Biomedical subjects

C A Murphy

Publications and source records attributed to C A Murphy.

At least 19 recordsLinked to original sources

PubMed2001

Effects of psychostimulant withdrawal on latent inhibition of conditioned active avoidance and prepulse inhibition of the acoustic startle response.

RATIONALE: Chronic intermittent administration of amphetamine and cocaine can precipitate psychotic episodes in humans and produce persistent behavioral changes (i.e. increased locomotion, stereotypy) in the rat. The psychostimulant sensitization model of psychosis holds that the repeated administration of drugs such as amphetamine and cocaine induces long-lasting neuroadaptations and behavioral outcomes in animals that parallel aspects of the schizophrenic condition. OBJECTIVES: In the present study, we attempted to validate this model further by examining the effects of short-term withdrawal from repeated administration of cocaine and amphetamine on performance in two animal behavioral models of cognitive deficits found in schizophrenia: latent inhibition and prepulse inhibition. Reductions in both of these behavioral phenomena have been reported in schizophrenic patients and in acutely amphetamine-treated rats. METHODS: Animals were tested after 4 days of withdrawal from 5 days of daily systemic 20 mg/kg cocaine or 1.5 mg/kg amphetamine injections for either latent inhibition of two-way active avoidance acquisition or prepulse inhibition of an acoustic startle response. RESULTS: Our results indicate that, rather than reducing the expression of these behaviors, withdrawal from either cocaine or amphetamine enhanced the expression of latent inhibition of the active avoidance response while having no effect on prepulse inhibition of acoustic startle. CONCLUSIONS: These data indicate that although the sensitized response to amphetamine and cocaine administration may model some aspects of schizophrenic psychosis, behaviors exhibited by sensitized animals in the absence of an acute drug challenge are not consistent with models of the positive symptoms of schizophrenia.

Acoustic Stimulation↗

PubMed2001

Interactions between environmental stimulation and antipsychotic drug effects on forebrain c-fos activation.

The immediate-early gene product Fos is differentially induced in the rat brain by the antipsychotic drugs haloperidol and clozapine. It is often claimed that although both drugs induce Fos in the nucleus accumbens, haloperidol but not clozapine increases Fos-like immunoreactivity in the striatum, whereas clozapine but not haloperidol increases Fos-like immunoreactivity in prefrontal cortex. Investigations of antipsychotic drug effects on Fos have typically administered high doses with pronounced sedative effects to behaviorally naive animals. In the present study, we compared the effects of low doses of haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) on Fos-like immunoreactivity in rats which were either behaviorally naive, exposed to a novel environment or tested for two-way active avoidance. We determined that haloperidol increased Fos in the striatum and nucleus accumbens regardless of testing condition whereas clozapine markedly reduced the induction of Fos by behavioral testing in these regions; moreover, haloperidol dramatically increased prefrontal cortical Fos expression in animals placed in a novel environment, but not in testing-naive controls. From these results we suggest that antipsychotic drug-induced patterns of Fos expression in the rat are highly dependent on animals' concurrent behavioral status, perhaps reflecting neuroanatomically specific interactions between antipsychotic drugs and environmental stressors which also may occur in the schizophrenic condition.

Animals↗

PubMed2001

Selective responding of nucleus accumbens core and shell dopamine to aversively conditioned contextual and discrete stimuli.

Dopamine transmission within the nucleus accumbens has been implicated as a neurochemical substrate of associative learning processes. It has been suggested that the acquisition of classically conditioned fear to a specific environment, or context, differs fundamentally from the development of conditioned fear to a discrete stimulus, such as a light or a tone. In this study, we assessed extracellular dopamine in the rat nucleus accumbens shell and core during the expression of a conditioned fear response. Animals were aversively conditioned to either a context or a tone and extracellular dopamine was measured in the nucleus accumbens shell and core by in vivo microdialysis over the next 2 days as animals were returned first to the conditioning chamber (day 1: context test), and subsequently as animals were again returned to the chamber and presented with the conditioned tone stimulus (day 2: tone test). Dopamine levels in the core were significantly higher in the Context-Shock group compared to the Tone-Shock group during the 30-min exposure to context while dopamine levels in the nucleus accumbens shell did not differ significantly during the context test between groups. In contrast, extracellular dopamine in the shell but not the core of Tone-Shock animals increased significantly during presentation of the tone. Dopamine in both the shell and core remained unchanged during the tone test in the Context-Shock groups.These data suggest distinct roles for shell and core dopamine transmission in the expression of a conditioned emotional response. While dopamine increased in the shell primarily during the presentation of a discrete tone conditioned stimulus, core dopamine responded more to a contextual conditioned stimulus. These results may reflect differences in either the type of information acquired or the salience of the learned associations which are formed to a context vs. a discrete tone cue.

