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Biomedical subjects

P Skolnick

Publications and source records attributed to P Skolnick.

At least 343 records · Page 19Linked to original sources
PubMed1981

Interaction between purine and benzodiazepine: Inosine reverses diazepam-induced stimulation of mouse exploratory behavior.

Inosine, 2-deoxyinosine, and 2-deoxyguanosine completely reversed the increase in exploratory activity elicited in mice by diazepam. The inhibition of exploratory behavior by purines occurred at doses that when given alone have no effect on exploratory behavior. 7-Methylinosine, which does not bind to the brain benzodiazepine binding site in vitro, had no effect on the diazepam-induced increase in exploratory behavior. Behavioral effects produced by various combinations of inosine and diazepam indicate that the interaction between purine and benzodiazepine is antagonistic and support the hypothesis that the naturally occurring purines function in anxiety-related behaviors that respond to benzodiazepine treatment.

Animals↗
PubMed1981

Depressed patients have decreased binding of tritiated imipramine to platelet serotonin "transporter".

The high-affinity tritiated (3H) imipramine binding sites are functionally (and perhaps structurally) associated with the presynaptic neuronal and platelet uptake sites for serotonin. Since there is an excellent correlation between the relative potencies of a series of antidepressants in displacing 3H-imipramine from binding sites in human brain and platelet, we have examined the binding of 3H-imipramine to platelets from 14 depressed patients and 28 age- and sex-matched controls. A highly significant decrease in the number of 3H-imipramine binding sites, with no significant change in the apparent affinity constants, was observed in platelets from the depressed patients compared with the controls. These results, coupled with previous studies showing a significant decrease in the maximal uptake of serotonin in platelets from depressed patients, suggest that an inherited or acquired deficiency of the serotonin transport protein or proteins may be involved in the pathogenesis of depression.

Adult↗
PubMed1981

The benzodiazepines and inosine antagonize caffeine-induced seizures.

The induction of generalized tonic-clinic seizures in mice by the methylxanthine stimulant caffeine is described. These seizures are indistinguishable in quality from those induced by pentylenetetrazol (PTZ), and pretreatment with low doses of caffeine potentiates PTZ-induced seizures. Benzodiazepines inhibit caffeine-induced seizures with a rank order potency that parallels their affinities for the central nervous system (CNS) benzodiazepine receptor in vitro. Inosine, a purine that has recently been shown to be a competitive inhibitor of [3H] diazepam binding in vitro, antagonizes caffeine-induced seizures, while 7-methyl-inosine, a purine that lacks receptor binding inhibitory activity, has no effect on seizures. Since the benzodiazepines, inosine, caffeine, and pentylenetetrazol all competitively inhibit [3H] diazepam binding and have marked effects on inducing or antagonizing seizures, further study of this receptor-ligand system may provide additional insights that concern possible biochemical mechanisms of seizures.

Animals↗
PubMed1981

Anticonvulsant doses of inosine result in brain levels sufficient to inhibit [3H] diazepam binding.

Several purines have been shown to be competitive inhibitors of [3H] diazepam binding. Inosine has also been shown to have benzodiazepine-like neurophysiologic, pharmacologic and behavioral effects, and to partially inhibit caffeine-induced seizures in mice. Using presumptive therapeutic doses of inosine, levels were determined in mouse brain at various times following injection. Inosine and hypoxanthine concentrations in brain increased several fold following inosine administration, indicating that inosine permeated the blood-brain barrier. The levels of inosine and hypoxanthine attained in brain were sufficient to inhibit by more than 50% the GABA-stimulated [3H] diazepam binding. These data suggest that the anticonvulsant properties of inosine are related to its interaction with the benzodiazepine receptor.

Animals↗
PubMed1981

Differential electrophysiological and behavioral responses to optically active derivatives of phencyclidine.

Dextro- and levorotatory isomers of 1-(1-phenylcyclohexyl)-3-methylpiperidine (PCMP) were synthesized. Both isomers inhibited spontaneous cerebellar Purkinje neuron firing when applied locally by pressure ejection. This effect was dose-dependent, with the (+)-isomer about 5--7 times more potent than the (-)-isomer. Both isomers also depressed rotarod performance in mice. Again, the (+)-isomer was about 5 times more potent than the (-)-isomer. Both rotarod performance and Purkinje cells discharge were depressed maximally 10--15 min after i.p. injection of drug. Our results suggest a correlation between behavioral performance and central neuron electrophysiological activity and suggest that the central actions of PCP or its derivatives are probably mediated at one locus, by a stereospecific mechanism.

Animals↗
PubMed1981

In vivo effects of two novel alkylating benzodiazepines, irazepine and kenazepine.

Intracerebroventricular administration of the alkylating benzodiazepines irazepine or kenazepine (20 nmol) resulted in a complete protection against convulsant doses of pentylenetetrazole (PTZ) for at least one hour, and a statistically significant protection for at least two and four hours, respectively. In contrast, administration of the non-alkylating parent benzodiazepine Ro-7/1986 or diazepam (20-60 nmol) resulted in no detectable anticonvulsants effects at fifteen minutes post-injection, the earliest interval examined. These results suggest that alkylating benzodiazepines which bind to brain benzodiazepine receptors in a non-competitive (covalent) fashion in vitro may exert a long lasting anticonvulsants effect by a similar mechanism.

