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Andrew Holmes

Publications and source records attributed to Andrew Holmes.

47 records · Page 3Linked to original sources
PubMed2003

Galanin GAL-R1 receptor null mutant mice display increased anxiety-like behavior specific to the elevated plus-maze.

The neuropeptide galanin coexists with norepinephrine and serotonin in neural systems mediating emotion. Previous findings suggested that galanin modulates anxiety-related behaviors in rodents. Three galanin receptor subtypes have been cloned; however, understanding their functions has been limited by the lack of galanin receptor subtype-selective ligands. To study the role of the galanin GAL-R1 receptor subtype in mediating anxiety-related behavior, we generated mice with a null mutation in the Galr1 gene. GAL-R1 -/- are viable and show no abnormalities in health, neurological reflexes, motoric functions, or sensory abilities. On a battery of tests for anxiety-like behavior, GAL-R1 -/- showed increased anxiety-like behavior on the elevated plus-maze test. Anxiety-related behaviors on the light/dark exploration, emergence, and open field tests were normal in GAL-R1 -/-. This test-specific anxiety-like phenotype was confirmed in a second, independent cohort of GAL-R1 null mutant mice and +/+ controls. Principal components factor analysis of behavioral scores from 279 mice suggested that anxiety-like behavior on the elevated plus-maze was qualitatively distinct from behavior on other tests in the battery. In addition, exposure to the elevated plus-maze produced a significantly greater neuroendocrine response than exposure to the light/dark exploration test, as analyzed in normal C57BL/6J mice. These behavioral findings in the first galanin receptor null mutant mouse are consistent with the hypothesis that galanin exerts anxiolytic actions via the GAL-R1 receptor under conditions of relatively high stress.

Animals↗
PubMed2003

Prior exposure to the elevated plus-maze sensitizes mice to the acute behavioral effects of fluoxetine and phenelzine.

A single undrugged experience of the elevated plus-maze modifies future drug responses in the test. The present study investigated the effects of maze-experience on the acute behavioral effects of the monoamine oxidase inhibitor phenelzine and the serotonin reuptake inhibitor fluoxetine. Phenelzine (2.5-12.5 mg/kg) had no clear effect on plus-maze behavior in test-naive Swiss Webster mice, but dose-dependently increased anxiety-like behavior in maze-experienced subjects. Similarly, fluoxetine (5-20 mg/kg) produced non-significant trends for increased anxiety-like behavior in maze-naive mice, but significantly and dose-dependently increased anxiety-like behavior and suppressed locomotor activity in maze-experienced mice. The anxiogenic effects of the benzodiazepine receptor inverse agonist N-methyl-beta-carboline-3-carboxamide (FG 7142) (20 mg/kg) was abolished by prior test experience, suggesting an alteration in gamma-aminobutyric acid (GABA)/benzodiazepine receptor function with maze-experience. However, the benzodiazepine receptor antagonist flumazenil (5-20 mg/kg) produced a silent profile regardless of maze-experience. Present findings provide further evidence demonstrating that prior test history is a critical consideration in mouse studies of anxiety-related behavior.

Animals↗
PubMed2003

Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders.

The health burden of stress-related diseases, including depression and anxiety disorders, is rapidly increasing, whereas the range of available pharmacotherapies to treat these disorders is limited and suboptimal with regard to efficacy and tolerability. Recent findings support a major role for neuropeptides in mediating the response to stress and thereby identify neuropeptide systems as potential novel therapeutic targets for the treatment of depression and anxiety disorders. In preclinical models, pharmacological and/or genetic manipulation of substance P, corticotropin-releasing factor (CRF), vasopressin, neuropeptide Y and galanin function alters anxiety- and depression-related responses. Recently, specific and highly potent small-molecule neuropeptide receptor agonists and antagonists have been developed that can readily cross the blood-brain barrier. Clinical assessment of several compounds is currently underway, with antidepressant efficacy confirmed in double-blind, placebo-controlled trials of tachykinin NK(1) (substance P) receptor antagonists, and preliminary evidence of antidepressant activity in an open-label trial of a CRF(1) receptor antagonist.

