Benzodiazepine receptors: Cellular and behavioral characteristics

Lippa, Arnold S.; Critchett, Donald J.; Sano, Mary; Klepner, Claire A.; Greenblatt, E. N.; Coupet, Joseph; Beer, Bernard

doi:10.1016/0091-3057(79)90342-3

Cited by 147 publications

(18 citation statements)

References 26 publications

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“…Nonetheless, autoradiographic studies indicate that a significant regional heterogeneity in the distribution of BZ receptor agonists exists in the brains of animals with HE, such that local concentrations of BZ receptor agonists may be much higher than whole-brain concentrations (15). In these studies, radioligand binding to BZ receptors in the cortex and cerebellum of animals with HE was reduced by 22% and 42%, respectively (15), which is similar to the level of BZ receptor occupation observed following the administration of diazepam at 4-18 mg/kg (an anticonvulsant and hypnotic dose) to normal rats (22,23). Moreover, the ability of BZ receptor antagonists to correct both the electrophysiological and behavioral manifestations of HE in animal models (3)(4)(5) and humans (12)(13)(14) indicates that the concentrations of BZ receptor agonists found in liver failure appear sufficient to produce some of the behavioral manifestations of HE.…”

Section: Discussionmentioning

confidence: 54%

Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy.

Basile

Pannell

Jaouni

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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Brain extracts from rats with hepatic encephalopathy due to thioacetamide-induced fulminant hepatic failure contained 4-to 6-fold higher concentrations of substances that inhibit radioligand binding to benzodiazepine receptors than corresponding control rat extracts. Both isocratic and gradient-elution HPLC indicated that this inhibitory activity was localized in 3-8 peaks with retention times corresponding to deschlorodiazepam, deschlorolorazepam, lorazepam, oxazepam, diazepam, and N-desmethyldiazepam. The presence of diazepam and N-desmethyldiazepam was confirmed by mass spectroscopy. Both mass spectroscopic and radiometric techniques indicated that the concentrations of N-desmethyldiazepam and diazepam in brain extracts from encephalopathic rats were 2-9 and 5-7 times higher, respectively, than in control brain extracts. While benzodiazepines have been identified previously in mammalian and plant tissues, this report demonstrates that concentrations of these substances are increased in a pathophysiological condition. These findings provide a rational basis for the use of benzodiazepine receptor antagonists in the management of hepatic encephalopathy in humans.Hepatic encephalopathy (HE) is a complex neuropsychiatric disorder arising from the metabolic abnormalities associated with acute or chronic liver failure (1). It has been proposed that an increase in the activity of y-aminobutyric acid (GABA)-containing pathways contributes to the manifestations of this disorder (2). Studies of visual evoked responses in the galactosamine-treated rabbit model of HE due to fulminant hepatic failure (FHF) (3) and in rats with HE due to thioacetamide (TAA)-induced FHF (4) indicate that central nervous system (CNS) GABAergic tone is increased in these models of HE. Electrophysiologic studies of single cerebellar Purkinje neurons in the rabbit model of HE further support this hypothesis. These neurons are hypersensitive to depression by the GABA receptor agonist muscimol and the benzodiazepine (BZ) receptor agonist flunitrazepam, but not to the a-adrenergic receptor agonist phenylephrine (5). In contrast, BZ receptor antagonists increase the spontaneous firing rate of these neurons and reverse their hypersensitivity to muscimol at concentrations that do not affect the firing rates of control neurons (5). Furthermore, BZ receptor antagonists correct the abnormalities in visual evoked responses associated with HE while transiently reversing the behavioral manifestations of this syndrome in both the rabbit and rat models of this disorder (3, 4).These observations indicate that the increase in "GABAergic tone" found in HE may be mediated by the BZ receptor, possibly as a consequence of an increase in the concentration or availability of a BZ receptor ligand with agonist (BZ-like) properties (6, 7). Elevated concentrations of substances that competitively and reversibly inhibit radioligand binding to BZ receptors have recently been found in extracts of brain and peripheral tissues from the TAA-treated rat model of HE (8)....

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Section: Discussionmentioning

confidence: 54%

Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy.

