rapid efflux of 36Cl- that could be measured as early as 10 s following dilution. In the presence of barbiturates such as pentobarbital and hexobarbital there was a significant increase in 36Cl- efflux which was not observed with the pharmacologically-inactive barbiturate, barbital. The effect of barbiturates in enhancing 36Cl- efflux was also stereospecific [(-)-DMBB greater than (+)-DMBB] and reversed by picrotoxin. By contrast, picrotoxin alone significantly inhibited 36Cl- efflux. These data demonstrate pharmacologically relevant Cl- transport for the first time in a subcellular brain preparation.

Animals↗
PubMed1984

Characteristics of [3H](+)-amphetamine binding sites in the rat central nervous system.

Recent studies in our laboratory have demonstrated the presence of specific binding sites for [3H] (+)-amphetamine in crude membrane preparations derived from rat brain. In this report we have further characterized the specific binding of [3H] (+)-amphetamine in various subcellular fractions of rat brain and demonstrate a greater than five-fold enrichment in the crude synaptosomal (P2) fraction compared to a crude membrane preparation. Specific [3H] (+)-amphetamine binding in crude synaptosomal membranes is saturable and stereospecific with an apparent dissociation constant, Kd, of 2.8 +/- 0.5 microM and an estimated maximum number of binding sites, Bmax, of 60.4 +/- 8.4 pmoles/mg protein derived by Scatchard or Klotz analysis of binding data using filtration assays. Centrifugation assays yield a similar Kd though the apparent Bmax is higher. In addition specific [3H] (+)-amphetamine binding is: rapidly reversible, temperature sensitive, labile to preincubation in Tris buffer, inhibited by sodium ions and unevenly distributed in various brain regions. Specific [3H] (+)-amphetamine binding sites are found almost exclusively in the rat central nervous system (the brainstem, hypothalamus, and striatum exhibiting relatively high levels of binding), whereas peripheral tissues such as liver, kidney and heart have very low to undetectable levels of specific binding.

Amphetamine↗
PubMed1984

Electrophysiological and pharmacological actions of the convulsant benzodiazepine Ro 5-4864.

Ro 5-4864 (4'-chlorodiazepam) elicited convulsions in mice with a CD50 of 23.5 mg/kg (i.p.) and increased the firing rate of substantia nigra zona reticulata neurons in a dose dependent fashion (0.5-4 mg/kg i.v.). Diazepam and clonazepam, but not Ro 15-1788, were potent inhibitors of Ro 5-4864 induced convulsions. Ro 15-1788 was also ineffective in reversing Ro 5-4864 induced increases in cell firing of zone reticulata neurons. Muscimol potently inhibited the seizures and reversed increases in cell firing elicited by Ro 5-4864. Phenobarbital and pentobarbital inhibited Ro 5-4864 induced convulsions with moderate potencies, while phenytoin and carbamazepine were ineffective at doses of up to 100 mg/kg. These observations suggest that Ro 5-4864 does not elicit its pharmacologic actions through a direct action at a 'brain-type' benzodiazepine receptor. However, both the profile and potency of compounds effective in inhibiting the electrophysiological and pharmacological effects of Ro 5-4864 suggest that this compound may act by perturbation of a component of the GABA-benzodiazepine receptor chloride ionophore complex. These findings do not, however, rule out a direct involvement of the high affinity 'peripheral-type' benzodiazepine receptors found in brain.

Animals↗
PubMed1984

A benzodiazepine receptor-mediated model of anxiety. Studies in nonhuman primates and clinical implications.

beta-Carboline-3-carboxylic acid ethyl ester (beta-CCE) binds with high affinity to brain benzodiazepine receptors and has potent behavioral and physiologic effects in primates. Dose-related increases in behavioral agitation, plasma cortisol level, BP, and heart rate were observed after administration of doses between 50 and 500 micrograms/kg of beta-CCE to rhesus monkeys. All of these effects were blocked by pretreatment with diazepam. Pretreatment with clonidine hydrochloride and propranolol hydrochloride, both of which have been reported to have anxiolytic actions in man, attenuated only selective aspects of the response to beta-CCE. The behavioral, endocrine, and physiologic effects of low doses of beta-CCE in monkeys are similar to those observed in anxious patients or normal subjects under anxiety-provoking or stressful situations. Administration of benzodiazepine receptor active antagonists such as beta-CCE to primates may, therefore, provide a valid and reproducible model of human anxiety that could be used to investigate specific biologic aspects of anxiety disorders.