Animals↗
PubMed2003

Mice lacking the serotonin transporter exhibit 5-HT(1A) receptor-mediated abnormalities in tests for anxiety-like behavior.

The serotonin transporter (5-HTT) regulates serotonergic neurotransmission via clearance of extracellular serotonin. Abnormalities in 5-HTT expression or function are found in mood and anxiety disorders, and the 5-HTT is a major target for antidepressants and anxiolytics. The 5-HTT is further implicated in the pathophysiology of these disorders by evidence that genetic variation in the promoter region of the HTT (SLC6A4) is associated with individual differences in anxiety and neural responses to fear. To further evaluate the role of the 5-HTT in anxiety, we employed a mouse model in which the 5-HTT gene (htt) was constitutively inactivated. 5-HTT -/- mice were characterized for anxiety-related behaviors using a battery of tests (elevated plus maze, light<-->dark exploration test, emergence test, and open field test). Male and female 5-HTT -/- mice showed robust phenotypic abnormalities as compared to +/+ littermates, suggestive of increased anxiety-like behavior and inhibited exploratory locomotion. The selective 5-HT(1A) receptor antagonist, WAY 100635 (0.05-0.3 mg/kg), produced a significant anxiolytic-like effect in the elevated plus maze in 5-HTT -/- mice, but not +/+ controls. The present findings demonstrate abnormal behavioral phenotypes in 5-HTT null mutant mice in tests for anxiety-like and exploratory behavior, and suggest a role for the 5-HT(1A) receptor in mediating these abnormalities. 5-HTT null mutant mice provide a model to investigate the role of the 5-HTT in mood and anxiety disorders.

Animals↗
PubMed2002

The role of inositol 1,4,5-trisphosphate receptors in Ca(2+) signalling and the generation of arrhythmias in rat atrial myocytes.

Various cardio-active stimuli, including endothelin-1 (ET-1), exhibit potent arrhythmogenicity, but the underlying cellular mechanisms of their actions are largely unclear. We used isolated rat atrial myocytes and related changes in their subcellular Ca(2+) signalling to the ability of various stimuli to induce diastolic, premature extra Ca(2+) transients (ECTs). For this, we recorded global and spatially resolved Ca(2+) signals in indo-1- and fluo-4-loaded atrial myocytes during electrical pacing. ET-1 exhibited a higher arrhythmogenicity (arrhythmogenic index; ratio of number of ECTs over fold-increase in Ca(2+) response, 8.60; n = 8 cells) when compared with concentrations of cardiac glycosides (arrhythmogenic index, 4.10; n = 8 cells) or the beta-adrenergic agonist isoproterenol (arrhythmogenic index, 0.11; n = 6 cells) that gave similar increases in the global Ca(2+) responses. Seventy-five percent of the ET-1-induced arrhythmogenic Ca(2+) transients were accompanied by premature action potentials, while for digoxin this proportion was 25 %. The beta-adrenergic agonist failed to elicit a significant number of ECTs. Direct activation of inositol 1,4,5-trisphosphate (InsP(3)) receptors with a membrane-permeable InsP(3) ester (InsP(3) BM) mimicked the effect of ET-1 (arrhythmogenic index, 14.70; n = 6 cells). Inhibition of InsP(3) receptors using 2 microM 2-aminoethoxydiphenyl borate, which did not display any effects on Ca(2+) signalling under control conditions, specifically suppressed the arrhythmogenic action of ET-1 and InsP(3) BM. Immunocytochemistry indicated a co-localisation of peripheral, junctional ryanodine receptors with InsP(3)Rs. Thus, the pronounced arrhythmogenic potency of ET-1 is due to the spatially specific recruitment of Ca(2+) sparks by subsarcolemmal InsP(3)Rs. Summation of such sparks efficiently generates delayed after depolarisations that trigger premature action potentials. We conclude that the particular spatial profile of cellular Ca(2+) signals is a major, previously unrecognised, determinant for arrhythmogenic potency and that the InsP(3) signalling cassette might therefore be a promising new target for understanding and managing atrial arrhythmia.