Acoustic Stimulation↗

PubMed2001

Putative steroidal pheromones in the round goby, Neogobius melanostomus: olfactory and behavioral responses.

To identify potential hormonal pheromones of the round goby (Neogobius melanostomus), a species recently introduced to the Great Lakes, we used electro-olfactogram (EOG) recording to examine olfactory responsiveness to more than 100 steroids and prostaglandins. Neogobius detected free and conjugated 18-, 19- and 21-carbon steroids, but did not detect prostaglandins. EOG cross-adaptation, used to determine if Neogobius can discriminate the detected compounds at the sensory level, suggested that the detected steroids act on four classes of olfactory receptor mechanisms named (according to the most potent ligand for each): estrone, 17 beta-estradiol-3 beta-glucuronide, etiocholanolone, and dehydroepiandrosterone-3-sulfate. Although none of the detected steroids induced reproductive behaviors, exposure to steroids from three of the four receptor classes (estrone, 17 beta-estradiol-3 beta-glucuronide, or etiocholanolone) increased ventilation rate in males, whereas only etiocholanolone increased ventilation rate in females. Using the ventilation increase as a behavioral bioassay of steroid detection, behavioral cross-adaptation studies in males demonstrated that steroids discriminated at the sensory level are also discriminated behaviorally. These findings suggest the round goby may use steroids as putative pheromones.

Animals↗

PubMed2001

Latent inhibition, but not prepulse inhibition, is reduced during withdrawal from an escalating dosage schedule of amphetamine.

The enhanced locomotor and stereotypic responses of the rat to repeated amphetamine (AMPH) administration are considered to be an animal model of positive schizophrenic symptoms. In contrast, behaviors observed during withdrawal from repeated AMPH are believed to model depression or anxiety. In the present study, the authors tested whether AMPH withdrawal might also elicit behaviors consistent with animal models of schizophrenia, specifically, disruptions in latent inhibition (LI) of 2-way active avoidance and prepulse inhibition (PPI) of startle. Rats treated with escalating doses of AMPH (6 days, 1-5 mg/kg ip) or saline were tested for LI and PPI during withdrawal. LI was eliminated by prior AMPH treatment in rats tested at 4, 13, and 28 days of withdrawal. In contrast, PPI did not differ between AMPH and control groups. These results support an interrelationship between repeated-AMPH and LI-disruption, but not PPI-disruption, models of schizophrenia.

Amphetamine↗

PubMed2001

Acute withdrawal from repeated cocaine treatment enhances latent inhibition of a conditioned fear response.

Psychostimulant-induced locomotor sensitization and disrupted latent inhibition (LI) of a classically conditioned association are two paradigms that have been widely studied as animal behavioural models of psychosis. In this study we assessed the effects of withdrawal from the repeated intermittent administration of cocaine on LI of a conditioned fear response. Animals which were either preexposed (PE) to a tone conditioned stimulus (CS) or naive to the tone (i.e. non-preexposed: NPE) subsequently experienced 10 pairings of the tone CS with footshock. Afterwards, both groups received five daily injections of cocaine (20 mg/kg, i.p.) or saline. After 3 days of withdrawal from drug treatment, animals were tested for conditioned freezing to the context of the footshock chamber, and 1 day later, for conditioned freezing to the tone CS. Cocaine-sensitized animals exhibited markedly enhanced LI compared to saline-treated animals, due to the fact that NPE-cocaine animals spent more time freezing during the tone CS than NPE-saline animals, whereas PE-cocaine animals showed a tendency toward reduced freezing compared to the saline groups. While these results suggest the presence of increased anxiety in cocaine-withdrawn NPE animals, the absence of this effect in cocaine-withdrawn PE rats indicates that cocaine withdrawal also influences the retrieval of previously learned information.

