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Biomedical subjects

J N Crawley

Publications and source records attributed to J N Crawley.

At least 127 records · Page 7Linked to original sources
PubMed1987

Site of action of anorectic drugs: glucoprivic- versus food deprivation-induced feeding.

Feeding induced by 2-deoxyglucose was compared with feeding induced by food deprivation in terms of antagonism by anorectic drugs and of anatomical site of action. Glucoprivic feeding was completely blocked by microinjection of amphetamine, fenfluramine, and mazindol into the paraventricular nucleus of the hypothalamus (PVN). Deprivation-induced feeding was not blocked by amphetamine, fenfluramine, or mazindol microinjected into the PVN. Neither the feeding induced by 2-deoxyglucose nor its reversal by amphetamine were blocked by pretreatment with the beta-adrenergic antagonist, propranolol. Amphetamine and fenfluramine blocked both glucoprivic- and deprivation-induced feeding when microinjected into the perifornical region of the lateral hypothalamus. These data suggest that food consumption induced by 2-deoxyglucose treatment can be antagonized by anorectic drugs acting at recognition sites present in several hypothalamic nuclei, while deprivation-induced feeding acts through different receptor mechanisms which may be specific to the perifornical region of the lateral hypothalamus.

Amphetamine↗
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

Anxiolytic action of CGS 9896 on mouse exploratory behavior.

A new non-benzodiazepine compound proposed as a non-sedating anxiolytic was tested in the mouse exploratory model of anxiety. CGS 9896 significantly increased the number of light dark transitions at doses beginning at 7.5 mg/kg i.p. Analysis of general locomotor activity at these doses revealed no change in spontaneous motor activity in a photocell equipped activity monitor. Pretreatment with the benzodiazepine receptor antagonist, Ro15-1788, 10 mg/kg i.p., blocked the increase in light dark transitions produced by CGS 9896. These data support the interpretation that CGS 9896 acts as an anxiolytic through the benzodiazepine receptor, and appears to have no sedating properties within the anxiolytic dose range.

Animals↗
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

Anxiolytic activity of an endogenous adrenal steroid.

The A-ring reduced metabolite of deoxycorticosterone, 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone (THDOC) was recently shown to act at the gamma-aminobutyric acid receptor-chloride ion channel complex in rat brain. The behavioral profile of THDOC was investigated using two animal models of anxiety, the two-chambered mouse exploration test and the lick suppression conflict test. THDOC showed anxiolytic activity in both animal models, with an anxiolytic dose range, 5-15 mg/kg i.p., separable from the sedative dose range, above 20-30 mg/kg i.p.

Animals↗
PubMed1986

Cholinergic induction of seizures in the rat prefrontal cortex.

Intracerebral microinjection of the cholinergic agonist, carbachol, into the medial prefrontal cortex of the rat, induced a profound behavioral syndrome consisting of repetitive, stereotyped forepaw treading in an upright posture. Electroencephalographic analysis revealed multiple bursts of sharp waves, 200-300 microV, accompanying the carbachol-elicited motor behavior. Pretreatment with intraperitoneal doses of three anticonvulsant drugs, clonazepam, diazepam, and pentobarbital, blocked the manifestation of the motor behavior. These observations suggest that activation of cholinergically innervated regions of the rat medial prefrontal cortex induces an atypical form of seizures.

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

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

Regulation of [3H]mazindol binding to subhypothalamic areas: involvement in glucoprivic feeding.

The distribution of low-affinity sodium-sensitive binding sites of [3H]mazindol were studied in rat hypothalamic nuclei. Using microdissection methods, it was demonstrated that the highest level of [3H]mazindol binding is localized to the paraventricular nucleus (PVN) and the lowest binding is observed in the lateral hypothalamus. Following food deprivation, a significant decrease in [3H]mazindol binding in the PVN and ventromedial hypothalamus (VHM) were observed. Refeeding food-deprived rats resulted in restoration of the level of binding in the PVN, and this was correlated with changes in blood glucose levels. Thus, changes in the binding of [3H]mazindol in the PVN may reflect local changes in glucose levels. In related studies, the involvement of the PVN in the regulation of food deprivation or 2-deoxyglucose (2-DG)-induced food intake was studied. Application of amphetamine (20 micrograms) into the PVN had no effect on food deprivation induced feeding, but significantly inhibited 2-DG induced (glucoprivic) feeding. The PVN may play an important role in the glucostatic regulation of feeding and in mediating the anorectic action of amphetamine and related anorectic drugs on glucoprivic feeding.

