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Biomedical subjects

P Skolnick

Publications and source records attributed to P Skolnick.

At least 235 records · Page 13Linked to original sources
PubMed1987

Behavioral studies with anxiolytic drugs. IV. Serotonergic involvement in the effects of buspirone on punished behavior of pigeons.

Interactions of the nonbenzodiazepine anxiolytic, buspirone, with serotonin (5-HT) were studied using behavioral and neurochemical procedures. Punished responding was studied in pigeons as this behavior is a generally acknowledged preclinical predictor of anxiolytic activity and because buspirone increases punished responding of pigeons with greater potency and efficacy than in other species. Keypeck responses were maintained under either fixed-interval or fixed-ratio schedules of food presentation; every 30th response produced a brief electric shock and suppressed responding (punishment). Buspirone (0.1-5.6 mg/kg i.m.) produced dose-related increases in punished responding which reached a maximum at 1 mg/kg. A serotonin agonist, MK-212 (0.01 mg/kg), antagonized whereas the 5-HT antagonist, cyproheptadine (0.01 mg/kg), potentiated the effects of buspirone without having behavioral effects of their own. The characteristics of [3H]-5-HT binding in pigeon brain membranes were similar to results reported in mammalian brain. Neither buspirone, MJ-13805 (gepirone, a related analog), nor MJ-13653 (a buspirone metabolite), significantly affected [3H]-5-HT binding and none of the compounds appreciably inhibited uptake of [3H]-5-HT into pigeon cerebral synaptosomes. Hill coefficients significantly less than unity for all drugs except 5-HT suggested multiple serotonergic binding sites for buspirone and analogs. Buspirone and MJ-13805 (1 nM) inhibited [3H]ketanserin binding (a measure of 5-HT2 binding sites) in pigeon cerebrum with Ki values above 10(-6) M. The number of [3H]ketanserin binding sites was estimated to be 109 fmol/mg of protein in pigeon cerebrum compared to 400 fmol/mg of protein in rat cerebrum.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Aldosterone-reversible decrease in the density of renal peripheral benzodiazepine receptors in the rat after adrenalectomy.

A statistically significant decrease in the density of peripheral benzodiazepine receptors was observed in renal membranes of rats beginning 2 weeks after adrenalectomy when compared with sham-operated controls. This decrease in peripheral benzodiazepine receptor density was manifest as a decrease in the maximum binding of two ligands, [3H]Ro 5-4864 and [3H]PK 11195, without accompanying changes in their Kd for this site. Similar changes were not seen in another aldosterone-sensitive organ, the submandibular salivary gland. The decrease in peripheral benzodiazepine receptor density observed in adrenalectomized rat renal membranes was restored to control levels after 1 week of aldosterone administration using a dose (12.5 micrograms/kg/day) that had no effect on peripheral benzodiazepine receptor density in sham-operated animals. In contrast, dexamethasone administration (50 micrograms/kg/day, 1 week) had no effect on renal peripheral benzodiazepine receptor density when administered to either adrenalectomized or sham-operated rats. Further, adrenal demedullation had no effect on renal peripheral benzodiazepine receptor density or affinity. The decrease in peripheral benzodiazepine receptor density was localized to the renal cortex and the outer stripe of the medulla by gross dissection of renal slices and renal tissue section autoradiography. The specific effect of adrenalectomy on renal peripheral benzodiazepine receptor density, the lack of direct effect of aldosterone on [3H] Ro 5-4864 binding and the localization of the change in peripheral benzodiazepine receptor density to the renal cortex and outer stripe suggest that these changes may reflect an adaptation of the renal nephron (possibly the distal convoluted tubule, intermediate tubule and/or the collecting duct) to the loss of mineralocorticoid hormones.

Adrenal Cortex↗
PubMed1987

Local anesthetics differentiate dihydropyridine calcium antagonist binding sites in rat brain and cardiac membranes.