Acoustic Stimulation↗

PubMed2001

Development of Onchocerca volvulus (Filarioidea: Onchocercidae) in the West African black fly Simulium yahense (Diptera: Simuliidae) in Liberia.

Simulium yahense black flies infected with microfilaria of Onchocerca volvulus were kept in a defined insectary environment in Liberia, West Africa. A daily sample of infected flies was dissected for larvae developing in the thoracic muscles and examined for growth in stadial development. Microfilariae ingested by black flies transformed to the L1 larval stage without molting. Successive larval development included molting to the L2 stage and, finally, to the L3 stage, which was infective in humans. The cephalic cap, consisting of a laterally located hook and central stoma, occurs in the first larval stage. The caudal appendix and the laterally located anal opening are apparent in the L1 larva. In the L2 stage, the cephalic cap is lost and the large circular stoma becomes surrounded with elevated flaps. The caudal appendix was lost after larvae molted to the L3 stage, and in its place, 3 terminal papillae developed. Sense organs, such as 2 opposing phasmids and 8 papillae that were arranged into 2 circles, developed in the cephalic region of the L3 larva. The evidence of pathological consequences due to the presence of the L3 larva in the fly host are illustrated and discussed.

Animals↗

PubMed2000

Down-regulation of the macrophage lineage through interaction with OX2 (CD200).

OX2 (CD200) is a broadly expressed membrane glycoprotein, shown here to be important for regulation of the macrophage lineage. In mice lacking CD200, macrophage lineage cells, including brain microglia, exhibited an activated phenotype and were more numerous. Upon facial nerve transection, damaged CD200-deficient neurons elicited an accelerated microglial response. Lack of CD200 resulted in a more rapid onset of experimental autoimmune encephalomyelitis (EAE). Outside the brain, disruption of CD200-CD200 receptor interaction precipitated susceptibility to collagen-induced arthritis (CIA) in mice normally resistant to this disease. Thus, in diverse tissues OX2 delivers an inhibitory signal for the macrophage lineage.

Animals↗

PubMed2000

Protistan parasite QPX of hard-shell clam Mercenaria mercenaria is a member of Labyrinthulomycota.

Biomass of the protistan parasite QPX (quahaug parasite X) of hard-shell clam Mercenaria mercenaria was enriched from in vitro culture. The nuclear gene encoding the 18S RNA of the small-subunit ribosomal (ssu-rDNA) was recovered using the polymerase chain reaction (PCR) and sequenced. Phylogenetic analysis clearly showed that QPX is a member of phylum Labyrinthulomycota, within which it appears as a specific relative of Thraustochytrium pachydermum. These results confirm the provisional assignment of QPX to the Labyrinthulomycota made previously on the basis of morphological and ultrastructural characters found in some, but not all, geographic isolates.

Animals↗

PubMed2000

Ichthyophonus irregularis sp. nov. from the yellowtail flounder Limanda ferruginea from the Nova Scotia shelf.

A previously described unusual form of the protistan parasite Ichthyophonus, differing in morphological and developmental features from I. hoferi sensu Plehn & Mulsow, was recovered from yellowtail flounder Limanda ferruginea Storer from the Brown's Bank area of the Nova Scotia shelf. The nuclear gene encoding the rRNA of the small ribosomal subunit was amplified from this unusual form of Ichthyophonus using the polymerase chain reaction, sequenced and aligned with other eukaryote small subunit (ssu)-rDNAs. Inferred phylogenetic trees clearly show that its ssu-rDNA is distinct from those of 2 isolates of I. hoferi sensu Plehn & Mulsow from different hosts and geographical locations (herring in the North Sea, and yellowtail flounder from the Nova Scotia shelf). We consider the unusual form to be a separate species, I. irregularis. The occurrence of a second, distinct type of Ichthyophonus within a single host species raises the possibility that ichthyophoniasis could be produced by different (although related) pathogens, and in some cases, by concurrent infections of the two.