Action Potentials↗
PubMed2002

Reduced aggression in mice lacking the serotonin transporter.

RATIONALE: Dysregulation of the brain serotonergic system has been implicated in the pathophysiology of violence and aggression. As a key regulator of central serotonergic activity, dysfunction of the serotonin transporter (5-HTT) represents a potential mechanism mediating pathological aggression. OBJECTIVES: To assess aggressive behavior in 5-HTT knockout (KO) mice. To examine home cage activity and 5-HT(1A/1B) receptor function in 5-HTT KO mice as factors contributing to an aggressive phenotype. METHODS: Isolated male 5-HTT KO mice were compared to +/+ control mice using the resident-intruder test for aggression over two encounters. Locomotor activity was measured in the home cage over a 24-h period. 5-HT(1A/1B) receptor function was assessed via the pharmacological effects of the 5-HT(1A/1B) receptor agonist, RU24969, on locomotion. RESULTS: 5-HTT -/- mice were slower to attack the intruder and attacked with less frequency than +/+ littermates, but showed equivalent social investigation. 5-HTT +/- mice were as quick to attack, but made fewer overall attacks, as compared to +/+ controls. Aggression increased with repeated exposure to an intruder in 5-HTT +/- and +/+ mice, but not in 5-HTT -/- mice. 5-HTT -/- mice showed a normal circadian pattern of home cage activity, but less activity overall, as compared to 5-HTT +/- and +/+ mice. RU24969 (5 mg/kg) produced hyperlocomotor effects in 5-HT +/- and +/+, but not 5-HTT -/- mice. CONCLUSIONS: Deletion of the 5-HTT gene produces a reduction in aggressive behavior and home cage activity. Desensitization of 5-HT(1A/1B) receptor function may contribute to reduced aggression in 5-HTT KO mice.

Aggression↗
PubMed2002

Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter.

Inhibition of the serotonin transporter (5-HTT) is a principal initial target of many antidepressants. However, the contribution of the 5-HTT to their therapeutic efficacy is incompletely understood. We utilized a targeted gene mutation approach to examine the role of the 5-HTT in the behavioral actions of antidepressants. The 5-HTT mutation was bred onto two separate genetic backgrounds, C57BL/6J and 129S6. On a preliminary screen for gross physical, neurological and behavioral functions, all measures were normal with the exception that 5-HTT -/- mice on the C57BL/6J background showed increased body weight and poor rotarod performance, and 5-HTT -/- mice on the 129S6 background showed reduced neuromuscular strength. On the tail suspension test, 5-HTT -/- mice on the 129S6 background showed a baseline antidepressant-like reduction in immobility. In contrast, the same mice showed increased immobility in the forced swim test, possibly due to compromised neuromuscular strength. 5-HTT -/- mice on the C57BL/6J background showed no baseline antidepressant-related phenotype on either test. The behavioral effects of three antidepressants were tested in 5-HTT mutant mice (C57BL/6J background) in the tail suspension test. The anti-immobility effects of the serotonin reuptake inhibitor, fluoxetine (30 mg/kg), were abolished in 5-HTT -/- mice, confirming that the 5-HTT gene is required for the behavioral effects of fluoxetine. In contrast, 5-HTT-/- mice retained sensitivity to the anti-immobility effects of the norepinephrine reuptake inhibitor, desipramine (20 mg/kg), and the mixed serotonin/norepinephrine reuptake inhibitor, imipramine (25 mg/kg). 5-HTT knockout mice provide a valuable tool for delineating the neuropsychopharmacological actions of antidepressants.

Animals↗
PubMed2002

Platelets and cardiovascular disease.

