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Biomedical subjects

P Skolnick

Publications and source records attributed to P Skolnick.

At least 361 records · Page 20Linked to original sources
PubMed1980

Receptors for the age of anxiety: pharmacology of the benzodiazepines.

Investigation of the actions of the benzodiazepines has provided insights into the neurochemical mechanisms underlying anxiety, seizures, muscle relaxation, and sedation. Behavioral, electrophysical, pharmacological, and biochemical evidence indicates that the benzodiazepines exert their therapeutic effects by interacting with a high-affinity binding site (receptor) in the brain. The benzodiazepine receptor interacts with a receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter, and enhances its inhibitory effects. The benzodiazepine receptor may also interact with endogenous substances and several naturally occurring compounds, including the purines and nicotinamide, are candidates for this role. Both the purines and nicotinamide possess some benzodiazepine-like properties in vivo, although further work will be required to confirm their possible roles as endogenous benzodiazepines.

Animals↗
PubMed1980

Pharmacologic and behavioral effects of EMD 28422: a novel purine which enhances (3H) diazepam binding to brain benzodiazepine receptors.

A novel purine, (N6-2-(4-chlorophenyl)-bicyclo 2.2.2.-octyl-(3)-adenosine) EMD 28422 increases the binding of (3H) diazepam to benzodiazepine receptors in vivo within 10 min after intraperitoneal administration. This increase in (3H) diazepam binding is due to an increase in the number of benzodiazepine receptors (Bmax) rather than an altered affinity of the radioligand for receptor (Kd), EMD 28422 protects mice against pentylenetetrazole and caffeine-induced seizures and potentiates the anticonvulsant action of subeffective doses of diazepam in a dose-dependent fashion. Furthermore, EMD 28422 also produces a significant increase in punished responding in a conflict situation (rats), and a long-lasting, dose-dependent decrease in spontaneous motor activity (mice). In contrast, neither EMD 39011 nor adenosine (the two component molecules of EMD 28422) possess anticonvulsant properties at doses up to five mole-equivalents of EMD 28422. These data indicate that the purine EMD 28422 produces a spectrum of pharmacologic effects similar to the benzodiazepines, yet in contrast to the benzodiazepines (and other purines), increases benzodiazepine receptor number. Thus, EMD 28422 may represent the prototype of a class of synthetic purines exerting a unique neurochemical effect on benzodiazepine receptors and possessing several therapeutic actions of the benzodiazepines.

Adenosine↗
PubMed1980

Heterogeneity of benzodiazepine receptors in the central nervous system demonstrated with kenazepine, an alkylating benzodiazepine.

Binding studies using the alkylating benzodiazepine kenazepine strongly suggest the existence of several populations of benzodiazepine receptors in the CNS. Kenazepine reacts noncompetitively and irreversibly with some receptors and competitively (reversibly) with others. Cerebellum contains the largest proportion (approx. 80%) of the noncompetitive type, while hippocampus and cortex contain a preponderance of competitive-type receptors (approx. 80 and 50%, respectively). The Hill coefficients for kenazepine are approx. 0.7 in cortex and cerebellum, and near unity in dorsal hippocampus. Different populations of benzodiazepine receptors may mediate different physiologic and pharmacologic effects in vivo.

Animals↗
PubMed1980

Brain-specific benzodiazepine receptors and putative endogenous benzodiazepine-like compounds.

The recent demonstration of high-affinity binding sites for the benzodiazepines in the mammalian CNS has provided new information on the mechanism of action of this important class of drugs. The presence of these binding sites has prompted studies on their pharmacological and physiological significance, including attempts at isolating an endogenous ligand. The results presented here support the pharmacological importance of these binding sites as receptors, since there is a highly significant correlation between the occupation of these sites by various benzodiazepines and their clinical effects. Our results further support the physiological significance of the benzodiazepine receptor since brain-specific receptors can be demonstrated in the intact animal under physiological conditions. The isolation of a number of substances from bovine brain that competitively inhibit 3H-diazepam binding to synaptosomal membranes suggests the presence of an endogenous ligand. Two of these substances have been identified as the purines inosine and hypoxanthine. Pharmacological studies of these purines suggest that they may have diazepam-like effects in vivo. These results support the existence in brain of endogenous benzodiazepine-like compounds that could normally be involved in ameliorating anxiety and (or) seizure activity.

Animals↗
PubMed1980

Purines as endogenous ligands of the benzodiazepine receptor.

Endogenous inhibitors of [3H]benzodiazepine binding have been isolated from the mammalian central nervous system and identified as the purines inosine and hypoxanthine. The affinities of these compounds for the benzodiazepine receptor are many orders of magnitude lower than those reported for clinically effective benzodiazepines. However, the enhanced formation of these compounds, which occurs during electrical or chemical depolarization of brain tissue, coupled with the small number of receptors that must be occupied to manifest the pharmacologic effects of benzodiazepines in vivo are consistent with a purinergic modulation of the benzodiazepine receptor. The pharmacologic, electrophysiologic, and neurochemical observations presented in this review further support either a neurotransmitter or neuromodulatory role of purines in the function of the benzodiazepine receptor.

Animals↗
PubMed1979

Estrogen-induced efflux of endogenous catecholamines from the hypothalamus in vitro.