Animals↗
PubMed1984

Absence of intrinsic antagonist actions of benzodiazepine antagonists on an exploratory model of anxiety in the mouse.

Recent reports suggest that antagonists of benzodiazepine receptors have intrinsic anxiogenic and convulsant properties. An exploratory model in the mouse, specific for anxiolytics, was employed to test further, the hypothesis that antagonists have intrinsic actions pharmacologically opposite to those of the benzodiazepines. The drugs Ro 15-1788 (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H- imidiazo -[1,5-a] [1,4]benzodiazepine-3-carboxylate), CGS-8216 (2-phenylpyrazolo[4,3-c] quinolin -3[5H]one), beta-CCM (3-carbomethoxy-beta-carboline) and FG-7142 (N1-methyl-beta-carboline-3-carboxamide) all effectively blocked the anxiolytic actions of diazepam. None of these antagonists demonstrated intrinsic or anxiogenic or anxiolytic activity in this model system. These findings suggest that both the species and paradigm employed will determine the pharmacological profile of drugs which act at the GABA-benzodiazepine receptor complex.

Animals↗
PubMed1984

Regulation of "peripheral-type" binding sites for benzodiazepines in the pineal gland.

The density of "peripheral-type" binding sites for benzodiazepines (PBS) in the rat pineal gland was reduced by approximately 50% three weeks after superior cervical ganglionectomy or exposure to constant light; the apparent affinity of [3H]Ro 5-4864 (the prototype ligand for these sites) remained unchanged. In contrast, neither the density of PBS nor the apparent affinity of [3H]Ro 5-4864 for these sites was altered in cerebral cortex by these procedures. The demonstration that PBS density is under neural control in the pineal gland suggests that these sites may have a physiologic role. The high density of PBS in pineal (approximately 24 pmol/mg protein) suggests that this tissue may be a useful model to study both the physiologic and pharmacologic function of these sites.

Animals↗
PubMed1984

Biomimetic approach to potential benzodiazepine receptor agonists and antagonists.

Several beta-carbolines, isoquinolines, imidazopyridines , and canthin -6-ones prepared in biomimetic fashion were tested for their ability to bind to the benzodiazepine receptor. Methyl isoquinoline-3-carboxylate, methyl 6,7- dimethoxyisoquinoline -3-carboxylate (3b) 1-phenyl-3- carbomethoxyimidazopyridine , (6B,) and canthin -6- one ( 13a ) bound with moderate affinities, while 2- carbomethoxycanthin -6- one ( 13b ) bound to benzodiazepine receptors with an affinity comparable to several pharmacologically active benzodiazepines. The potency of 13b suggests that the benzodiazepine receptor(s) can tolerate substitution at positions 1 and 9 of a beta-carboline without loss of activity if the substituents are trigonal and maintain a planar topography. Moreover, displacement of the carbonyl group by two atoms from the aromatic ring (C) of the beta-carboline skeleton caused a marked decrease in binding to the benzodiazepine receptor. This observation supports the hypothesis that maximum binding affinity of beta-carbolines is achieved when the carbonyl group at position 3 is attached directly to the aromatic pyridine ring.

Animals↗
PubMed1984

Nifedipine blocks sleep induction by flurazepam in the rat.

Previous studies have implicated the benzodiazepine receptor in the sleep-inducing effects of these widely used hypnotics, but the effector mechanism of this process is poorly understood. There is also in vitro evidence that benzodiazepines enhance calcium entry into synaptosomal preparations, leaving open the possibility that altered calcium flux may be involved in their actions. In order to explore this hypothesis, we administered intraventricular nifedipine, a calcium blocking agent. It was found that pretreatment with a dose of nifedipine which by itself does not affect sleep will prevent sleep induction by flurazepam in rats. Effects on anticonvulsant properties of flurazepam or anxiolytic effects of diazepam were not apparent. This suggests that changes in calcium channel function may be involved in the hypnotic action of benzodiazepines.