Platelets play an important, but often under-recognized role in cardiovascular disease. For example, the normal response of the platelet can be altered, either by increased pro-aggregatory stimuli or by diminished anti-aggregatory substances to produce conditions of increased platelet activation/aggregation and occur in active cardiovascular disease states both on a chronic (e.g. stable angina pectoris) and acute basis (e.g. acute myocardial infarction). In addition, platelet hyperaggregability is also associated with the risk factors for coronary artery disease (e.g. smoking, hypertension, and hypercholesterolaemia). Finally, the utility of an increasing range of anti-platelet therapies in the management of the above disease states further emphasizes the pivotal role platelets play in the pathogenesis of cardiovascular disease. This paper provides a comprehensive overview of the normal physiologic role of platelets in maintain homeostasis, the pathophysiologic processes that contribute to platelet dysfunction in cardiovascular disease and the associated role and benefits of anti-platelet therapies.

Blood Platelets↗
PubMedDate not supplied

Deficits in trace cued fear conditioning in galanin-treated rats and galanin-overexpressing transgenic mice.

Galanin inhibits the release of several neurotransmitters and produces performance deficits in a variety of spatial and aversive learning and memory tasks. The experiments in this study investigated the role galanin has in emotional learning and memory using a standard delay cued and contextual fear conditioning task. Rats were administered galanin into the lateral ventricles before training, and scored for freezing behavior in the same context and in a novel context with and without an auditory cue (CS) that had been paired previously with an aversive stimulus (US). Galanin-overexpressing transgenic mice were tested in an identical behavioral protocol. The galanin-administered rats and the transgenic mice were not significantly different from their respective controls on this task. A more challenging trace cued and contextual fear conditioning procedure was administered to separate groups of galanin-treated rats and galanin-overexpressing transgenic mice. Subjects were trained with the same CS and US, however, a 2.5-sec delay was inserted between CS offset and US onset. Following the trace conditioning, rats administered galanin and mice overexpressing galanin both exhibited significantly less freezing to the CS in the novel context as compared with their control groups. These results indicate that the observed disruption of cued fear conditioning was specific to the more difficult trace conditioning task. These findings are the first demonstration that galanin impairs performance on an emotional memory task and support the hypothesis that galanin-induced deficits are specific to more difficult cognitive tasks.

Acoustic Stimulation↗
PubMedDate not supplied

Evaluation of an anxiety-related phenotype in galanin overexpressing transgenic mice.

Understanding the role of neuropeptides in mediating emotional behaviors is an important avenue for discovering novel drug targets for anxiety disorders. A role for galanin in mediating anxiety-related behavior is suggested by the pattern of distribution in the CNS and the coexistence of galanin with norepinephrine in the locus coeruleus. Studies in rats have shown that central administration of galanin modulates anxiety-related behaviors, and galanin release blocks the proanxiety effects of noradrenergic activation in prestressed rats. To further investigate the role of galanin in anxiety behaviors, we conducted a comprehensive behavioral phenotyping of galanin overexpressing transgenic mice (GAL-tg). GAL-tg mice were normal on measures of general health, neurological reflexes, home cage social behaviors, sensory functions, motor coordination, and exploratory locomotor activity. In three separate tests for anxiety-related behaviors, the elevated plus-maze, light <--> dark exploration, and open field center time, GAL-tg mice showed no anxiety-like phenotype. GAL-tg mice and wild-type littermate controls were equally responsive to the anxiolytic effects of chlordiazepoxide (10 mg/kg) in the light <--> dark exploration test, indicating normal benzodiazepine receptor function in GAL-tg mice. Stimulation of noradrenergic cells via administration with an alpha2 adrenoreceptor antagonist, yohimbine (2.5 mg/kg), produced proanxiety effects in wild type mice in the light <--> dark exploration test, but not in the GAL-tg mice. These data suggest that galanin contributes to the modulation of anxiety states induced by high levels of noradrenergic activation, but is silent under less challenging situations. A specific role for galanin in extreme anxiety states represents an attractive target for the development of novel anxiolytic treatments.

Adrenergic alpha-Antagonists↗