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Biomedical subjects

J N Crawley

Publications and source records attributed to J N Crawley.

At least 55 records · Page 3Linked to original sources
PubMed1997

Analysis of galanin and the galanin antagonist M40 on delayed non-matching-to-position performance in rats lesioned with the cholinergic immunotoxin 192 IgG-saporin.

Galanin is a 29-amino-acid neuropeptide that is overexpressed in Alzheimer's disease (AD) and impairs performance on rodent learning and memory tasks. M40, a peptidergic galanin receptor ligand, blocks galanin-induced impairments on delayed non-matching-to-position (DNMTP). The present experiments used the 192IgG-saporin lesion model of AD to evaluate the actions of galanin and M40 on DNMTP when cholinergic transmission was reduced. Hippocampal choline acetyltransferase levels were correlated with DNMTP choice accuracy in lesioned rats. Intracerebroventricular (icv) galanin reduced choice accuracy in both the lesioned and sham groups. M40 alone, either icv or intrahippocampal, did not affect choice accuracy in either group. These results suggest that excess galanin can produce further deficits in DNMTP performance in a lesion model of AD, but blocking endogenous galanin is not sufficient alone to improve performance in lesioned rats.

Alzheimer Disease↗
PubMed1997

Galanin-acetylcholine interactions in rodent memory tasks and Alzheimer's disease.

Galanin is a 29-amino-acid neuropeptide that is widely distributed in the mammalian central nervous system. Galanin-immunoreactive cell bodies, fibres and terminals, and galanin binding sites, are located in the basal forebrain of rats, monkeys and humans. Galanin fibres hyperinnervate the surviving cholinergic cell bodies in patients with Alzheimer's disease (AD). In rats, galanin inhibits acetylcholine release and produces deficits in learning and memory. These findings suggest that overexpressed galanin may contribute to the cognitive impairments exhibited by patients with AD. This paper reviews the literature on galanin distribution and function in light of its putative role in the mnemonic deficits in patients with AD, the effects of galanin on tests of learning and memory, and preliminary experiments with galanin antagonists in animal models of AD.

Acetylcholine↗
PubMed1996

Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin.

Enkephalins are endogenous opioid peptides that are derived from a pre-proenkephalin precursor protein. They are thought to be vital in regulating many physiological functions, including pain perception and analgesia, responses to stress, aggression and dominance. Here we have used a genetic approach to study the role of the mammalian opioid system. We disrupted the pre-proenkephalin gene using homologous recombination in embryonic stem cells to generate enkephalin-deficient mice. Mutant enk-/- animals are healthy, fertile, and care for their offspring, but display significant behavioural abnormalities. Mice with the enk-/- genotype are more anxious and males display increased offensive aggressiveness. Mutant animals show marked differences from controls in supraspinal, but not in spinal, responses to painful stimuli. Unexpectedly, enk-/- mice exhibit normal stress-induced analgesia. Our results show that enkephalins modulate responses to painful stimuli. Thus, genetic factors may contribute significantly to the experience of pain.

Aggression↗
PubMed1996

Atm-deficient mice: a paradigm of ataxia telangiectasia.

A murine model of ataxia telangiectasia was created by disrupting the Atm locus via gene targeting. Mice homozygous for the disrupted Atm allele displayed growth retardation, neurologic dysfunction, male and female infertility secondary to the absence of mature gametes, defects in T lymphocyte maturation, and extreme sensitivity to gamma-irradiation. The majority of animals developed malignant thymic lymphomas between 2 and 4 months of age. Several chromosomal anomalies were detected in one of these tumors. Fibroblasts from these mice grew slowly and exhibited abnormal radiation-induced G1 checkpoint function. Atm-disrupted mice recapitulate the ataxia telangiectasia phenotype in humans, providing a mammalian model in which to study the pathophysiology of this pleiotropic disorder.

Animals↗
PubMed1996

Individual differences in sugar consumption predict amphetamine-induced dopamine overflow in nucleus accumbens.