Animals↗

PubMed2000

Differential involvement of dopamine in the shell and core of the nucleus accumbens in the expression of latent inhibition to an aversively conditioned stimulus.

Latent inhibition, the process whereby pre-exposure to a conditioned stimulus without consequence impairs subsequent learning of an association between the conditioned stimulus and an unconditioned stimulus, is reportedly disrupted in both amphetamine-treated rats and in acute schizophrenics. This has led to the suggestion that disruptions in latent inhibition model some of the cognitive impairments associated with hyperactive dopamine transmission as it is expressed in schizophrenic patients. Specifically, fluctuations in dopamine neurotransmission within the nucleus accumbens have been implicated in the mediation of latent inhibition; however, it has not been established whether these dopamine-mediated effects occur in the shell or core subregion of the nucleus. In the present study, 48h after conditioned stimulus-pre-exposed and non-pre-exposed animals experienced 10 pairings of tone and footshock, we measured extracellular levels of dopamine in the shell and core during the expression of latent inhibition to an aversively conditioned tone using in vivo microdialysis. Our results show that pre-exposure to the tone eliminated the conditioned release of dopamine in the shell of the nucleus accumbens and resulted in an attenuated conditioned freezing response to the tone conditioned stimulus. In contrast, dopamine release in the core was not affected by pre-exposure to the tone. These data suggest that it is specifically the shell of the nucleus accumbens in which alterations of dopaminergic tone, whether pharmacologically induced in rodents or the result of disease in humans, may act to disrupt latent inhibition.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Low-dose clozapine pretreatment partially prevents haloperidol-induced deficits in conditioned active avoidance.

The effectiveness of neuroleptics in disrupting conditioned active avoidance has led to the widespread use of this test as an index of antipsychotic efficacy, whereas the tendency for these drugs to induce catalepsy is believed to reflect their propensity to cause extrapyramidal motor side-effects. Although the typical neuroleptic haloperidol produces catalepsy as well as profound deficits in conditioned active avoidance, the atypical neuroleptic clozapine does not induce catalepsy and is less effective than haloperidol in disrupting active avoidance. Furthermore, clozapine pretreatment prevents haloperidol-induced catalepsy. We investigated whether clozapine pretreatment might also reduce the disruptive effects of haloperidol on two-way active avoidance. We assessed the avoidance acquisition of the following drug treatment groups in which all animals received two injections prior to testing: vehicle + vehicle, vehicle + haloperidol (0.1 mg/kg, i.p.), clozapine (2.5, 5.0 or 10 mg/kg, i.p.) + haloperidol (0.1 mg/kg, i.p.), or clozapine (2.5, 5.0 or 10 mg/kg, i.p.) + vehicle. Haloperidol-pretreated animals showed markedly impaired active avoidance, deficits which were improved by 2.5 and 5 mg/kg but not by 10 mg/kg clozapine pretreatment. These data suggest that the disruptive effects of haloperidol on conditioned active avoidance partially mirror its capacity to induce catalepsy and extrapyramidal motor symptoms. Furthermore, this study indicates that clozapine may be effective in reducing motor side-effects caused by typical neuroleptics.

Animals↗

PubMed1999

Prenatal cocaine produces signs of neurodegeneration in the lateral habenula.

