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Biomedical subjects

R C Drugan

Publications and source records attributed to R C Drugan.

14 recordsLinked to original sources
PubMed1992

Angiotensin II rapidly modulates the renal peripheral benzodiazepine receptor.

The effects of acute exposure to angiotensin II (AII) on the renal peripheral benzodiazepine receptor were studied in rats. As little as 37.5 micrograms of AII injected s.c. over an 80 min period caused immediate reductions in [3H]Ro5-4864 binding. Scatchard analysis revealed that the reduction in [3H]Ro5-4864 binding induced by AII was due to a drop in receptor density or Bmax. The influence of AII on the peripheral benzodiazepine receptor is similar to that of stress.

Angiotensin II↗
PubMed1992

Impact of psychological dynamics of stress on the peripheral benzodiazepine receptor.

In an attempt to dissociate the relative impact of psychological vs. physiological concomitants of stress on the peripheral benzodiazepine receptor (PBR), the influence of stressor controllability and predictability was investigated in rats. In addition, the effect of a purely psychological stressor, contextually conditioned fear, was examined. The response of the PBR in rats confronted with a naturalistic threat, a cat, was also tested. Various peripheral and CNS tissues were analyzed. Specific binding of [3H]Ro 5-4864 was significantly reduced in the kidneys of subjects receiving either controllable or uncontrollable shock. Similar changes were seen in the kidneys of subjects receiving either predictable or unpredictable shock. Mean [3H]Ro 5-4864 binding in lung was reduced following both predictable and unpredictable shock, but only the reduction in the predictable shock group reached significance. Controllability appeared to protect against the stress-induced reduction in [3H]Ro 5-4864 binding in lung. Contextually conditioned fear only affected PBR in the olfactory bulb, and exposure to a cat was without effect. These data suggest that the PBR responds only to potent stressors, and psychological influences on the PBR are tissue specific.

Animals↗
PubMed1992

Controllability and duration of stress alter central nervous system depressant-induced sleep time in rats.

Rats were exposed to either 80 escapable shocks or yoked inescapable shocks and then injected with several hypnotic doses of sodium pentobarbital, midazolam, or ethanol; their sleep-time duration was compared with that of naive controls. Inescapable shock exposure resulted in a significant increase in ethanol-induced sleep time compared with the escapable shock and naive control groups. Both escape and yoked groups showed an increase in barbiturate-induced sleep time compared with controls, although no difference was observed for midazolam. Acute stress (twenty 5-s inescapable shocks) did not alter the depressant-induced sleep time for any of the drugs tested. These results illustrate the importance of psychological aspects of stress and its influence on the potency of certain depressants.

Animals↗
PubMed1991

Differential effects of anxiogenic central and peripheral benzodiazepine receptor ligands in tests of learning and memory.

Previous research has demonstrated that low doses of anxiogenic central benzodiazepine receptor (CBR) ligands, the beta-carbolines, improve performance in various learning and memory tests in animals if administered prior to training. The present experiments compared the effect of a beta-carboline (FG 7142) with that of a pharmacologically distinct anxiogenic compound, a peripheral benzodiazepine receptor (PBR) ligand, 4'-chlorodiazepam (Ro5-4864), in two tests of learning and memory in rats. As expected, FG 7142 significantly improved performance in a passive avoidance test. Ro5-4864 was without effect. In a shuttlebox escape test, Ro5-4864 significantly impaired performance while FG 7142 had no effect. The effect of Ro5-4864 was antagonized by the specific peripheral benzodiazepine receptor antagonist, PK 11195. These results indicate that the differential impact of CBR and PBR anxiogenic ligands on performance in aversively-motivated learning tests may be a reflection of their distinct pharmacologies.

Animals↗
PubMed1991

Sexual dimorphism of stress-induced changes in renal peripheral benzodiazepine receptors in rat.

Adult male and female rats were exposed to either inescapable shock or no treatment. In vitro [3H]Ro 5-4864 (4'-chlorodiazepam) binding (1 nM) to peripheral benzodiazepine receptors (PRB) in both CNS and peripheral tissues indicated no gender differences in olfactory bulb, heart, lung or adrenal gland but a significant effect was observed in renal tissue. Female rats showed an attenuated stress-induced reduction (23%) in PBR in comparison to males (55%). This difference was shown to be an alteration of Bmax and not kD by Scatchard analysis. These data are the first demonstration of a sexual dimorphism in environmentally-induced alterations in PBR.

Animals↗
PubMed1991

Central and peripheral benzodiazepine receptors: involvement in an organism's response to physical and psychological stress.

The present review discusses the current knowledge of the molecular pharmacology and neuroanatomical and subcellular localization of both the central benzodiazepine/GABA-chloride ionophore receptor complex and the peripheral benzodiazepine receptor. It then reviews all of the literature to date on how these two receptor sites are modulated by environmental stress. The possible role of these sites in learning and memory is also discussed. Finally, a theoretical model is presented which examines the differential, and perhaps complementary, alterations of these two sites in an organism's response to stress.

Animals↗
PubMed1990

Pentobarbital blocks the stress-induced decrease in [3H]Ro 5-4864 binding in rat kidney.

Exposure to environmental stress causes changes in the binding of [3H]Ro 5-4864 to peripheral benzodiazepine receptors (PBRs). The influence of the central nervous system (CNS) in these stress-induced modifications is unclear. The present study examined whether pretreatment with a dose-response regimen of sodium pentobarbital would impact the stress-induced reduction in renal PBR. Administration of either a sedative/ataxic (20 mg/kg) or hypnotic (60 mg/kg) dose of pentobarbital prior to stress blocks the stress-induced decrease of [3H]Ro 5-4864 binding to renal PBR in rat. These findings suggest that higher-order, supraspinal mechanisms play a critical role in marshalling the renal PBR changes in response to stress.

