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J N Crawley

Publications and source records attributed to J N Crawley.

At least 145 records · Page 8Linked to original sources
PubMed1985

Clarification of the behavioral functions of peripheral and central cholecystokinin: two separate peptide pools.

Cholecystokinin is localized in two distinct systems, the gastrointestinal and the central nervous systems. At both locations, cholecystokinin (CCK) is synthesized, stored, and released, and high affinity binding sites for CCK have been identified. The blood-brain barrier is thought to completely block passage of CCK from the gut to the brain compartment, although CCK can pass from the cerebrospinal fluid out into the blood. A variety of behavioral actions of CCK have been described. Evidence that the actions of CCK on feeding and behavioral sedation are mediated through the peripheral site is reviewed. Recent studies demonstrating behavioral effects of CCK administered in nanogram doses directly into brain nuclei are reviewed. Caveats against administration of microgram doses of CCK into the cerebral ventricles are raised, emphasizing the interpretational difficulties inherent in this approach.

Animals↗
PubMed1985

The effects of cholecystokinin-like peptides in schizophrenics and normal human subjects.

Eight neuroleptic-resistant schizophrenic patients were treated with ceruletide, a cholecystokinin-like peptide, in a placebo-controlled, double-blind, crossover study. Ceruletide or placebo was administered intramuscularly twice a day for 4 consecutive days while patients were maintained on a constant dose of fluphenazine. There were no changes in either the positive or negative symptoms of schizophrenia between the periods of placebo and ceruletide administration. To further characterize ceruletide actions we also administered it to seven normal volunteers and evaluated its effects on cognition and mood. Volunteers were administered ceruletide (0.3 micrograms/kg or 0.6 micrograms/kg) or saline placebo intramuscularly. Ceruletide had no effects on recent or remote memory or attention, but the higher dose did cause a significant increase in fatigue. These results suggest that although CCK-like peptides lack antipsychotic or cognitive effects they do induce mild sedation. This sedation may be part of a "satiety-like" state induced by peripheral administration of CCK.

Adult↗
PubMed1985

Animal models of self-destructive behavior and suicide.

In this article we have addressed selected aspects of animal models that may have ramifications in our understanding of suicide and human self-destructive behavior. It should be kept in mind that these human behaviors have many determinants. In considering animal models, we do not propose that similar behaviors necessarily have the same causation nor that a particular experimental manipulation that produces a behavioral syndrome in one species will produce that response in another species. Even if environmental conditions or the resulting behaviors vary for different species, the biochemical intermediaries may be similar. The simplification inherent in the laboratory modeling of an aspect of human behavior should not mean that the complexity of the human syndrome be forgotten. However, if a simple explanation can account for the production of a particular behavioral syndrome in animals, it can help to structure our thoughts regarding the etiology of the behavior in humans. The ethologic observations discussed in this article may help to place human self-destructive behavior in a continuum with that of animals in the wild. Although care should be given to drawing direct parallels, the clear conclusion is that humans are not alone in exhibiting self-initiated behaviors that ultimately produce self-harm or death. Whereas laboratory models have been extensively used for modeling psychiatric illnesses or for producing specific pharmacologic manipulations of the CNS, surprisingly little attention has been given to the modeling of self-destructive behaviors themselves. Emphasis on self-destructive behaviors, as well as on their biologic and genetic underpinnings, represent an important future direction for work on animal models in psychiatry.

Altruism↗
PubMed1985

Neuropharmacological antagonism of the beta-carboline-induced "anxiety" response in rhesus monkeys.

A behavioral and physiological syndrome of stress-related responses was reported in primates following treatment with the benzodiazepine receptor antagonist, beta-carboline-3-carboxylic acid ethyl ester (beta-CCE). The behavioral and physiological effects of beta-CCE are similar to those observed during stressful or "anxiety"-related conditions characterized in rhesus monkeys under natural conditions. Pharmacological agents which are known to antagonize anxiety responses in other paradigms were tested for their ability to antagonize the actions of beta-CCE. Diazepam (1 mg/kg) completely blocked the effects of beta-CCE (200 micrograms/kg) on anxiety-related behaviors, heart rate and blood pressure, plasma catecholamines, cortisol, and adrenocorticotrophic hormone. A presynaptically active dose of the alpha-adrenoreceptor agonist, clonidine (10 micrograms/kg), significantly attenuated the effects of beta-CCE on all parameters, whereas the beta-adrenoreceptor agonist, propranolol (3 mg/kg), failed to alter the increases in plasma catecholamines, cortisol, or ACTH. In addition to these adrenergic agents, the serotonin antagonist, cyproheptadine (1 mg/kg), and the GABA-mimetic, 4,5,6,7-tetrahydroisoxazolo(5,4-C)pyrindin-3-ol (1 mg/kg), partially blocked the behavioral, physiological, and biochemical changes after beta-CCE. Manifestation of the complete "anxiety" syndrome evoked by beta-CCE in primates may require the functional activity of several neurotransmitter systems.