Animals↗
PubMed1984

Characterization of the binding of [3H]Ro 5-4864, a convulsant benzodiazepine, to guinea pig brain.

The density of high affinity binding sites for [3H]4'-chlorodiazepam [( 3H]Ro 5-4864) in guinea pig cerebral cortex is significantly higher (3.8-fold) than the density reported in the rat, and is nearly equal to the density of binding sites for other [3H]benzodiazepines (e.g., diazepam, flunitrazepam). The density of these [3H]Ro 5-4864 binding sites was generally higher in guinea pig brain than in rat brain, with the exception of olfactory bulb. Both the subcellular distribution and pharmacologic profile of these sites in guinea pig brain appears qualitatively similar to observations previously reported in the rat. The high density of binding sites for [3H]Ro 5-4864, coupled with the potency of this compound as a convulsant in the guinea pig, suggest this species will be a valuable model for elucidating putative pharmacologic and physiologic functions of these sites in brain.

Animals↗
PubMed1984

A novel chemically induced animal model of human anxiety.

The ethyl ester of beta-carboline-3-carboxylic acid (beta-CCE) has a high affinity for benzodiazepine receptors and can antagonize some of the pharmacologic actions of benzodiazepines in rodents. Administration of beta-CCE (2.5 mg/kg) to chair-adapted, male rhesus monkeys (7-9 kg) elicited a behavioral syndrome characterized by extreme agitation, head and body turning, distress vocalization and other behaviors which might be termed 'anxious'. Concomitant increases in plasma cortisol, epinephrine, norepinephrine, heart rate, and mean arterial blood pressure were observed. Pretreatment of animals with the benzodiazepine receptor antagonist Ro 15-1788 (5 mg/kg) antagonized the behavioral, endocrine, and somatic changes produced by beta-CCE, but did not elicit any significant changes in these parameters when administered alone. Thus, administration of beta-CCE to primates may be a reliable and reproducible model of human anxiety and, as much, may prove valuable for studying the postulated role of 'stress' or 'anxiety' in a variety of human disorders. In toto, these results strongly suggest that benzodiazepine receptors not only mediate the pharmacologic actions of benzodiazepines, but may also subserve both the affective and physiologic expression of anxiety.

Animals↗
PubMed1984

beta-Carboline-induced anxiety states.

Several C-3-substituted beta-carbolines (e.g., the ethyl ester of beta-carboline-3-carboxylic acid) have high affinities for benzodiazepine receptors and can antagonize the principal pharmacologic actions of the benzodiazepines. The observation that some of these compounds also possess 'intrinsic' actions, best described as pharmacologically opposite to the benzodiazepines, has provided a chemically induced model of extreme stress or anxiety. The actions of such compounds in currently used animal models of anxiety are reviewed, as well as the effects of these compounds in primates, including man.

Animals↗
PubMed1983

Pharmacokinetic and pharmacodynamic factors contributing to the convulsant action of beta-carboline-3-carboxylic acid esters.

Both the methyl ester of beta-carboline-3-carboxylic acid and the 6,7-dimethoxy-4-ethyl derivative of this compound are potent convulsants in rodents, while the ethyl ester of beta-carboline-3-carboxylic acid does not cause convulsions, even when administered at very high doses. The rate of degradation of these compounds by rat plasma (in vitro) parallels their potencies as convulsants. In contrast, 3-carboethoxy-beta-carboline was found to potently elicit tonic and clonic convulsions in the squirrel monkey (Saimiri sciureus). Furthermore, the rate of degradation of 3-carboethoxy-beta-carboline in monkey plasma (in vitro) is negligible compared with rats. No significant differences were observed in either the potency or efficacy of GABA to inhibit [3H]beta-carboethoxy-beta-carboline binding in rat and monkey brain. These data strongly suggest that pharmacokinetic, as well as pharmacodynamic, factors may determine the pharmacologic profile of these beta-carboline-3-carboxylic acid esters.