Local anesthetics were used to probe differences in the binding of [3H]nitrendipine to dihydropyridine calcium antagonist binding sites on rat brain and cardiac membranes. Local anesthetics inhibited [3H]nitrendipine binding to brain and cardiac membranes with the rank order of potency, dibucaine = proadifen much greater than tetracaine greater than meproadifen greater than RAC-109 (S) greater than RAC-109 (R) greater than benzocaine. Lidocaine, procaine, piperocaine and bupivacaine produced either a small potentiation or inhibition of [3H]nitrendipine binding. Dibucaine inhibited [3H]nitrendipine binding to brain membranes (IC50, 4.9 +/- 0.5 microM) by increasing the Kd, whereas in cardiac membranes (IC50, 8.5 +/- 0.9 microM) it both increased the Kd and decreased the maximum binding site capacity of [3H]nitrendipine. The potency of dibucaine to inhibit [3H]nitrendipine binding was reduced in both tissues by monovalent (Li+ greater than Na+ = K+ = Rb+; EC50, 40-50 mM) and divalent (Ca++, Mg++ and Mn++; EC50, 10-50 microM) cations. These cations reduced the effect of dibucaine on the Kd of [3H]nitrendipine in brain and on the maximum binding site capacity of [3H]nitrendipine in cardiac membranes. Inhibition of [3H]nitrendipine binding by dibucaine was best described by high (2 microM) and low (50 microM) affinity sites. The apparent affinities of these sites, but not the fractional occupancies, were similar in brain and cardiac membranes. Na+ modulated the occupancies of these sites in brain, but not in cardiac membranes, whereas Ca++ inhibited occupancy of the high affinity site in both tissues. The effects of Li+ were similar to those of Ca++. These findings indicate that brain and cardiac dihydropyridine calcium antagonist binding sites are coupled to different allosteric effectors or exist in a different membrane environment.

Anesthetics, Local↗
PubMed1986

A selective imidazobenzodiazepine antagonist of ethanol in the rat.

Ethanol, at pharmacologically relevant concentrations of 20 to 100 mM, stimulates gamma-aminobutyric (GABA) receptor-mediated uptake of 36Cl-labeled chlorine into isolated brain vesicles. One drug that acts at GABA-benzodiazepine receptors, the imidazobenzodiazepine Ro15-4513, has been found to be a potent antagonist of ethanol-stimulated 36Cl- uptake into brain vesicles, but it fails to antagonize either pentobarbital- or muscimol-stimulated 36Cl- uptake. Pretreatment of rats with Ro15-4513 blocks the anticonflict activity of low doses of ethanol (but not pentobarbital) as well as the behavioral intoxication observed with higher doses of ethanol. The effects of Ro15-4513 in antagonizing ethanol-stimulated 36Cl- uptake and behavior are completely blocked by benzodiazepine receptor antagonists. However, other benzodiazepine receptor inverse agonists fail to antagonize the actions of ethanol in vitro or in vivo, suggesting a novel interaction of Ro15-4513 with the GABA receptor-coupled chloride ion channel complex. The identification of a selective benzodiazepine antagonist of ethanol-stimulated 36Cl- uptake in vitro that blocks the anxiolytic and intoxicating actions of ethanol suggests that many of the neuropharmacologic actions of ethanol may be mediated via central GABA receptors.

Animals↗
PubMed1986

Effects of beta-carboline-3-carboxylic acid ethyl ester on suppressed and non-suppressed responding in the rhesus monkey.

The effects of the putative 'anxiogenic' compound beta-carboline-3-carboxylic acid ethyl ester (beta-CCE) were studied on non-suppressed and suppressed responding of rhesus monkeys. Responding was maintained under a fixed-interval 2 min schedule of food presentation (non-suppressed responding) and a fixed-interval 2 min schedule of food presentation where each 10th response produced a 3-5 mA footshock (suppressed responding). Rates of suppressed responding were 60-90% lower than those for non-suppressed responding. beta-CCE reliably decreased non-suppressed responding over the range of 0.03-0.3 mg/kg (ED50 approximately 0.04 mg/kg) while consistent decreases in suppressed responding were not obtained in all animals until doses of 1-3 mg/kg (ED50 approximately 2 mg/kg) were given. Doses of beta-CCE greater than 0.01 mg/kg slightly increased blood pressure, moderately increased heart rate and greatly increased plasma ACTH levels for both types of response. In contrast, diazepam increased suppressed responding without affecting non-suppressed responding at low doses (0.3-1 mg/kg), while higher doses were required to decrease suppressed responding. Diazepam had little effect on blood pressure or mean heart rate. Ro 15-1788 (1 mg/kg) blocked the rate-decreasing effects of beta-CCE on non-suppressed responding, suggesting the decrease is mediated via a benzodiazepine recognition site. These results show that under conditions where relatively low doses of diazepam have an anxiolytic effect (i.e. selectively increase rates of suppressed responding), relatively low doses of beta-CCE selectively decrease non-suppressed responding, questioning current notions of how to define an anxiogenic drug effect.