Rats exhibit individual differences in their consumption of sugar and in their response to amphetamine treatments. Intrinsic variation in the functioning of the mesolimbic dopamine system is one potential mechanism underlying the expression of these individual differences. The present experiment examined the relationship between sugar consumption and the dopaminergic response to amphetamine. In vivo microdialysis was used to assess amphetamine-stimulated dopamine overflow in the posterior-medial nucleus accumbens in LOW and HIGH sugar feeders. Sugar consumption correlated significantly with amphetamine-stimulated accumbens-dopamine overflow. HIGH rats exhibited significantly higher levels of amphetamine-stimulated accumbens-dopamine overflow than LOW rats. These results suggest that the propensity to ingest sugar is a predictor of the nucleus accumbens dopaminergic response to amphetamine treatment.

Amphetamine↗
PubMed1996

Galanin microinjected into the medial septum inhibits scopolamine-induced acetylcholine overflow in the rat ventral hippocampus.

Galanin-like immunoreactive terminals hyperinnervate the basal forebrain cholinergic neurons in Alzheimer's disease. To investigate the hypothesis that galanin acts directly on basal forebrain cell bodies, in vivo microdialysis studies were conducted in awake rats which analyzed the actions of galanin on acetylcholine release. Microinjection of galanin into the cholinergic cell body region of the medial septum-diagonal band (MS-DBB) inhibited acetylcholine release in the ventral hippocampus. These results are consistent with an interpretation that galanin terminals synapsing on cholinergic cell bodies of the basal forebrain may serve to inhibit the release of acetylcholine in the terminal fields of the cholinergic neurons.

Acetylcholine↗
PubMed1996

Minireview. Galanin-acetylcholine interactions: relevance to memory and Alzheimer's disease.

The neuropeptide, galanin, and its receptors are localized in the cholinergic basal forebrain and its projection areas in mammalian brain. Centrally administered galanin inhibits acetylcholine release in the rat ventral hippocampus, and produces deficits in learning and memory tasks. In Alzheimer's disease, galanin is overexpressed in terminals innervating the nucleus basalis of Meynert cell bodies. Selective galanin receptor antagonists provide a novel approach for increasing cholinergic function, as a potential adjunct to the clinical treatment of dementias.

Acetylcholine↗
PubMed1996

Olfactory bulbectomy increases prepro-galanin mRNA levels in the rat locus coeruleus.

The effects of olfactory bulbectomy (OBX) on galanin (GAL) gene expression in the locus coeruleus (LC) were examined with quantitative in situ hybridization histochemistry. OBX increased prepro-GAL levels 3 and 14 days after surgery, as compared to sham-operated controls. Levels of mRNA encoding prepro-neuropeptide Y (NPY) were unchanged, and levels of mRNA encoding tyrosine hydroxylase (TH) were elevated in the LC only on day 3. The results indicate that GAL gene expression in the LC increases after lesioning a terminal field.

Analysis of Variance↗
PubMed1996

Galanin receptor antagonist M40 blocks galanin-induced choice accuracy deficits on a delayed-nonmatching-to-position task.

Galanin is a 29-amino acid neuropeptide that coexists with acetylcholine in the medial septum/diagonal band in the rat and impairs choice accuracy on an operant delayed-nonmatching-to-position (DNMTP) working-memory task. M40, a peptidergic galanin antagonist, has previously been shown to block several physiological actions of galanin. The present experiments tested the ability of M40 to block the effects of galanin on DNMTP performance. M40 completely blocked choice-accuracy deficits induced by galanin administration in both the lateral ventricle and ventral hippocampus, at doses of M40 approximately 5-fold the molar dose of galanin. M40 appears to be an effective galanin antagonist in a rodent memory paradigm, indicating that this compound may prove useful in investigating the role of endogenous galanin in learning and memory.