The lateral habenula is a nucleus in the dorsal thalamus that innervates midbrain dopaminergic and serotonergic nuclei via projections through its major efferent pathway, the fasciculus retroflexus (FR). It was previously demonstrated that cocaine administered continuously to adult rats over several days produces neurodegeneration in the lateral habenula and FR. Because exposure to cocaine during pregnancy reportedly can cause neurobehavioral deficits, we examined whether rat fetuses exposed to continuous cocaine during the last week of gestation would similarly demonstrate selective neurodegeneration in the lateral habenula. On day 17 of gestation, dams were implanted with two silicone pellets, each containing either vehicle or one of 2 doses of cocaine (80 mg or 55 mg per pellet). Degenerating neurons containing silver deposits were counted in lateral habenula and in the striatum. Cocaine-exposed pups had significantly more silver-stained cells in the lateral habenula than vehicle-treated pups, but similar numbers of silver-stained cells were present in the striatum of all three groups. When similarly treated vehicle- and cocaine-exposed animals were tested behaviorally at 60 days of age, they did not differ on measures of open field activity, open arm avoidance on the elevated plus-maze or conditioned place preference for cocaine, although a linear trend analysis indicated some hyperactivity of the cocaine-pretreated pups during the place preference test. These results indicate that continuous cocaine exposure has selective neurotoxic effects on the habenula of the developing fetus similar to cocaine's effects in the adult.

Animals↗

PubMed1999

The prognosis of small primary breast cancers.

The Nottingham Prognostic Index (NPI) is an integrated prognostic index used to predict patient survival for women with invasive breast cancer. The index is based on invasive tumour size, histological lymph node stage and tumour grade. The value of such an index has been questioned in small invasive breast cancers and it has been suggested that size is the only necessary prognostic determinant. The aims of this study were to determine the extent of regional lymph node involvement and survival in women with small invasive breast cancers and to assess the value of the NPI. Between 1976 and 1994, 2684 women aged < or = 70 years were treated for primary operable invasive breast cancers of < or = 5 cm in maximum diameter, of which 318 measured < or = 1 cm. Follow-up data were evaluated to determine histological factors important in predicting survival outcomes in women with cancers < or = 1 cm in diameter and comparing their survival according to the NPI with all women treated for primary operable breast cancers < or = 5 cm in maximum diameter. Histological lymph node involvement was demonstrated in 56/318 (18%) of cancers of < or = 1 cm in diameter. Significant survival differences were demonstrated for small breast cancers according to lymph node stage, vascular invasion and histological tumour grade. Only lymph node stage and histological tumour grade were independent prognostic indicators using a multivariate Cox model. The survival curves for small tumours stratified by the NPI were similar to those of cancers up to 5 cm in diameter. The results indicate that lymph node staging and histological grading are still important prognostic determinants for breast cancers < or = 1 cm in diameter. An axillary node staging procedure should be performed for all invasive breast cancers < or = 1 cm in diameter. The NPI remains relevant for small breast cancers.

Adult↗

PubMed1999

Genomic rearrangements in the flagellin genes of Proteus mirabilis.

Molecular analyses have revealed that Proteus mirabilis possesses two genes, flaA and flaB, that are homologous to each other and to flagellin genes of many other species. Both swimmer and swarmer cells transcribe flaA, but not flaB. FlaA- mutants are non-motile and do not differentiate showing the essential role of flaA in swarmer cell differentiation and behaviour. At a low frequency, motile, differentiation-proficient revertants have been found in FlaA-populations. These revertants produce an antigenically and biochemically distinct flagellin protein. The revertant flagellin is the result of a genetic fusion between highly homologous regions of flaA and flaB that places the active flaA promoter and the 5' coding region of flaA adjacent to previously silent regions of flaB generating a hybrid flagellin protein. Analysis of the flaA-flaB region of two such revertants reveals that a portion of this locus has undergone a rearrangement and deletion event that is unique to each revertant. Using a polymerase chain reaction (PCR) to amplify the falA-flaB locus from wild-type swimmer cells, swarmer cells and cells obtained after urinary tract infection, we uncover at least six general classes of rearrangements between flaA and flaB. Each class of rearrangement occurs within one of nine domains of homology between flaA and flaB. Rearrangement of flaA and flaB results in a hybrid flagellin protein of nearly identical size and biochemical properties, suggesting a concerted mechanism may be involved in this process. The data also reveal that the frequency and distribution of flaAB rearrangements is predicted on environmental conditions. Thus, rearrangement between flaA and flaB may be a significant virulence component of P. mirabilis in urinary tract infections.

Amino Acid Sequence↗

PubMed1998

A computer controlled analysis of freezing behaviour.

