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J N Crawley

Publications and source records attributed to J N Crawley.

At least 19 recordsLinked to original sources
PubMed1992

Polyamines inhibit N-methyl-D-aspartate antagonist-induced darting behavior in the rat prefrontal cortex.

The competitive NMDA (N-methyl-D-aspartate) receptor antagonist, CPP (3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid), microinjected into the medial prefrontal cortex of rats, induces a unique behavioral syndrome termed 'darting', characterized by rapid leaping across an open field arena. In addition, CPP induces generalized hyperactivity when microinjected into the medial prefrontal cortex, nucleus accumbens, and caudate nucleus. Polyamine modulation of the NMDA receptor was tested at the medial prefrontal cortex microinjection site in this behavioral paradigm. The polyamine spermidine, and its diamine precursor, putrescine, blocked CPP-induced darting behavior, as well as CPP-induced hyperactivity, at doses which did not decrease locomotor activity when administered alone. The putative polyamine antagonists, ifenprodil and diethylenetriamine, did not prevent spermidine from inhibiting CPP-induced darting. These results suggest that polyamines, presumably by acting as positive allosteric modulators of the NMDA receptor, can inhibit the CPP-induced behavioral syndrome at the prefrontal cortex site.

Animals↗
PubMed1992

Galanin in the medial septal area impairs working memory.

Galanin, a peptide of 29 amino acids, is co-localized with acetylcholine in a subpopulation of neurons of the medial septal area (MSA) that project to the hippocampus. Galanin reverses the actions of acetylcholine in several biochemical and behavioral procedures, and may be involved in memory processes. To test the possibility that galanin acts on the cell bodies of MSA neurons, two measures of septohippocampal function were assessed following intra-septal microinfusion of galanin or two synthetic fragments of galanin (1-16 and 21-29). The behavioral measure was choice accuracy in a working memory task in a T-maze. The electrophysiological measure was hippocampal theta activity recorded from the dentate hilus. The galanin fragment, 1-16, and the complete peptide, 1-29, decreased choice accuracy and decreased hippocampal theta activity in a dose-dependent fashion. Saline and the 21-29 fragment had no effect on choice accuracy and hippocampal theta. Sensorimotor performance was unaffected. These findings demonstrate that galanin impairs working memory when administered directly into the MSA and suggest that galanin inhibits MSA neural activity.

Animals↗
PubMed1992

Failure of a protein synthesis inhibitor to modify glutamate receptor-mediated neurotoxicity in vivo.

The delayed neuronal death (DND) resulting from brief forebrain ischemia has recently been reported to be markedly attenuated by parenteral administration of the reversible protein synthesis inhibitor, anisomycin. Previous work suggests that ischemia-induced DND is mediated by glutamate acting at one or more glutamate receptors, since glutamate receptor antagonists have been reported to reduce ischemia-induced DND. Consequently, we tested whether anisomycin could modify DND induced by direct intracerebral administration of the excitotoxins, N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxasole (AMPA) or kainic acid. Anisomycin, administered parenterally, in multiple doses did not alter DND induced by any of these excitotoxins, nor did combined parenteral and direct intracerebral injection of anisomycin protect against DND induced by AMPA. Thus, neurotoxicity induced by direct intracerebral administration of NMDA, AMPA or kainic acid does not appear to require de novo protein synthesis, and, therefore, is not likely to be mediated by the expression of a programmed cell death cascade.

Animals↗
PubMed1992

Expression of tyrosine hydroxylase in cerebellar Purkinje neurons of the mutant tottering and leaner mouse.