Amphetamine↗
PubMed1986

Antagonists of central and peripheral behavioral actions of cholecystokinin octapeptide.

Pharmacological studies on the behavioral functions of sulfated cholecystokinin (CCK) in the gut and in the brain require potent, specific antagonists to CCK. Compounds identified as competitive antagonists at the peripheral receptors for CCK were tested for their ability to block the behavioral effects of CCK administered centrally and peripherally. Behavioral effects of CCK (8.8 X 10-10 mmol) administered centrally into the nucleus accumbens, i.e., potentiation of dopamine-induced hyperlocomotion in rats, were effectively blocked by pretreatment with proglumide (6 X 10(-5) mmol of nucleus accumbens), by benzotript (3 X 10(-5) mmol of nucleus accumbens) and by rabbit antiserum raised against CCK (0.2 microliter/nucleus accumbens), but not by CCK26-33 (1.7 X 10(-7) mmol) or unsulfated CCK26-33 (1.9 X 10(-6) mmol). The behavioral effects of peripherally administered CCK, i.e. reduced food consumption and reduced exploratory behaviors in mice, were blocked effectively by pretreatment with proglumide (0.3-0.9 mmol/kg), and by benzotript (0.03 mmol/kg), but not by CCK30-33 (0.003 mmol/kg). None of the compounds administered peripherally significantly affected food consumption or exploratory behaviors when given alone. Furthermore, none of the compounds significantly affected locomotion when administered alone into the nucleus accumbens, or significantly affected dopamine-induced hyperlocomotion when given into the nucleus accumbens before dopamine. Benzotript, proglumide and a CCK antibody appear to act as specific antagonists of the behavioral effects of CCK at both the peripheral gastrointestinal site and at the central nucleus accumbens site. Neither unsulfated CCK26-33 or CCK30-33 were effective as antagonists of peripheral or central behavioral effects of CCK. However, whereas benzotript and proglumide may be useful as pharmacologically specific antagonists, the high doses required suggest that more potent CCK antagonists are required for investigating the behavioral functions of endogenous CCK.

Animals↗
PubMed1986

Cholecystokinin-dopamine coexistence: electrophysiological actions corresponding to cholecystokinin receptor subtype.

Cholecystokinin (CCK)-like peptides when administered intravenously produce 2 distinct actions on the single-unit activity of mesencephalic dopamine (DA) neurons in the rat: an excitatory action and a potentiation of the inhibitory effects of DA agonists. The ability of several CCK fragments that have been shown to bind selectively to the peripheral and/or the central CCK-binding sites were examined for their ability to induce either excitation or a potentiation of DA. Only sulfated CCK-8 was able to induce excitation of mesencephalic DA neurons, but both sulfated and unsulfated CCK-8, as well as CCK-4, potentiated the inhibitory effects of the DA agonist apomorphine (APO). CCK-3 failed to potentiate APO-induced inhibition. Both of these effects appeared to be confined to cell bodies in regions of the ventral tegmental area and substantia nigra, zona compacta that have been reported to contain both DA and CCK. Thus, CCK-like peptides that have been shown to bind to the high-affinity CCK binding site in brain potentiated the effects of DA. In contrast, the ability of CCK-like peptides to induce neuronal excitation corresponds with their affinity for the peripheral-type CCK binding site.

Animals↗
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↗
PubMed1985

Topographical analysis of nucleus accumbens sites at which cholecystokinin potentiates dopamine-induced hyperlocomotion in the rat.