Basile

Pannell

Jaouni

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition to the amygdala, there is also evidence for the importance of BZ action at the level of the frontal cortex (Lippa et al 1979) for anxiolytic effects. It seems likely that a variety of structures are involved in mediating the anxiolytic effects of BZs, depending upon the nature of the stressor (see Gonzalez et al 1996).…”

Section: Discussionmentioning

confidence: 99%

The Effects of Early Rearing Environment on the Development of GABAA and Central Benzodiazepine Receptor Levels and Novelty-Induced Fearfulness in the Rat

Caldji

Francis

Sharma

et al. 2000

Neuropsychopharmacology

516

333

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We compared the effects of handling or maternal separation from the day following birth until postnatal day 14 on behavioral responses to novelty and on GABA A and central benzodiazepine (CBZ) receptor levels in the rat. As adults, handled animals showed reduced startle responsivity, increased exploration in a novel open field, and decreased novelty-induced suppression of feeding relative to the handled (H) and/or maternal separation (MS) groups. As compared with handled animals, both nonhandled (NH) and MS animals displayed: (1) reduced GABA A receptor levels in the locus coeruleus (LC) and the n. tractus solitarius (NTS); (2) reduced CBZ receptor sites in the central and lateral n. of the amygdala, the frontal cortex, and in the LC and NTS; and (3) The development of behavioral and endocrine responses to acute stress is greatly influenced by the early postnatal rearing environment (for reviews see Levine 1975;Denenberg 1964;Meaney et al. 1996). These environmental effects persist throughout the life of the animal, resulting in stable individual differences in stress reactivity. Indeed, there is considerable plasticity in the development of these systems. Postnatal handling during the first week of life greatly decreases behavioral fearfulness and hypothalamic-pituitary-adrenal (HPA) responses to stress; whereas, repeated periods of prolonged maternal separation produce enhanced reactivity. Increased stress reactivity has been associated with an enhanced risk for several forms of illness, including affective disorders, diabetes, autoimmune disorders, and coronary heart disease (Chrousos and Gold 1992;Higley et al. 1991;McEwen and Steller 1993;Seckl and Meaney 1994). Thus, in determining the magnitude of behavioral and endocrine responses to stress, early life events NO . 3 contribute to vulnerability to disease in later life (Seckl and Meaney 1994). The critical question, then, concerns the mechanisms for these early environmental effects on the development of behavioral and endocrine responses to stress.Postnatal handling has been shown to decrease fearfulness to novelty (Levine 1962(Levine , 1957Denenberg 1964;Bodnoff et al. 1987). As adults, handled (H) rats show reduced novelty-induced suppression of appetitive behavior and increased exploration in novel environments. The behavioral effects of repeated maternal separation in rats are less documented, although, in primates, there is considerable evidence for enhanced fearfulness in animals exposed to maternal separation in early life (Sackett 1969).The mechanisms underlying these early environmental effects on behavioral responses to novelty are unclear. Bodnoff et al. (1987) reported that neonatal handling increased forebrain central benzodiazepine (CBZ) receptor levels, with no indication of where in the forebrain such differences might exist. Nevertheless, these data are certainly consistent with the wellestablished, anxiolytic effects of benzodiazepines on behavioral responses to novelty (see File 1995 for a review). Moreover, these findings are a...

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“…Short-acting benzodiazepines, It has been proposed that the wide pharmacoin appropriate dosage, have indeed been shown logical effects of benzodiazepines are sustained Reprint requests to: Dr G. Bensimon, Service de Pharmacologie clinique, Division Ambroise Pare, 47 Bd de l'H6pital, 75651 Paris Cedex 13, France at a biological level by low benzodiazepine receptor-subtype selectivity, with the underlying assumption that to each receptor-subtype would correspond a different behavioural effect (Dubnick et al, 1983;Lippa et al, 1979).…”

Section: Introductionmentioning

confidence: 99%

Daytime wakefulness following a bedtime oral dose of zolpidem 20 mg, flunitrazepam 2 mg and placebo.

Bensimon

Foret

Warot

et al. 1990

Brit J Clinical Pharma

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Benzodiazepine receptors: Cellular and behavioral characteristics

Cited by 147 publications

References 26 publications

Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy.

Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy.

The Effects of Early Rearing Environment on the Development of GABAA and Central Benzodiazepine Receptor Levels and Novelty-Induced Fearfulness in the Rat

Daytime wakefulness following a bedtime oral dose of zolpidem 20 mg, flunitrazepam 2 mg and placebo.

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