Adrenocorticotropic Hormone↗
PubMed1985

Cholecystokinin-induced excitation in the substantia nigra: evidence for peripheral and central components.

Cholecystokinin (CCK), one of the most common brain peptides, coexists with dopamine (DA) in neurons of the medial substantia nigra (SN). CCK has been shown to excite these neurons following either direct iontophoretic or systemic administration suggesting that peripherally administered CCK may cross the blood brain barrier to act directly on nigral DA cells. However, biochemical evidence suggests that CCK does not cross the blood brain barrier, and several studies have shown that the behavioral and the satiety-inducing effects of peripherally administered CCK are abolished by vagotomy. In order to test for vagal mediation of the nigral response to systemically administered CCK, we examined the effects of a series of lesions to the vagal pathways on CCK-induced excitation in the SN. Neither acute thoracic nor chronic subdiaphragmatic vagotomies had any effect on the excitatory response of nigral DA neurons to systemically administered CCK. High cervical spinal cord transections were similarly without effect. In contrast, lesions of either vagal fibers in the medulla or of the efferent pathways from the nucleus tractus solitarii, the primary sensory nucleus of the vagus, produced significant attenuations of the nigral effects of systemically administered CCK. However, neither lesion blocked effects of CCK completely. We suggest that peripherally administered CCK has two components to its excitatory action in the SN; a component probably mediated through CCK receptors in the nucleus tractus solitarii and a direct action on DA neurons.

Animals↗
PubMed1985

Cholecystokinin potentiates dopamine-mediated behaviors: evidence for modulation specific to a site of coexistence.

Cholecystokinin coexists with dopamine in mesolimbic neurons in mammalian brain. When injected directly into the nucleus accumbens, cholecystokinin (CCK) potentiated dopamine (DA)-induced hyperlocomotion and apomorphine-induced stereotypy. These effects were not mimicked by nonsulfated CCK, but were blocked by proglumide, a putative CCK antagonist, as well as by antisera raised against sulfated CCK. CCK alone had no effect on locomotion or sterotypy, indicating that this peptide acts primarily as a modulator of DA-mediated behaviors in the mesolimbic pathway. In addition, CCK did not potentiate DA-induced hyperlocomotion or apomorphine-induced stereotypy when injected into the caudate nucleus, where CCK and DA are localized in separate neurons in rats. Facilitation of DA-mediated behaviors by CCK may represent a functional interaction specific to the neuromodulator-neurotransmitter coexistence phenomenon.

Animals↗
PubMed1984

Bilateral midbrain transections block the behavioral effects of cholecystokinin on feeding and exploration in rats.

The mechanism by which peripherally administered cholecystokinin (CCK) reduces feeding and exploration involves a sensory feedback pathway from the gastrointestinal regions, via the vagus nerve through the nucleus tractus solitarius (NTS). Bilateral dorsal midbrain transections rostral to the NTS abolish the ability of CCK to reduce food consumption, decrease exploratory approaches, and increase pauses of behavioral inactivity, as compared to these actions of CCK in normal and sham-lesioned control rats, suggesting that ascending NTS fibers are a necessary component in this feedback system.

Afferent Pathways↗
PubMed1984

The antagonism of bombesin in the CNS by substance P analogues.

The ability of substance P analogues to inhibit the action of bombesin in the CNS was investigated using receptor binding and biological assays. The putative substance P antagonists inhibited binding to central receptors for both substance P and bombesin-like peptides. Spantide, which was the most potent analogue tested, reversed the bombesin induced hypothermia and grooming. Therefore the putative substance P antagonists may also antagonize the actions of bombesin in the CNS.

Animals↗
PubMed1984

Convulsant potencies of tetrazoles are highly correlated with actions on GABA/benzodiazepine/picrotoxin receptor complexes in brain.

A series of tetrazole convulsants were examined for their potencies in displacing [35S]-t-butylbicyclophosphorothionate (TBPS) from the picrotoxin site on the benzodiazepine-GABA-chloride ionophore receptor complex. All of the tetrazole derivatives tested inhibited [35S]-TBPS binding from rat forebrain membranes, and except for one (undecamethylenetetrazole), had Hill coefficients near unity. Similar to other chemically unrelated convulsants the inhibition of [35S]-TBPS binding by the various tetrazole derivatives was unaffected by the addition of the bicucculine-like GABA antagonist, R 5135. To ascertain whether the inhibition of specific [35S]-TBPS binding by the tetrazole derivatives was related to their convulsant properties, we compared their in vitro potencies in displacing [35S]-TBPS binding with their minimum convulsant potencies in mice. A very good correlation was observed (r = 0.96, p less than 0.001) between their relative affinities for the [35S]-TBPS binding site and their convulsant potencies, indicating that pentamethylenetetrazol and related tetrazoles may produce their convulsant and anxiogenic actions via the GABA-benzodiazepine-chloride ionophore receptor complex.