In situ hybridization histochemistry, Northern blot analysis and immunohistochemistry were used to examine tyrosine hydroxylase (TH) mRNA concentrations and immunoreactivity in the locus coeruleus and cerebellum of the tottering (tg/tg), leaner (tgla/tgla), compound heterozygous (tg/tgla) and wild type control (+/+) mice, bred on a C57BL/6J background. Cerebellar Purkinje neurons, long considered to be GABAergic, showed high levels of TH mRNA in the caudal vermis and the lateral hemispheres of the cerebellum of tg/tg, tg/tgla, and tgla/tgla mice. Analysis of grain density over individual Purkinje cells showed significantly greater concentrations of TH mRNA in tg/tg, tg/tgla, and tgla/tgla mice as compared to +/+ wild type control mice. Comparison of adult (greater than or equal to 2 months) and young, pre-seizure (less than or equal to 3 weeks) mutant mice showed Purkinje cells densely labelled for TH mRNA at both ages, suggesting that TH gene expression in Purkinje cells is independent of the onset of seizures. Northern blot analysis confirmed the findings from the in situ hybridization studies, demonstrating a single band identical to TH mRNA. Immunohistochemistry confirmed the presence of TH protein in Purkinje cells of the caudal vermis and the lateral hemispheres of the cerebellum in both control and mutant mice. Quantitation of mRNA for TH and the coexisting neuropeptide, galanin, in the locus coeruleus detected no significant differences between adult tg/tg, tg/tgla and +/+ control mice. The present findings demonstrate that the classically GABAergic Purkinje cells in the cerebellum express low levels of TH, and that the mutant tottering and leaner strains of mice express extremely high levels of mRNA and protein for TH.

Animals↗
PubMed1992

Subtype-selective cholecystokinin receptor antagonists block cholecystokinin modulation of dopamine-mediated behaviors in the rat mesolimbic pathway.

Subtype-selective antagonists of the peripheral-type (CCK-A) and the central-type (CCK-B) cholecystokinin (CCK) receptors were employed to determine the receptor subtype(s) mediating the modulatory actions of CCK on dopamine-induced changes in exploratory activity at three sites in the mesolimbic pathway of the rat. The CCK-A antagonist L-364,718 (10 ng) blocked CCK potentiation of dopamine-induced hyperlocomotion in the medial posterior nucleus accumbens. The CCK-B antagonist CI-988 (20 ng) blocked CCK inhibition of dopamine-induced hyperlocomotion in the anterior nucleus accumbens. The CCK-B antagonists CI-988 (20 ng) and L-365,260 (10 ng) blocked CCK potentiation of dopamine-induced hypolocomotion in the ventral tegmental area. These data indicate a CCK-B pharmacology in the cell body and anterior terminal field, and a CCK-A pharmacology in the posterior terminal field, of the mesolimbic dopamine pathway. Behavioral analyses using the selective CCK antagonists did not detect a contribution of endogenous CCK to exploratory locomotion. L-364,718 (10 ng), L-365,260 (10 ng), and CI-988 (20 ng or 2 micrograms), microinjected into the medial posterior nucleus accumbens, anterior nucleus accumbens, or ventral tegmental area, had no effect on baseline exploratory locomotion or on dopamine-induced changes in exploratory locomotion. Using a dark-induced hyperlocomotion paradigm, the CCK antagonists at these doses at these sites and intraperitoneally had no effect on the high levels of exploratory locomotor activity exhibited by the rats in the dark testing environment, or the lower levels of exploratory activity in the lighted environment. Endogenous CCK may not be released during dopamine-induced hyperlocomotion or dark-induced hyperlocomotion, or endogenous CCK may not contribute significantly to exploratory behaviors mediated through the mesolimbic dopamine pathway. Utilization of these potent, selective, nonpeptide CCK antagonists, with the doses, vehicles, and routes of administration developed in the present studies, will guide further investigations into the role of endogenous CCK in other facets of mesolimbic function.

Animals↗
PubMed1991

Cholecystokinin-dopamine interactions.

Cholecystokinin (CCK) coexists with dopamine in a large proportion of the ventral tegmental and substantia nigra neurons in rodents and primates. In this review Jacki Crawley integrates the neurophysiological, behavioral, and release studies which demonstrate both excitatory effects of CCK, and facilitatory modulating effects of CCK on the inhibitory actions of dopamine, in the mesolimbic pathway. Nonpeptide antagonists selective for the CCKA and CCKB receptors have recently been developed, and provide long-awaited tools to test hypotheses about the role of endogenous CCK as a modulator of dopaminergic function, and the potential of CCK-based drugs as treatments for neuropsychiatric disorders.