Short-term organ cultures of the intact hypothalamus were used to study the effects of various estrogenic compounds on catecholamine release. Estradiol-17 beta (0.1--20 microM) produced a concentration-dependent efflux of norepinephrine and dopamine while its biologically inactive enantiomer, estradiol-17 alpha, was ineffective at concentrations up to 20 microM. Diethylstilbestrol, a potent non-steroidal estrogen, was as effective as estradiol-17 beta in inducing catecholamine efflux. In contrast, weakly or non-estrogenic steroids such as estrone, estriol, and corticosterone were without effect. The time course of the estrogen-induced efflux of hypothalamic catecholamines was similar to that previously reported for the estrogen-induced accumulation of hypothalamic cAMP, providing further evidence for the involvement of catecholamines in this effect. Theses results suggest that estrogen may facilitate the release of catecholamines within the hypothalamus.

Animals↗
PubMed1979

Correlation between benzodiazepine receptor occupation and anticonvulsant effects of diazepam.

The benzodiazepines are potent anticonvulsants for a wide variety of experimental and clinical seizure disorders. The demonstration of saturable, high-affinity and stereospecific binding sites for the benzodiazepines in the mammalian central nervous system suggests the presence of pharmacological receptors mediating the anticonvulsant properties of these compounds. The good correlation between the anticonvulsant potencies of a series of benzodiazepines and their ability to inhibit 3H-diazepam binding in vitro further supports this hypothesis, but evidence for a direct interaction between benzodiazepines and their receptors, and a subsequent inhibition of seizure activity (or elevation of seizure threshold) is lacking. Recent reports from our laboratory and others have demonstrated the feasibility of labelling benzodiazepine receptors in vivo following parental administration of tritiated benzodiazepine. This technique permits one to study the relationship between the anticonvulsant activity of the benzodiazepines in vivo and the number of 'drug-occupied' receptors in vitro. We now report that there is an excellent correlation between benzodiazepine receptor occupancy by diazepam and protection against pentylenetetrazol-induced seizures. Furthermore, these results demonstrate that only a small fraction of benzodiazepine receptors need be occupied to produce a complete anticonvulsant effect.

Animals↗
PubMed1979

Inosine may be an endogenous ligand for benzodiazepine receptors on cultured spinal neurons.

Mouse spinal neurons grown in tissue culture were used to study the membrane effects of the benzodiazepine flurazepam and the naturally occurring purine nucleoside inosine, which competes for benzodiazepine receptor sites in the central nervous system. Application of inosine elicited two types of transmitter-like membrane effects: a rapidly desensitizing excitatory response and a nondesensitizing inhibitory response. Flurazepam produced a similar excitatory response which showed cross-desensitization with the purine excitation. Flurazepam also blocked the inhibitory inosine response. The results provide electrophysiological evidence that an endogenous purine can activate two different conductances on spinal neurons and that flurazepam can activate one of the conductances and antagonize the other.

Animals↗
PubMed1979

A rapid and sensitive radioreceptor assay for benzodiazepine in plasma.

We describe a rapid and sensitive radioreceptor assay for measuring benzodiazepines in plasma. This method is based on the competition between tritiated diazepam and pharmacologically active benzodiazepines present in plasma, for binding sites on rat brain synaptosomal membranes. No interference is obtained with drug-free plasma or plasma samples containing high concentrations of other commonly used drugs. High correlations (r = 0.98; P less than .001) were obtained between the "diazepam equivalents" measured in plasma with the radioreceptor assay and the levels of diazepam and nordiazepam obtained by gas-liquid chromatography. The radioreceptor assay is rapid, sensitive, specific, and requires no sophisticated equipment or methods. It should therefore prove useful in monitoring blood benzodiazepine levels for both therapeutic and toxicologic purposes.

Animals↗
PubMed1979

CNS benzodiazepine receptors: physiological studies and putative endogenous ligands.

The recent demonstration of benzodiazepine receptors in the mammalian CNS has provided new information on the mechanism of action of this important class of drugs. In addition, the presence of these receptors has prompted studies on their physiological significance, including attempts at isolating an endogenous ligand. The isolation of a number of substances from bovine brain that competitively inhibit (3H)-diazepam binding to synaptosomal membrane suggests the presence of an endogenous ligand. Two of these substances have been identified as the purines inosine and hypoxanthine. Pharmacological studies of these purines suggest that they may have diazepam-like effect in vivo. The possibility that the brain may contain its own benzodiazepine-like compound is currently being studied.

Animals↗
PubMed1979

Demonstration of two new endogenous "benzodiazepine-like" compounds from brain.

The recent report that purines are competitive inhibitors of specific [3H] diazepam binding to brain membranes has prompted further work concerning the characterization of possible endogenous ligands for the benzodiazepine receptor. In this report, two previously undescribed fractions capable of apparent competitive inhibition of [3H] diazepam binding are reported. Both factors are heat stable and resistant to proteolytic degradation. The larger factor (approximately 700 to 30,000 daltons) is present only in brain and pituitary. The smaller factor (500 to 600 daltons) is found in pituitary, liver, and muscle, but the highest levels are found in brain.

Animals↗