Animals↗
PubMed1984

Abolition of the behavioral effects of cholecystokinin following bilateral radiofrequency lesions of the parvocellular subdivision of the nucleus tractus solitarius.

Cholecystokinin (CCK) has been implicated as a signal for the syndrome of satiety in a variety of species. Several lines of evidence point to a peripheral site of action for the behavioral effects of CCK. Peripheral CCK receptors appear to activate a gut-brain pathway involving the sensory fibers of the vagus nerve. To investigate the central anatomical substrate of this visceral-behavioral control system, the terminal regions of the sensory tract of the vagus were lesioned. Selective destruction of the parvocellular subdivisions of the nucleus tractus solitarius (NTS) blocked the effects of acute doses of CCK on exploratory behaviors. Sham lesions and lesions destroying only the remaining regions of the NTS or the vagal motor nuclei had no effect on baseline exploratory behaviors and did not influence the ability of CCK to decrease spontaneous exploratory behaviors. These findings delineate the first central site along the ascending sensory pathway which appears to mediate the satiety-related behavioral effects of CCK.

Animals↗
PubMed1984

Anxiolytic-like properties of fominoben.

Fominoben, a centrally acting antitussive, has been shown recently to bind to the brain benzodiazepine binding site and to antagonize pentylenetetrazol-induced seizures. The present study reports the ability of fominoben to produce anti-anxiety effects analogous to diazepam in a mouse exploratory model for anxiolytics. This action of fominoben was blocked by Ro15-1788, a benzodiazepine receptor antagonist, implicating a brain benzodiazepine binding site in this anxiolytic action of fominoben.

Animals↗
PubMed1984

Absence of intrinsic antagonist actions of benzodiazepine antagonists on an exploratory model of anxiety in the mouse.

Recent reports suggest that antagonists of benzodiazepine receptors have intrinsic anxiogenic and convulsant properties. An exploratory model in the mouse, specific for anxiolytics, was employed to test further, the hypothesis that antagonists have intrinsic actions pharmacologically opposite to those of the benzodiazepines. The drugs Ro 15-1788 (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H- imidiazo -[1,5-a] [1,4]benzodiazepine-3-carboxylate), CGS-8216 (2-phenylpyrazolo[4,3-c] quinolin -3[5H]one), beta-CCM (3-carbomethoxy-beta-carboline) and FG-7142 (N1-methyl-beta-carboline-3-carboxamide) all effectively blocked the anxiolytic actions of diazepam. None of these antagonists demonstrated intrinsic or anxiogenic or anxiolytic activity in this model system. These findings suggest that both the species and paradigm employed will determine the pharmacological profile of drugs which act at the GABA-benzodiazepine receptor complex.

Animals↗
PubMed1984

Cholecystokinin accelerates the rate of habituation to a novel environment.

Cholecystokinin (CCK8), an octapeptide present in high concentrations in both gut and brain, has been proposed as a putative satiety signal in a variety of species. Exploratory and social behaviors in particular are inhibited by exogenously administered CCK8. One hypothesis for the mechanism by which CCK reduces feeding and exploration is that CCK8 is reducing arousal and attention to environmental stimuli. This possibility was tested by analyzing the rate of habituation to the novelty of objects placed in an unfamiliar arena. A video-tracking computer-assisted animal behavior monitor measured four parameters of exploratory behaviors in rats pretreated with intraperitoneal CCK8. During the first 30 minutes in the novel environment, CCK8-treated animals showed a reduced latency to cessation of exploration as compared to saline controls. In repeated five minute sessions on consecutive days, CCK8 treatment accelerated the decline in exploration over daily sessions. Pentobarbital, a known sedative, induced low levels of exploration throughout the repeated daily sessions. These data suggest that CCK8 is inducing a more rapid rate of habituation to the novelty of environmental stimuli. An accelerated rate of habituation might underlie some of the satiety-related behavioral effects of this peptide.

Animals↗
PubMed1984

Evaluation of a proposed hamster separation model of depression.

Phodopus sungorus, the Siberian dwarf hamster, exhibits a number of reproducible and quantifiable behavioral changes when the members of a male-female pair bond are separated. Preliminary evaluation of the syndrome revealed a significant increase in body weight, decrease in social interaction, and decrease in exploratory behaviors, which occurred predominantly in separated males. Some, but not all, of the behavioral effects of separation are reversed by the tricyclic antidepressant, imipramine. 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↗
PubMed1984

beta-Carboline-induced anxiety states.

Several C-3-substituted beta-carbolines (e.g., the ethyl ester of beta-carboline-3-carboxylic acid) have high affinities for benzodiazepine receptors and can antagonize the principal pharmacologic actions of the benzodiazepines. The observation that some of these compounds also possess 'intrinsic' actions, best described as pharmacologically opposite to the benzodiazepines, has provided a chemically induced model of extreme stress or anxiety. The actions of such compounds in currently used animal models of anxiety are reviewed, as well as the effects of these compounds in primates, including man.

Animals↗