Adrenocorticotropic Hormone↗
PubMed1986

Rapid, stress-induced modification of the benzodiazepine receptor-coupled chloride ionophore.

Rapid changes in the chloride ionophore component of the benzodiazepine-GABA receptor complex were observed in cerebral cortical membranes from rats exposed to a brief, ambient temperature swim stress. These changes were manifest as: an increase in both the efficacy and potency of chloride ions to enhance [3H]flunitrazepam binding, and an increase in both the number of [35S]t-butylbicyclophosphorothionate (a ligand that binds at or near the GABAA receptor-gated chloride ionophore) binding sites and the apparent affinity of this radioligand. These studies demonstrate that the GABA-gated, benzodiazepine-coupled chloride ionophore, which can be considered the effector component of this 'supramolecular complex', is rapidly modulated by acute stress. Such changes could represent the compensatory response of an organism to stressful or anxiety provoking changes in the environment.

Animals↗
PubMed1986

Glucostatic regulation of hypothalamic and brainstem [3H](+)-amphetamine binding during food deprivation and refeeding.

Saturable and stereospecific binding sites for [3H](+)-amphetamine have been identified in rat hypothalamus and structure-activity studies suggest that these sites may mediate the anorectic actions of amphetamine and related phenylethylamines. In order to determine whether these binding sites may be involved in the physiological control of appetite, [3H](+)-amphetamine binding was measured in crude synaptosomal membranes prepared from various brain regions following food deprivation and refeeding. Rats deprived of food for 24 to 72 h exhibited time-dependent reductions in body weight, blood glucose concentration, and specific [3H](+)-amphetamine binding in hypothalamus and brainstem. No change in specific [3H](+)-amphetamine binding was found in the frontal cortex, striatum, cerebellum, or liver prepared from these same animals. The decrease in specific [3H](+)-amphetamine binding in both the hypothalamus and brain stem following food deprivation was rapidly and completely reversed by allowing animals brief access to food or a 10% glucose solution. The changes in [3H](+)-amphetamine binding in hypothalami and brainstem of food-deprived and refed rats were also highly correlated with blood glucose concentration. Further, parenteral administration of D-glucose, but not L-glucose, to either fed or food-deprived rats significantly increased the number of [3H](+)-amphetamine binding sites in hypothalamus. These data suggest that the [3H](+)-amphetamine binding site in the hypothalamus and (or) brainstem may function in the 'glucostatic' regulation of appetite.

Animals↗
PubMed1986

Electroconvulsive shock increases endogenous monoamine oxidase inhibitor activity in brain and cerebrospinal fluid.

Chronic daily administration of electroconvulsive shock (ECS) to cats resulted in a progressive elevation of seizure threshold which was accompanied by a sustained elevation in the activity of an endogenous monoamine oxidase inhibitor (EMAOI) present in cerebrospinal fluid (CSF). The increase in EMAOI activity in CSF following chronic ECS was observed maximally at 24-48 h. In rats, a single application of ECS resulted in a rapid but short-lasting increase in EMAOI activity present in the crude membrane fraction from brain. These findings demonstrate that both acute and chronic ECS modify the activity of an EMAOI in brain and CSF which may contribute to both the antidepressant and anticonvulsant effects of ECS treatment.

Animals↗
PubMed1986

Dihydropyridine calcium channel antagonists binding in non-mammalian vertebrates: characterization and relationship to 'peripheral-type' binding sites for benzodiazepines.

The densities of dihydropyridine calcium antagonist binding sites were examined in brains and cardiac issues of representative species from 4 classes of non-mammalian vertebrates (aves, pigeon; amphibia, frog; reptilia, chameleon; and osteichthyes, trout) previously shown to have low or undetectable levels of 'peripheral-type' binding sites for benzodiazepines. Dihydropyridine binding sites were present in brain and cardiac tissue of these 4 classes of non-mammalian vertebrates. The apparent dissociation constants for [3H]nitrendipine in non-mammalian vertebrates were comparable to those found in mammalian (rat) tissues. The densities of [3H]nitrendipine binding sites in brain and cardiac tissues were highest in the pigeon, with lower densities in tissues from chameleon, frog and trout. The densities of dihydropyridine binding sites in the latter tissues were comparable to those observed in the rat. Thus, dihydropyridine binding sites are phylogenetically diverse yet have similar kinetic characteristics in mammals and non-mammalian vertebrates. Despite the pharmacologic evidence that links dihydropyridine binding sites and peripheral binding sites for benzodiazepines in mammals, the earlier evolutionary appearance of the former sites suggest that even though they may share one or more common effector mechanisms, they are discrete entities.