Animals↗
PubMed1996

Mice lacking both subunits of lysosomal beta-hexosaminidase display gangliosidosis and mucopolysaccharidosis.

The GM2 gangliosidoses, Tay-Sachs and Sandhoff diseases, are caused by mutations in the HEXA (alpha-subunit) and HEXB (beta-subunit) genes, respectively. Each gene encodes a subunit for the heterodimeric lysosomal enzyme, beta-hexosaminidase A (alpha beta), as well as for the homodimers beta-hexosaminidase B (beta beta) and S (alpha alpha). In this study, we have produced mice that have both Hexa and Hexb genes disrupted through interbreeding Tay-Sachs (Hexa-/-) and Sandhoff (Hexb-/-) disease model mice. Lacking both the alpha and beta-subunits these 'double knockout' mice displayed a total deficiency of all forms of lysosomal beta-hexosaminidase including the small amount of beta-hexosaminidase S present in the Sandhoff disease model mice. More surprisingly, these mice showed the phenotypic, pathologic and biochemical features of the mucopolysaccharidoses, lysosomal storage diseases caused by the accumulation of glycosaminoglycans. The mucopolysaccharidosis phenotype is not seen in the Tay-Sachs or Sandhoff disease model mice or in the corresponding human patients. This result demonstrates that glycosaminoglycans are crucial substrates for beta-hexosaminidase and that their lack of storage in Tay-Sachs and Sandhoff diseases is due to functional redundancy in the beta-hexosaminidase enzyme system.

Animals↗
PubMed1995

Lack of effect of chronic morphine treatment and naloxone-precipitated withdrawal on tyrosine hydroxylase, galanin, and neuropeptide Y mRNA levels in the rat locus coeruleus.

Morphine dependence was experimentally induced in rats by daily injection of increasing doses of morphine for seven days. Withdrawal was precipitated in half of the morphine-dependent rats by a single injection of naloxone on day 8. Behavioral signs of withdrawal were evident in the morphine/naloxone group. Gene expression in locus coeruleus (LC) neurons was investigated using quantitative in situ hybridization analysis. Messenger RNA (mRNA) levels for tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, and for precursors to galanin (GAL) and neuropeptide Y (NPY), peptides that coexist with norepinephrine in LC neurons, were not altered by chronic morphine treatment or naloxone-precipitated withdrawal. In contrast, mRNA levels for c-fos were dramatically elevated in the LC following naloxone-precipitated withdrawal. Chronic morphine treatment caused a small decrease in levels of mRNA encoding the precursor to corticotropin-releasing factor (CRF) in Barrington's nucleus. Although long-term adaptations of LC neurons have previously been implicated in the development of morphine tolerance, dependence, and withdrawal, alterations in the levels of TH, GAL, or NPY mRNA in the LC apparently do not underlie this process.

Animals↗
PubMed1995

Genetic analysis of anxiety-related behaviors and responses to benzodiazepine-related drugs in AXB and BXA recombinant inbred mouse strains.

Recombinant inbred (RI) strains derived from the C57BL/6J and A/J mouse strains were used for behavioral studies designed to estimate the number and location of chromosomal loci responsible for anxiety-related behaviors and differential sensitivity to agonists and inverse agonists of the gamma-aminobutyric acidA (GABAA)/benzodiazepine receptor complex. The phenotypes of the parental inbred strains and of 28 RI strains were characterized for the number of transitions in the light<-->dark exploratory model, anxiolytic response to diazepam, vertical and ambulatory activities in an open field, and sensitivity to the convulsant properties of methyl-beta-carboline-3-carboxylate (beta-CCM). The strain distribution patterns and estimates of the minimal number of loci obtained for each trait suggest that multiple chromosomal loci contribute to differences in anxiety-related behavioral phenotypes and the behavioral responses to diazepam and beta-CCM between C57BL/6J and A/J mice. The best probabilities of linkage were found between the variables characterizing response to diazepam and loci on chromosomes 1 (Xmv-41) and 10 (D10Mit2) and between the sensitivity to the convulsant actions of beta-CCM and locus D15Mit5 on chromosome 15.