Animals↗
PubMed1983

3-carboethoxy-beta-carboline (beta-CCE) elicits electroencephalographic seizures in rats: reversal by the benzodiazepine antagonist CGS 8216.

Intravenous administration of 3-carboethoxy-beta-carboline (beta-CCE, 10 mg/kg) to rats resulted in multiple bursts of rhythmic waves (2-4 second duration, 5-7 Hz) with amplitudes of 100-250 microV. Pretreatment of animals with the benzodiazepine receptor antagonists CGS 8216 prevented the electroencephalographic seizures elicited by beta-CCE. This dose of CGS 8216 did not produce any electroencephalographic abnormalities when administered alone. These observations suggest that the electroencephalographic seizures elicited by beta-CCE are mediated via an interaction with benzodiazepine receptors. An in vitro study of the rate of degradation of beta-CCE and 3-carbomethoxy-beta-carboline (beta-CCM) in rat plasma demonstrated that the rate of degradation of the former compound was three times more rapid than the latter. These observations, taken together with previous studies demonstrating that parenteral administration of beta-CCM elicits tonic and clonic seizures, suggests that pharmacokinetic factors may be involved in defining the pharmacologic profile of beta-carboline-3-carboxylic acid esters.

Animals↗
PubMed1983

Do benzodiazepine receptors mediate the anticonflict action of pentobarbital?

The effects of the benzodiazepine antagonist CGS 8216 (2-phenylpyrazolo[4,3-c]quinoline-3(5H)-one) were examined in a thirsty rat conflict test in the presence and absence of pentobarbital. CGS 8216 (2.5-10 mg/kg i.p.) did not affect nonpunished responding, but doses of 5 and 10 mg/kg significantly reduced the rate of punished responding (i.e., the number of 3 second drinking episodes in a "shock" contingency). However, a dose of CGS 8216 which did not significantly alter punished responding (2.5 mg/kg) antagonized the anticonflict actions of pentobarbital. These observations suggest that while high doses of CGS 8216 may elicit an "anxiogenic" response in rodents, lower doses of CGS 8216 antagonize the anticonflict actions of a compound which has been shown to enhance benzodiazepine affinity in vitro. These data imply that the anticonflict actions of pentobarbital may be mediated through benzodiazepine receptors.

Animals↗
PubMed1983

Antagonism of the anxiolytic action of diazepam and chlordiazepoxide by the novel imidazopyridines, EMD 39593 and EMD 41717.

The imidazopyridines EMD 35993 and EMD 41717 antagonized the anticonflict actions of diazepam and chlordiazepoxide in rodent models which are predictive for anxiolytic action in man. In contrast to other described benzodiazepine antagonists, these compounds did not antagonize either the anticonvulsant or muscle relaxant properties of either benzodiazepine. Both EMD 39593 and EMD 41717 competitively inhibit the binding of [3H]diazepam to brain membranes, but do not exhibit regional differences in potency. These observations suggest that both EMD 39593 and EMD 41717 display some selectivity in antagonizing the anxiolytic properties of benzodiazepines, and as such may be useful tools in identifying neuronal substrates of anxiety.

Animals↗
PubMed1983

Subcellular distribution of high affinity [3H]imipramine binding and [3H]serotonin uptake in rat brain.

The binding of [3H]imipramine to various subcellular fractions of rat brain was investigated. Using sodium free buffer or 0.5 microM chlorimipramine to define nonspecific binding, the specific binding was found to be associated with the synaptosomal fraction, as was the uptake of [3H]serotonin. A significant quantity of 'displaceable' binding was observed in the myelin and nuclear fractions when 'specific' binding was defined using only one concentration of [3H]imipramine and a large molar excess of chlorimipramine. This 'pseudospecific' binding was of low affinity and was not affected by the presence or absence of sodium.

Animals↗