Animals↗
PubMed1991

Repeated administration of desmethylimipramine blocks the reserpine-induced increase in tyrosine hydroxylase mRNA in locus coeruleus neurons of the rat.

The levels of tyrosine hydroxylase and galanin mRNA were measured by in situ hybridization histochemistry in the rat locus coeruleus after repeated (21 days) administration of desmethylimipramine (10 mg/kg/day), of reserpine (0.25 mg/kg/day), of coadministered desmethylimipramine and reserpine, or of vehicle. Reserpine administration resulted in increased levels of both tyrosine hydroxylase and galanin mRNAs in locus coeruleus neurons as compared to vehicle-treated controls. Administration of desmethylimipramine alone failed to alter either the tyrosine hydroxylase or galanin mRNA. However, coadministration of desmethylimipramine with reserpine blocked the elevation in tyrosine hydroxylase mRNA induced by reserpine alone.

Animals↗
PubMed1991

Centrally administered cholecystokinin suppresses feeding through a peripheral-type receptor mechanism.

Agonists and antagonists selective for the brain-type [cholecystokinin (CCK)-B] and the peripheral-type (CCK-A) CCK receptor were used to localize the site(s) of action at which CCK inhibits food consumption. BC 264, a highly selective CCK-B receptor agonist, did not decrease consumption of a palatable meal when administered either i.p. or into the lateral ventricles of the brain, whereas CCK decreased feeding when administered i.p. at the same doses. CCK decreased feeding when administered i.v.t. at a high dose, 5 micrograms. L-364,718, an antagonist selective for the CCK-A receptor, blocked completely the action of centrally administered CCK, whereas L-365,260, a selective CCK-B receptor antagonist, had no effect on the ability of centrally administered CCK to inhibit feeding. To estimate the quantity of i.v.t. administered CCK which reached the periphery, a tracer of radiolabeled [3H]p-CCK8 ([3H]CCK octapeptide sulfate), combined with unlabeled pCCK8 (5 micrograms) was administered i.c.t. Thirty minutes after administration, intact radiolabeled pCCK8 was extracted from the plasma and measured in the blood in nanomolar concentrations, exceeding the amounts of CCK octapeptide sulfate reported previously to be present in the plasma after a meal. Intraventricularly administered CCK thus appears to reduce feeding in the rat through a mechanism involving a CCK-A receptor subtype in the periphery.

Animals↗
PubMed1990

Neurotensin and cholecystokinin microinjected into the ventral tegmental area modulate microdialysate concentrations of dopamine and metabolites in the posterior nucleus accumbens.

Neurotensin and cholecystokinin, neuropeptides which coexist with dopamine in many ventral tegmental neurons, were microinjected into the ventral tegmental area during in vivo microdialysis in the posterior nucleus accumbens. Neurotensin significantly elevated concentrations of dopamine and its metabolites at doses of 10 pmol, 1 nmol, and 10 nmol, while cholecystokinin significantly elevated dopamine metabolite concentrations only at a dose of 10 nmol. These data suggest that neurotensin potently mediates the release of dopamine from the mesolimbic pathway via direct actions on the cell body.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Investigation of behavioral and electrophysiological responses induced by selective stimulation of CCKB receptors by using a new highly potent CCK analog, BC 264.

The new CCKB analog, Boc-Tyr (SO3H)-gNle-mGly-Trp-(NMe)-Nle-Asp-PheNH2 (BC 264) exhibited a high affinity (KI = 0.39 +/- 0.15 nM) and selectivity for central (B) versus peripheral (A) receptors (KI CCKA/KI CCKB = 910) in the rat. In agreement with these binding studies, BC 264 was at least 50 times more potent than CCK8 in stimulating the firing of rat CA hippocampal neurones. Furthermore stereotaxic injection of BC 264 or CCK8 in the VTA of rats resulted in potentiation of the dopamine-induced hypolocomotion. These two types of CCK8 responses have been previously shown in involve CCKB receptors. In contrast, after administration into the postero-median nucleus accumbens, the hypoexploration, the increase of emotionality of rats, or the potentiation of dopamine-induced hyperlocomotion were obtained after injection of CCK8 but not of BC 264, supporting the involvement of peripheral CCKA receptors in these CCK8 responses. Owing to its resistance to peptidases, BC 264 appears to be of great interest in the investigation of the still uncertain functional roles of CCK in the central nervous system.

