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J N Crawley

Publications and source records attributed to J N Crawley.

At least 163 records · Page 9Linked to original sources
PubMed1984

Analysis of the behavioral activity of C- and N-terminal fragments of cholecystokinin octapeptide.

Cholecystokinin (CCK) is a gut peptide which induces a syndrome of satiety, including reduced food intake and reduced exploratory behaviors. To investigate the minimal active sequence within the octapeptide molecule for reducing exploratory behavior, all C- and N-terminal fragments of CCK 26-33 (CCK8) were synthesized. Only CCK26-33 [H-Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] and CCK 27-33 [H-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] induced the behavioral effects within a physiological dose range. Smaller fragments as well as unsulfated CCK26-33 and CCK27-33 were inactive in doses as high as 10(-3) mol/kg. The requirement of the entire C-terminal heptapeptide for the behavioral effects of CCK is contrasted against the activity of smaller fragments at pancreatic, gastrointestinal and brain CCK receptors.

Amino Acid Sequence↗
PubMed1984

Preliminary report of a new rodent separation model of depression.

Phodopus sungorus, the Siberian dwarf hamster, exhibits an unusual set of behavioral changes when the members of a male-female pair bond are separated. Quantification of these behaviors reveals a significant increase in body weight, decrease in social interactions, and decrease in exploratory behaviors, predominantly in separated males. Preliminary data on antidepressant treatments to reverse the separation syndrome, and on neurochemical changes during the separation period, are presented. Separation of pair-bonded Siberian dwarf hamsters may provide a new animal model for depression, incorporating the practical advantages of a rodent model with the conceptual advantages of a naturalistic life event precipitant.

Animals↗
PubMed1983

Rapid development of tolerance to the behavioural actions of cholecystokinin.

Cholecystokinin (CCK) acts acutely to inhibit food consumption in fasted rats, mice, sheep, pigs, monkeys and humans. CCK has been proposed as a satiety signal, inducing the behavioural sequence of satiety, or as an aversive internal stimulus, which inhibits food intake by inducing malaise. Reductions in food intake and related exploratory behaviours are initiated by CCK at its peripheral receptor in the gut, which appears to transmit sensory feedback via the vagus nerve to brain regions mediating appetitive behaviours. The therapeutic potential of CCK as an appetite suppressant in obesity syndromes rests on the demonstration of significant, long-lasting body weight reduction. Chronic CCK administration by repeated injections is problematic, since this peptide is rapidly degraded in vivo. We chose the Alzet constant infusion osmotic minipump to investigate possible alterations in body weight and food intake during continuous infusion of CCK. We now report that no change was detected in either body weight or total daily food consumption at any time point during 2 weeks of intraperitoneally (i.p.) infused CCK. The mechanism underlying the lack of chronic CCK effects appears to be a rapid development of behavioural tolerance. Acute challenge doses of CCK which induced satiety-related behaviours in saline-infused rats were ineffective in CCK-infused rats. The behavioural tolerance was apparent within a few hours of minipump implantation. These results provide the first evidence that rapid and reversible tolerance develops to the actions of a gut peptide.

Animals↗
PubMed1983

Adenosine uptake inhibitors potentiate the sedative effects of adenosine.

A major action of adenosine is the induction of profound behavioral inactivity. 6-(4-Nitrobenzyl)-thioinosine (NBI) and 6-(2-hydroxy-5-nitrobenzyl)-thioguanosine (NBG) have been shown to inhibit adenosine uptake. To investigate the possible synergism between exogenous ligand and reuptake inhibition, mice were treated with NBI or NBG + adenosine. NBI and NBG potentiated the effects of adenosine at doses which did not in themselves induce behavioral inactivity. These behavioral results support the proposed role of NBI and NBG as adenosine uptake site blockers which increase synaptic concentrations of adenosine and postsynaptic responses to adenosine in vivo.

Adenosine↗
PubMed1983

Further characterization of a simple, automated exploratory model for the anxiolytic effects of benzodiazepines.

Anxiolytics specifically increase the number of exploratory transitions in a two-chambered model system for anxiety in mice. Characterization of parameters to optimize and standardize this model required analysis of multiple use of test animals, intertrial interval, and circadian variability. Time of day did not affect exploratory activity in mice treated with vehicle or diazepam between 10 a.m. and 11 p.m. Intertrial intervals of 1, 3, 5, or 7 days were equally effective. The diazepam-induced increase in exploratory activity was significant over the first three uses of test animals. These data recommend reuse of mice to a maximum of three trials, throughout the daytime or evening hours of their lighting schedule.

Animals↗
PubMed1983

Anxiolytics block excessive grooming behavior induced by ACTH1-24 and bombesin.