Animals↗
PubMed1981

Adenosine and cyclic AMP in rat cerebral cortical slices: effects of adenosine uptake inhibitors and adenosine deaminase inhibitors.

The endogenous levels of adenosine functionally linked to cyclic AMP systems in rat cerebral cortical slices are regulated by both adenosine deaminase and adenosine uptake systems. 2'-Deoxycoformycin (2'-DCF), an adenosine deaminase inhibitor, slightly increased basal, adenosine, and norepinephrine-elicited accumulations of cyclic AMP, whereas dipyridamole, an uptake inhibitor, had an even greater effect on cyclic AMP accumulations under the same conditions. Combinations of 2'-DCF and dipyridamole elicited a greater effect than either compound alone. Neither 2'-DCF nor dipyridamole significantly augmented accumulations of cyclic AP elicited by a depolarizing agent, veratridine, suggesting that the adenosine "released" during neuronal depolarization of brain slices is not as subject to inactivation by uptake or deamination as endogenous adenosine in control brain slices. The accumulation of cyclic AMP elicited by a combination of norepinephrine and veratridine was greater than additive. The response to a pure beta-adrenergic agonist, isoproterenol, was not potentiated by 2'-DCF, dipyridamole, or veratridine, consonant with minimal interaction of endogenous adenosine with beta-adrenergic systems.

Adenosine↗
PubMed1981

The benzodiazepine--GABA--chloride ionophore receptor complex: common site of minor tranquilizer action.

The demonstration of specific recognition sites for benzodiazepines in the mammalian CNS has altered current thinking on the mechanisms of action of the benzodiazepines as well as the neurochemical events which are associated with anxiety. Recent studies suggest that the physiological regulation of the benzodiazepine receptor is far more complex than initially believed and includes a functional coupling to both a GABA receptor and an associated chloride ionophore. It now appears that a number of other psychopharmacologic agents, including minor tranquilizers other than the benzodiazepines as well as several convulsants and anticonvulsants, may exert their pharmacologic effects by affecting one or more regulatory sites on the benzodiazepine receptor complex. In addition to a number of drugs, at least one endogenous small molecular weight compound that has been isolated from the crude synaptosomal fraction of bovine cerebral cortex also appears to modulate this receptor complex.

Animals↗
PubMed1980

Increased benzodiazepine receptor number elicited in vitro by a novel purine, EMD 28422.

EMD 28422 (N6-[2-(4-chlorophenyl)-bicyclo-2.2.2.octyl-(3)]-adenosine) was demonstrated to increase the number of binding sites for [3H]diazepam (Bmax) in vitro without an accompanying increase in receptor affinity (KD). The increase in receptor number was observed in both crude synaptosomal preparations (P2) and thrice-washed membrane preparations with and without the addition of 50 microM GABA. Furthermore, this effect appeared to be independent of the concentration of chloride ion, since the increases in Bmax were observed in both Tris-HCl and Tris-maleate buffer. The effects of EMD 28422 were stereospecifically antagonized by the GABA antagonist bicuculline, despite the lack of effect of EMD 28422 on [3H]muscimol binding at concentrations which markedly increased benzodiazepine receptor number. Neither EMD 39011 nor adenosine, the two parent moieties of EMD 28422, increased [3H]diazepam binding at concentrations of up to 1 mM. The increases in benzodiazepine receptor number observed with EMD 28422 in vitro suggests that this compound induces a conformational change in the benzodiazepine receptor which may cause the dissociation of an endogenous noncompetitive inhibitor of [3H]diazepam binding from the membrane, thus 'unmasking' binding sites. The stereospecific antagonism of this effect by bicuculline and the apparent inability of GABA to alter the action of EMD 28422 suggests the presence of a novel type or different functional state of GABA receptor which may play a permissive role in the rapid modulation of benzodiazepine receptor number in vitro.

Adenosine↗
PubMed1980

'Brain-specific' benzodiazepine receptors are localized in the inner plexiform layer of rat retina.

Saturable, high affinity binding sites for [3H] diazepam have recently been characterized in rat brain. A significant component of this binding was determined to occur to a population of receptors which is pharmacologically similar to receptors present in mammalian brain and spinal cord. Neonatal treatment of rats with monosodium glutamate (MSG), intraocular administration of kainic acid, and the use of pink-eyed, tan-hooded (PETH) rats with a genetic retinopathy (degeneration of photoreceptor cells) suggests that these 'brain-type' receptors are highly localized on neuronal elements of the inner plexiform layer and/or ganglion cells.

Animals↗
PubMed1980

Characterization of benzodiazepine receptors in primary cultures of fetal mouse brain and spinal cord neurons.

Primary cultures of fetal mouse brain and spinal cord were examined for the presence of binding sites for [3H]diazepam. Both brain and spinal cord cultures contain high affinity binding sites which resemble benzodiazepine receptors found in mammalian CNS with respect to both pharmacologic profile and response to exogenously applied GABA. These observations, coupled with the electrophysiologic properties of these cells suggest that primary cultures of fetal mouse brain and spinal cord may be valid models for studying the role and regulation of the benzodiazepine receptor.

Animals↗