Animals↗
PubMed1986

Low doses of muscimol produce anticonflict actions in the lateral septum of the rat.

Muscimol microinjected into the lateral septum of the rat produced a dose dependent increase in punished responding over the dose range of 100 pg-5 ng. The higher doses used (10 ng and 1 microgram) produced sedation and ataxia, markedly reducing the number of approaches to the water spout. This steep, biphasic dose response curve for the anticonflict actions of muscimol may explain contradictory findings in the literature concerning GABAergic involvement in the anxiolytic actions of benzodiazepines. The low dose of muscimol needed to produce a significant anticonflict effect in the lateral septum suggests that this nucleus may be a critical site in anxiety-related behaviors.

Animals↗
PubMed1986

Effects of calcium antagonists on phencyclidine behaviors.

The calcium antagonists nifedipine and verapamil were evaluated for their potential behavioral interactions with phencyclidine induced changes in mouse rotarod performance and motor activity. Nifedipine (2 and 10 mg/kg) and verapamil (2 mg/kg) significantly potentiated impairment of rotarod performance produced by phencyclidine. These doses of nifedipine and verapamil did not by themselves affect rotarod performance. This action does not appear to be dependent on the hypotensive properties of these drugs, since hypotensive doses of prazosin did not alter the effect of phencyclidine on rotarod performance. Nifedipine, 4.0 mg/kg, antagonized increases in ambulatory motor activity, and potentiated decreases in vertical motor activity (rearing) induced by phencyclidine. The effects of calcium antagonists to alter the behavioral actions of phencyclidine in mice may occur through an interaction with the dihydropyridine calcium antagonist binding site present in the central nervous system.

Animals↗
PubMed1986

Acylating phencyclidines irreversibly enhance brain calcium antagonist binding.

Phencyclidine was previously shown to allosterically increase the apparent affinity of the dihydropyridine ( [3H]nitrendipine) calcium antagonist binding site in a lysed synaptosomal membrane preparation of rat forebrain. Treatment of a similar preparation of mouse forebrain with 4-isothiocyanato-1-(1-phenylcyclohexyl) piperidine (FOURPHIT), an acylating phencyclidine derivative, resulted in a concentration dependent (0.1-10 microM), irreversible, increase in the apparent affinity of [3H]nitrendipine in contrast to the effects of phencyclidine which were reversible. The FOURPHIT isomer, 1-[1-(3-isothiocyanatophenyl) cyclohexyl] piperidine (METAPHIT), (10 microM) also irreversibly increased the apparent affinity of [3H]nitrendipine, but was much less efficacious than FOURPHIT. Phencyclidine blocked the irreversible increase in the apparent affinity of [3H]nitrendipine produced by FOURPHIT. The interactions of multivalent cations and the calcium antagonist diltiazem with the [3H]nitrendipine binding site were altered following treatment of membranes with FOURPHIT. These studies suggest that FOURPHIT irreversibly interacts with the same sites as PCP, and thus may be a useful tool with which to further probe both the behavioral and biochemical interactions between phencyclidine and the dihydropyridine calcium antagonist binding site.

Animals↗
PubMed1986

Inescapable shock reduces [3H]Ro 5-4864 binding to "peripheral-type" benzodiazepine receptors in the rat.

[3H]Ro 5-4864 binding to "peripheral-type" benzodiazepine receptors was examined in brain and peripheral tissues of rats subjected to inescapable tailshocks. Two hours after a session of 80 (five-second) inescapable tailshocks, a significant reduction in [3H]Ro 5-4864 (10 mM) binding was observed in membranes from kidney (31%), cerebral cortex (29%), heart (19%) and pituitary (17%) compared to tissues from naive animals. In contrast, inescapable shock did not effect [3H]Ro 5-4864 binding to hippocampal, lung, or adrenal membranes. Scatchard analyses of [3H]Ro 5-4864 binding to renal membranes demonstrated that this session of tailshock reduced the density (Bmax) of "peripheral-type" benzodiazepine receptors without effecting the apparent affinity (Kd) of the radioligand for these sites. The effects of graded stress on [3H]Ro 5-4864 binding to cerebral cortex and kidney were investigated using 5, 20, or 80 (five-second) inescapable shocks. In cerebral cortical membranes, sessions of either 5 or 20 shocks did not affect, while 80 shocks reduced (29%) [3H]Ro 5-4864 (10 mM) binding. In renal membranes, 5 shocks significantly increased (35%), 80 shocks significantly decreased [3H]Ro 5-4864 (10mM) binding (31%). These findings demonstrate that the density of "peripheral-type" benzodiazepine receptors in both peripheral tissues and the central nervous system can be rapidly modulated by stress.