Diazepam and meprobamate significantly attenuated the increases in grooming behavior induced by peptides. Significant increases in total grooming frequency over a thirty minute observation period were produced by intraventricular administration of 1 microgram ACTH1-24 and by 1 microgram bombesin to awake rats. Diazepam 1 mg/kg IP blocked the peptide-induced increases in grooming. Non-sedating doses of diazepam also completely reversed the grooming seen when rats were placed in a novel environment. The functional antagonism between anxiolytics and stress-related peptides supports the concept of interacting brain mechanisms mediating stress and anxiety.

Adrenocorticotropic Hormone↗
PubMed1982

Chronic benzodiazepine treatment increases [3H]muscimol binding in mouse brain.

High affinity [3H]muscimol receptors were analyzed in the forebrain and cerebellum of mice that had been treated on a chronic regimen with chlordiazepoxide and clonazepam. In the forebrain, only clonazepam induced an increase in the number of muscimol binding sites 2 hr after drug treatment. In the cerebellum, both the chlordiazepoxide and clonazepam-treated animals showed an increased number of muscimol binding sites 2 hr after drug treatment. At 26 hr after drug treatment, only the clonazepam-treated animals still revealed an increased number of cerebellar muscimol binding sites. Chronic benzodiazepine administration, therefore, induced an increase in the apparent number of high affinity muscimol binding sites in both the forebrain and cerebellum.

Animals↗
PubMed1982

Chronic clonazepam administration induces benzodiazepine receptor subsensitivity.

Clonazepam and chlordiazepoxide were administered chronically in increasing doses for three weeks in two different strains of mice. Forebrain [3H]diazepam binding was assayed in groups of mice sacrificed at 2, 26, 50 hr and 10 days following the last dose. Scatchard and single point analyses revealed a significant decrease in the number of [3H]diazepam binding sites [Bmax] which persisted for at least two days following chronic clonazepam treatment. The Bmax changes observed following chlordiazepoxide treatment were less pronounced than those elicited by clonazepam. No significant changes in receptor binding affinity (Kd) were detected with either drug. In the clonazepam-treated animals, Bmax values returned to normal by day 10 after drug treatment. Chronic benzodiazepine administration therefore induced a decrease in the apparent number of benzodiazepine binding sites in the mouse forebrain. The magnitude and duration of the observed subsensitivity appears to depend on the potency of the administered benzodiazepine.

Animals↗
PubMed1982

Electroencephalographic analysis of the sleep-inducing actions of cholecystokinin.

Cortical EEG analysis of the effects of cholecystokinin (CCK) on sleep were performed in rats treated intraperitoneally with 1,10, or 20 micrograms/kg CCK8. Latency to the first episode of non-REM sleep was significantly reduced from 29 minutes to 16 minutes. No change in total waking time, total non-REM sleep, or total REM sleep was seen at any dose over the first hour after CCK administration. Locomotor activity was significantly reduced by 10 micrograms/kg CCK8 during the first ten minutes only. The temporal separation between the sleep-latency reduction and the behavioral inactivity induced by CCK indicate that these effects are distinguishable phenomena. Sleep does not appear to be a primary cause for the satiety-related behavioral effects of CCK.

Animals↗
PubMed1982

Baseline exploratory activity predicts anxiolytic responsiveness to diazepam in five mouse strains.

Inbred mouse strains showing variability in spontaneous exploratory behaviors displayed differential responsiveness to diazepam in an anxiety-related exploration model. C57B1/6J, BALB/cJ, Swiss Webster/NIH, Swiss Webster/Harlan Sprague-Dawley, and CF-1 mice demonstrated a significant correlation between baseline exploratory activity and maximal percentage increase in exploratory behavior induced by diazepam. No correlation was seen between those behavioral responses and the characteristics of brain benzodiazepine binding sites in the different strains. Anti-anxiety responsiveness appears to be a function of some genetically-determined substrate for spontaneous exploratory behaviors which may have multiple neurochemical substrates.

Animals↗
PubMed1982

Beta-carbolines: synthesis and neurochemical and pharmacological actions on brain benzodiazepine receptors.

We have prepared a series of tetrahydro-beta-carbolines (TH beta C), beta-carbolines (beta-C), and other nitrogen heterocycles and evaluated them in vitro with respect to their ability to bind to benzodiazepine receptors. The fully aromatic beta-C's were more potent than their corresponding TH beta C derivatives. When substituents possessing a carbonyl (CO2Me, COCH3, CHO) were introduced at the beta-C 3-position the in vitro potency was augmented. Alcohol substituents (CH2OH, CHOHCH3) demonstrated decreased in vitro potency. The importance of the carbonyl moiety was further demonstrated when beta-carboline-3-carboxylic acid was shown to bind tighter to benzodiazepine receptors at lower pH. A lower pH increases the concentration of the acid and decreases the concentration of the anion. 3-(Hydroxymethyl)-beta-carboline (24), 3-formyl-beta-carboline (25) and 3-acetyl-beta-carboline (27) were benzodiazepine antagonists in vivo. Methyl isoquinoline-3-carboxylate (31a) also had in vitro activity. The same structure-activity relationships seen in beta-C's were also observed for isoquinolines.

Animals↗
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↗