Sulfated cholecystokinin octapeptide (CCK) potentiates dopamine-induced hyperlocomotion in the nucleus accumbens of the rat. Immunocytochemical evidence has shown a topographical distribution of terminals containing both CCK and dopamine (DA), within the medial posterior nucleus accumbens. Seven sites within the nucleus accumbens were cannulated and tested for the ability of CCK to enhance the behavioral effects of DA. Close agreement was found between the anatomical sites of CCK-DA coexistence, and the anatomical sites at which CCK potentiated DA-induced hyperlocomotion. Behaviorally inactive sites were found primarily in the anterior nucleus accumbens, where DA-containing terminals do not contain CCK.

Animals↗
PubMed1985

A monoamine oxidase inhibitor reverses the 'separation syndrome' in a new hamster separation model of depression.

A broad spectrum monoamine oxidase inhibitor, tranylcypromine sulfate (Parnate) was tested in a new hamster separation model of depression. In this paradigm, male dwarf hamsters show increases in body weight, decreases in exploratory behaviors, and decreases in social interactions, when separated from female mates. Tranylcypromine (10 mg/kg s.c. daily for 14 days) effectively reduced body weight, increased exploration, and increased social interaction, in the separated males. Subsequent treatment with saline restored the separation-induced changes in body weight, exploratory behaviors, and other social behaviors. The 'separation syndrome' in dwarf hamsters appears to be completely reversed by at least one antidepressant treatment.

Animals↗
PubMed1985

Exploratory behavior models of anxiety in mice.

Parameters of exploratory behaviors responsive to anti-anxiety drugs are reviewed with respect to their sensitivity and specificity for anxiolytics in mice. Mouse models appear to rest on a disinhibition of natural exploratory tendencies by anxiolytic treatments. Analysis of agonists of the brain benzodiazepine binding site, such as chlordiazepoxide and diazepam, significantly increase exploration of a hole-board, of a two-chambered light in equilibrium dark apparatus, increase social interaction under high levels of illumination, increase consumption of a novel food in an unfamiliar environment, and increase punished crossings in a footshock conflict paradigm. These tests detect anxiolytic responses at doses of benzodiazepines well within the clinically effective range. Pharmacological specificity was established for the hole-board and light in equilibrium transition tests, showing that non-anxiolytic categories of psychoactive drugs did not produce false positives. Open field behaviors and isolation-induced aggression were reduced by anxiolytics, at doses which may be within the sedative-hypnotic range. Analysis of antagonists of the brain benzodiazepine binding site did not show active antagonist properties in the light in equilibrium transitions model, although the antagonist Ro-15-1788 appeared to have partial agonist properties in the open field test, suggesting that rat models may be more sensitive to anxiogenic compounds than are mouse models. The wide separation between anxiolytic and sedative doses in mouse models recommend these exploration paradigms as good predictive screens for the testing of novel anxiolytic compounds.

Aggression↗
PubMed1985

Neurochemical investigation of the afferent pathway from the vagus nerve to the nucleus tractus solitarius in mediating the "satiety syndrome" induced by systemic cholecystokinin.

The satiety syndrome induced by intraperitoneally administered cholecystokinin (CCK) requires an intact visceral sensory feedback system involving the afferent vagus nerve and the nucleus tractus solitarius (NTS). Since both the vagus and the NTS contain CCK, the vagal-NTS synapse could conceivably employ CCK as a transmitter. To test this hypothesis, CCK was injected directly into the NTS region in awake rats. CCK at doses of 1 ng, 10 ng, and 100 ng had no effect on food consumption or exploratory behaviors associated with the satiety syndrome. The acetylcholine agonist carbachol, injected directly into the NTS region, effectively mimicked the actions of intraperitoneally administered CCK on feeding and exploration. These data suggest that CCK is not the transmitter at the vagal-NTS site in the visceral sensory pathway projecting to brain regions mediating the reduced feeding and exploration actions of systemic CCK.

Afferent Pathways↗