Analysis of Variance↗
PubMed1986

Enhancement of brain calcium antagonist binding by phencyclidine and related compounds.

The abilities of compounds structurally or pharmacologically related to phencyclidine to increase the apparent affinity of the [3H]dihydropyridine calcium channel antagonist [3H]nitrendipine were examined in lysed synaptosomal membrane preparations of rat brain. The p-bromo analog of phencyclidine (1-(1-(4-bromophenyl)cyclohexyl)piperidine) was the most efficacious compound tested in enhancing the apparent affinity of [3H]nitrendipine. The efficacy of this compound was approximately two-fold greater than PCP. The stereoisomers of PCMP (1-(1-phenylcyclohexyl-3-methylpiperidine) were also more efficacious than phencyclidine, although only a small degree of stereoselectivity was observed. Levoxadrol, dexoxadrol and the enantiomers of ketamine did not potentiate [3H]nitrendipine binding. The enantiomers of SKF 10047 (n-allylormetazocine), dextrorphan, levorphanol and the ion channel toxins histrionicotoxin and pumiliotoxin-B also increased the apparent affinity of [3H]nitrendipine, while several local anesthetics and mu-opiate receptor ligands were without effect. These studies suggest that the ability of phencyclidine and structurally related compounds to increase the apparent affinity of [3H]nitrendipine is not mediated through an interaction with phencyclidine receptors, but may represent a unique site for allosteric modulation of neuronal dihydropyridine calcium channel antagonist binding sites.

Anesthetics, Local↗
PubMed1986

Characterization of benzodiazepine receptors in the bovine pineal gland: evidence for the presence of an atypical binding site.

Bovine and rat pineal benzodiazepine receptors were characterized using ligands with high affinities for either 'central-type' (CBR) or 'peripheral-type' (PBR) benzodiazepine receptors. The characteristics (Bmax = 83 +/- 10 fmol/mg protein, Kd = 3.88 +/- 0.46 nM) of benzodiazepine receptors in bovine pineal membranes measured with [3H]flunitrazepam (using flunitrazepam to define non-specific binding) were consistent with previously reported values. However, if non-specific binding was defined using Ro 15-1788 (a selective CBR ligand), the Bmax and Kd of [3H]flunitrazepam decreased 51 and 58%, respectively. In addition, when using PK 11195 to determine non-specific binding, the Bmax of [3H]flunitrazepam binding to bovine pineal decreased further (approximately 80%, Kd decreased approximately 39%). Together, these observations strongly suggested the presence of PBR in the bovine pineal. Bovine pineal PBR characterized with [3H]PK 11195 revealed a high density (relative to CBR) of high affinity binding sites (Kd = 1.08 +/- 0.30, Bmax = 776 +/- 33.0 fmol/mg protein). In contrast, when [3H]Ro 5-4864 (1-20 nM) was used to define PBR, no binding was detectable. These observations are in sharp contrast to the rat pineal gland, in which both [3H]Ro 5-4864 and [3H]PK 11195 bind to a large number of PBR with high affinity (Kd approximately equal to 1.9 nM, Bmax approximately equal to 26 pmol/mg protein). Bovine pineal PBR were further characterized with compounds structurally related to either Ro 5-4864 or PK 11195.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

A quantitative relationship between Cl- enhanced [3H]flunitrazepam and [35S]t-butylbicyclophosphorothionate binding to the benzodiazepine/GABA receptor chloride ionophore complex.

A quantitative relationship between the efficacy (i.e. maximum enhancement) of Cl- to increase [3H]flunitrazepam binding and the density of [35S]t-butylbicyclophosphorothionate binding sites was observed in well-washed membrane fragments of rat cerebral cortex previously exposed to phospholipase A2. This relationship (described by the equation y = ABx) was maintained when [3H]flunitrazepam was assayed at Cl- concentrations between 100 and 600 mM, and was not qualitatively altered by the presence of 100 microM pentobarbital. However, under experimental conditions that reduced the ratio of [35S]TBPS binding sites/benzodiazepine receptors, the effects of pentobarbital suggest that the conductance state of benzodiazepine receptor-coupled chloride channels may be the primary determinant of Cl- enhanced [3H]flunitrazepam binding.

Animals↗