Animals↗
PubMed1989

Stress-induced behavioral depression in the rat is associated with a decrease in GABA receptor-mediated chloride ion flux and brain benzodiazepine receptor occupancy.

Rats exposed to inescapable tailshock exhibit deficits in learning a simple shuttlebox escape task 24 h later. This syndrome has been termed 'behavioral depression' or 'learned helplessness', and is a model of stress-induced depression. In the present study a significant (25%) decrease in GABA receptor-mediated chloride ion flux as measured by muscimol-stimulated 36Cl- uptake in synaptoneurosomes was found in the cerebral cortices of rats that failed the shuttlebox task as compared to naive control rats. Rats which were exposed to tailshock and subsequently learned the escape task did not show a significant difference in muscimol-stimulated 36Cl- uptake as compared to naive control rats. Similarly, rats that failed to learn the shuttlebox escape task had significantly lower in vivo [3H]Ro15-1788 specific binding in cerebral cortex (43%), hippocampus (35%) and striatum (33%) as compared to naive control rats. In cerebellum and hypothalamus, there were significant reductions in specific [3H]Ro15-1788 binding in both animals that failed and animals that learned the shuttlebox escape task as compared to naive controls. To control the stress of the footshock associated with the shuttlebox escape task, we investigated the effect of gridshock in which total footshock received was equivalent to that received by rats who failed the shuttlebox task. There were no differences in muscimol-stimulated 36Cl- uptake or in vivo [3H]Ro15-1788 specific binding between naive controls and rats administered footshock independent of a learning task. These data suggest that the development of stress-induced behavioral depression may be associated with a decrease in GABA receptor-mediated chloride channel function.

Animals↗
PubMed1989

A pretest procedure reliably predicts performance in two animal models of inescapable stress.

Rats exposed to inescapable tailshock fail to learn a shuttle-escape task 24 hours later, an effect referred to as "learned helplessness." However, within most rat strains only 10-50% of the animals tested develop this syndrome. In the present study a significant correlation was found between rats that displayed learned helplessness on the first test and those that displayed learned helplessness on a second test performed either 2 weeks (r = .80, p less than 0.001) or 4 weeks (r = .74, p less than 0.001) later. An analysis of the mean session latency of the shuttlebox task in these two tests suggested a bimodal distribution of animals that failed and learned. A significant correlation was found between individual rats that learned this task on the first test and those which learned this task 2 or 4 weeks later. Similarly, in the "behavioral despair" test, a significant correlation was observed for floating time for individual rats on the first test and on the second test either 2 (r = .72, p less than 0.001) or 4 weeks (r = .63, p less than 0.001) later. However, for the forced-swim test, a unimodal and rather graded response was observed across individual subjects. Thus, performance on the first round predicted performance on the second round in both models. When rats experienced the learned helplessness paradigm on round 1 and the behavioral despair paradigm in round 2, there was no correlation between rats that displayed helplessness following inescapable tailshock and the rats that demonstrated "behavioral despair" on a later test.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Characterization of stress-induced alterations in [3H] Ro5-4864 binding to peripheral benzodiazepine receptors in rat heart and kidney.

Inescapable tailshock has been shown to elicit a tissue specific decrease in the density of peripheral benzodiazepine receptors (PBR). We have now explored possible mechanisms that may be responsible for this phenomenon. An 80 minute session of inescapable tailshock produced a reduction in the binding of [3H] Ro5-4864 to renal membranes at 0, 1 and 2 hr after stress, with values returning to control (naive) levels within 24 hr. In cardiac membranes, statistically significant reductions were observed only at 2 and 4 hr after stress. The role of the pituitary-adrenal axis and the sympathetic nervous system in this phenomenon was assessed by subjecting adrenalectomized, hypophysectomized, 6-OHDA-treated or control (sham-operated or saline-treated) rats to inescapable shock. Neither adrenalectomy, hypophysectomy, nor 6-OHDA pretreatment altered the stress-induced reduction in renal PBR. However, the stress-induced decrease in renal PBR was blocked by pretreatment with clonazepam (1 mg/kg), a potent anxiolytic with low affinity for PBR.

Adrenalectomy↗
PubMed1987

"Peripheral" benzodiazepine binding sites in the Maudsley reactive rat: selective decrease confined to peripheral tissues.

"Peripheral" benzodiazepine binding sites (PBS) were studied in both the CNS and peripheral tissues of Maudsley reactive (MR) and Maudsley non-reactive (MNR) rats using the PBS specific ligand [3H]Ro 5-4864. A statistically significant reduction in the density of PBS was found in heart and kidney of the MR compared to the MNR. Similar reductions in the density of PBS were not observed in a number of areas of the central nervous system (including cortex, hippocampus, and hypothalamus) or other peripheral tissues, such as lung and adrenal. This selective decrease in PBS in a strain selectively bred for a high degree of "fearfulness" may be related to previous findings of a reduction in the density of PBS in the same tissues in rats subjected to uncontrollable shock. These observations suggest that PBS in heart and kidney may be altered in response to fear or anxiety.

Adrenal Glands↗
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↗
PubMed1985

An anxiogenic benzodiazepine receptor ligand induces learned helplessness.

Rats treated with the anxiogenic beta-carboline, N-methyl-beta-carboline-3-carboxamide (FG-7142), failed to acquire an escape response 24 h after treatment. Administration of FG-7142 resulted in a behavioral effect equivalent to a session of inescapable tailshock in this paradigm of learned helplessness. Pretreatment of rats with the selective benzodiazepine receptor antagonist Ro15-1788 blocked the development of learned helplessness elicited by FG-7142. These findings suggest that 'anxiety' may be a major factor in the development of learned helplessness.

Animals↗