Action Potentials↗
PubMed1990

Tyrosine hydroxylase and galanin mRNA levels in locus coeruleus neurons are increased following reserpine administration.

The neuropeptide galanin coexists in 80-90% of the norepinephrine-containing neurons in the locus coeruleus. In situ hybridization histochemistry was used to examine the effects of reserpine treatment or swim stress on tyrosine hydroxylase and galanin mRNA concentrations in locus coeruleus neurons. Reserpine administration significantly increased tyrosine hydroxylase and galanin mRNA levels in the locus coeruleus. The reserpine-induced increase in tyrosine hydroxylase mRNA was significantly correlated with the reserpine-induced increase in galanin mRNA. Three consecutive days of swim stress did not significantly alter either tyrosine hydroxylase or galanin mRNA concentrations in the locus coeruleus. These data suggest that both tyrosine hydroxylase and galanin gene expression in locus coeruleus neurons may be regulated by a reserpine-sensitive mechanism.

Animals↗
PubMed1990

Tyrosine hydroxylase and cholecystokinin mRNA levels in the substantia nigra, ventral tegmental area, and locus ceruleus are unaffected by acute and chronic haloperidol administration.

1. The studies described herein were designed to test the hypothesis that a neuroleptic, haloperidol, may alter the level of expression of the tyrosine hydroxylase and cholecystokinin genes in discrete brain regions. 2. In situ hybridization was employed to quantitate changes in concentration of mRNA for tyrosine hydroxylase and cholecystokinin in the ventral tegmental area, substantia nigra, and locus ceruleus after acute or chronic treatment with haloperidol or vehicle. 3. Haloperidol had no effect on the level of tyrosine hydroxylase or cholecystokinin mRNAs, in the ventral tegmentum, substantia nigra, or locus ceruleus, at either 3 or 19 days of drug administration. 4. These data suggest that haloperidol administration does not alter the level of tyrosine hydroxylase or cholecystokinin mRNAs in midbrain dopamine neurons of the rat.

Animals↗
PubMed1990

Microdialysis as an approach to quantitate the release of neuropeptides.

1. In vivo microdialysis was performed on anesthetized and awake rats to measured release of cholecystokinin from the posterior nucleus accumbens. 2. Basal levels of cholecystokinin were detectable by radioimmunoassay in some, but not all animals. 3. Recovery through the microdialysis probe ranged from 0.1-2.4% for cholecystokinin, suggesting practical limitations to this approach with present technology.

Animals↗
PubMed1990

Activity of centrally administered galanin fragments on stimulation of feeding behavior and on galanin receptor binding in the rat hypothalamus.

Synthetic fragments of galanin 1-29 were administered intraventricularly or into the paraventricular nucleus of the hypothalamus for analysis of the critical amino acid sequence necessary to stimulate feeding behavior in rats. Galanin 1-29 and galanin fragment 1-16 significantly increased feeding at doses of 6 nmol microinjected into the lateral ventricles and 1 nmol microinjected into the hypothalamus. There was no significant effect of D-TRP2 galanin 1-16 microinjected into the hypothalamus, and no significant effect of galanin fragments 1-9, 10-20, 12-29, 17-29, or 21-29 microinjected intraventricularly, on food consumption. Synthetic fragments of galanin 1-29 were assayed for displacement of 125I-galanin 1-29 binding to rat hypothalamic membranes. The efficacies of the galanin fragments in the feeding paradigm were consistent with the relative affinities of these fragments for the hypothalamic galanin receptor in equilibrium binding experiments. The first 16 N-terminal amino acids appear to contain galanin agonist activity on increasing food consumption and to bind to the galanin receptor in the rat hypothalamus.

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↗