Animals↗
PubMed1995

Chronic social stress increases levels of preprogalanin mRNA in the rat locus coeruleus.

Galanin is a 29 amino acid neuropeptide that coexists with norepinephrine in approximately 80% of locus coeruleus (LC) neurons in the rat. The effects of chronic, naturalistic stress on preprogalanin mRNA in the LC was studied. The visible burrow system (VBS) served as the stress paradigm. Long-Evans rats (three males and two females) were housed together in the VBS for 13 days. The males established dominance hierarchies during this period. On day 14, preprogalanin mRNA in the LC was significantly elevated in subordinate rats compared to dominant and control rats, as measured by quantitative in situ hybridization. Levels of mRNA were positively correlated with the number of wounds by day 7 and day 14 and negatively correlated with body weight gain by day 14. These results suggest that the neuropeptide galanin may be overexpressed during chronic stress in rats.

Animals↗
PubMed1995

Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism.

Tay-Sachs and Sandhoff diseases are clinically similar neurodegenerative disorders. These two sphingolipidoses are characterized by a heritable absence of beta-hexosaminidase A resulting in defective GM2 ganglioside degradation. Through disruption of the Hexa and Hexb genes in embryonic stem cells, we have established mouse models corresponding to each disease. Unlike the two human disorders, the two mouse models show very different neurologic phenotypes. Although exhibiting biochemical and pathologic features of the disease, the Tay-Sachs model showed no neurological abnormalities. In contrast, the Sandhoff model was severely affected. The phenotypic difference between the two mouse models is the result of differences in the ganglioside degradation pathway between mice and humans.

Animals↗
PubMed1995

The CCK-B antagonist CI-988 increases dopamine levels in microdialysate from the rat nucleus accumbens via a tetrodotoxin- and calcium-independent mechanism.

CI-988, a water-soluble, selective cholecystokinin-B antagonist, was perfused through a microdialysis probe into the anterior nucleus accumbens, posterior nucleus accumbens, or caudate nucleus of anesthetized rats. High concentrations of CI-988 produced three- to fivefold increases in dopamine overflow, at all three sites, that were temporally correlated with the CI-988 perfusion and returned to baseline levels upon cessation of CI-988 perfusion. However, the cholecystokinin-A antagonist CAM-1481, and the relatively inactive enantiomer of CI-988, CAM-1241, also increased dopamine overflow in the nucleus accumbens. Furthermore, the ability of CI-988 to increase dopamine overflow persisted in the absence of calcium in the perfusate and was not sensitive to tetrodotoxin treatment. The mechanism by which locally administered CI-988 increases dopamine overflow appears not to be anatomically specific, not selective for one cholecystokinin receptor subtype, and may be nonvesicular.

Animals↗
PubMed1995

Galanin and the galanin antagonist M40 do not change fat intake in a fat-chow choice paradigm in rats.

The neuropeptide galanin has been proposed to play a role in the regulation of fat intake. The purpose of the present investigation was to determine if galanin and the galanin receptor antagonist M40 would have selective effects on fat intake in a fat-chow choice paradigm in rats. Rats were adapted to 22-h access to chow alone and 2-h daily access to separate sources of fat and chow in the early dark cycle. Galanin (300 pmol, 1 nmol) or M40 (2-500 pmol) was microinjected bilaterally into the paraventricular nucleus of the hypothalamus (PVN) before the 2-h choice period, and chow and fat intake were measured. M40 had no effect on chow or fat intake. Galanin stimulated chow intake and increased the ratio of chow to fat consumed but had no significant effect on fat intake alone. These results suggest that endogenous galanin in the PVN may not play a primary role in the regulation of fat intake when fat is available in addition to a nutritionally balanced diet.

Analysis of Variance↗