The conditioned freezing response in rats has been much used both by psychologists and neuroscientists to investigate the behavioural effects of brain lesions and of changes in motivational state. The primary advantage of the freezing response is that it can be used without motivational manipulations such as food or water deprivation. Previously, freezing has been measured by a human observer either from video recordings or during the test sessions themselves. But these methods of data collection have potential disadvantages. In the present paper, we describe a new, computer controlled, automated procedure for assessing conditioned freezing. Each conditioning chamber contains a mini-video camera. Behaviour is analysed on-line by means of a programme which compares every two adjacent seconds of video tape to generate a screen representing the percentage difference between them. A difference of <0.05% (50 pixels) is classified as a freezing response. Experiments are described in which we measure conditioned freezing and its development over time, in response to contextual cues and to a discrete tone which had been paired with foot shock. We demonstrate our apparatus and methods of data analysis to be sensitive to: number of tone-shock pairings, rat strain and tone pre-exposure.

Animals↗

PubMed1998

Odorant-binding proteins of true bugs. Generic specificity, sexual dimorphism, and association with subsets of chemosensory sensilla.

Odorant-binding proteins (OBPs) in insects occur within olfactory sensilla, and are thought to transport chemical stimuli to receptors on dendrites of sensory neurons. Until recently, knowledge of OBPs in insects was limited to moths and Drosophila. We discovered an antennal-specific protein (Lygus [lineolaris] antennal protein, LAP) with a unique N-terminal sequence in the true bug, Lygus lineolaris. We localized LAP to antennae, determined its molecular weight (16 kDa), and showed that while it was expressed in nymphal antennae, its levels dramatically increased in adults concurrent with increases in numbers of olfactory sensilla and electrical responses to odors. In our current study, we used immunological techniques to demonstrate in more detail that LAP occurs only in antennae, and to show its expression within Lygus species. LAP was expressed more in male antennae than in antennae of females for the Lygus species examined. Anti-LAP did not recognize antennal proteins of two other genera of bugs. Immunocytological studies showed LAP primarily within the sensillar lymph of type 1 and type 4 sensilla on antennae. These observations strongly suggest LAP to be an OBP, and our discovery and characterization of OBPs in true bugs provides a third order for use in the study of evolution of OBPs in insects.

Animals↗

PubMed1998

Motoneuron apoptosis is blocked by CEP-1347 (KT 7515), a novel inhibitor of the JNK signaling pathway.

Neurons undergoing apoptosis can be rescued by trophic factors that simultaneously increase the activity of extracellular signal-regulated kinase (ERK) and decrease c-Jun N-terminal kinase (JNK) and p38. We identified a molecule, CEP-1347 (KT7515), that rescues motoneurons undergoing apoptosis and investigated its effect on ERK1 and JNK1 activity. Cultured rat embryonic motoneurons, in the absence of trophic factor, began to die 24-48 hr after plating. During the first 24 hr ERK1 activity was unchanged, whereas JNK1 activity increased fourfold. CEP-1347 completely rescued motoneurons for at least 72 hr with an EC50 of 20 +/- 2 nM. CEP-1347 did not alter ERK1 activity but rapidly inhibited JNK1 activation. The IC50 of CEP-1347 for JNK1 activation was the same as the EC50 for motoneuron survival. Inhibition of JNK1 activation by CEP-1347 was not selective to motoneurons. CEP-1347 also inhibited JNK1 activity in Cos7 cells under conditions of ultraviolet irradiation, osmotic shock, and inhibition of glycosylation. Inhibition by CEP-1347 of the JNK1 signaling pathway appeared to be selective, because CEP-1347 did not inhibit p38-regulated mitogen-activated protein kinase-activated protein kinase-2 (MAPKAP2) activity in Cos7 cells subjected to osmotic shock. The direct molecular target of CEP-1347 was not JNK1, because CEP-1347 did not inhibit JNK1 activity in Cos7 cells cotransfected with MEKK1 and JNK1 cDNA constructs. This is the first demonstration of a small organic molecule that promotes motoneuron survival and that simultaneously inhibits the JNK1 signaling cascade.

Animals↗