Biomedical subjects

Richard J Davis

Publications and source records attributed to Richard J Davis.

17 recordsLinked to original sources

PubMed2006

Exposure to predator odor stress increases efflux of frontal cortex acetylcholine and monoamines in mice: comparisons with immobilization stress and reversal by chlordiazepoxide.

Psychogenic stress may be associated with the development of mood disorders and schizophrenia. The frontal cortex (FC) regulates stress responses, and its dysfunction contributes to certain neuropsychiatric disorders. We tested the effects of exposure to predator odor stress (POS), a psychogenic stressor, on the concurrent efflux of four major neurotransmitters within the FC in mice in comparison to immobilization stress (IMS), a physical/systemic stressor. POS and IMS significantly increased efflux of acetylcholine (ACh), serotonin (5-HT) and dopamine (DA), but not norephinephrine, within the FC. POS produced a somewhat longer-lasting efflux of 5-HT, as compared to IMS. The effects of POS and IMS on ACh, 5-HT and DA were blocked by chlordiazepoxide. Overall, we demonstrate a novel method to measure the effects of distinctly different stress modalities on FC neurotransmission and suggest that FC responsivity to stressors may be an important marker for evaluating anxiolytic drugs.

Acetylcholine↗

PubMed2006

CB1 receptor antagonism increases hippocampal acetylcholine release: site and mechanism of action.

Evidence indicates that blockade of cannabinoid receptors increases acetylcholine (ACh) release in brain cortical regions. Although it is assumed that this type of effect is mediated through CB1 receptor (CB1R) antagonism, several in vitro functional studies recently have suggested non-CB1R involvement. In addition, neither the precise neuroanatomical site nor the exact mechanisms underlying this effect are known. We thoroughly examined these issues using a combination of systemic and local administration of CB1R antagonists, different methods of in vivo microdialysis, CB1R knockout (KO) mice, tissue measurements of ACh, and immunochemistry. First, we showed that systemic injections of the CB1R antagonists N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR-141716A) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) dose-dependently increased hippocampal ACh efflux. Likewise, local hippocampal, but not septal, infusions of SR141716A or AM251 increased hippocampal ACh release. It is noteworthy that the stimulatory effects of systemically administered CB1R antagonists on hippocampal ACh release were completely abolished in CB1R KO mice. CB1R KO mice had similar basal but higher stress-enhanced hippocampal ACh levels compared with wild-type controls. It is interesting that dopamine D1 receptor antagonism counteracted the stimulatory effect of CB1R blockade on hippocampal ACh levels. Finally, immunohistochemical methods revealed that a high proportion of CB1R-positive nerve terminals were found in hippocampus and confirmed the colocalization of CB1 receptors with cholinergic and dopaminergic nerve terminals. In conclusion, hippocampal ACh release may specifically be controlled through CB1Rs located on both cholinergic and dopaminergic neuronal projections, and CB1R antagonism increases hippocampal ACh release, probably through both a direct disinhibition of ACh release and an indirect increase in dopaminergic neurotransmission at the D1 receptors.

Acetylcholine↗

PubMed2006

Carotid sinus hypersensitivity in asymptomatic older persons: implications for diagnosis of syncope and falls.

BACKGROUND: Carotid sinus hypersensitivity is the most commonly reported cause of falls and syncope in older persons. Recent guidelines recommend 5 to 10 seconds of carotid sinus massage in supine and upright positions with beat-to-beat monitoring. The aim of this study was to determine the prevalence of carotid sinus hypersensitivity in (1) an unselected community sample of older people and (2) a subsample with no history of syncope, dizziness, or falls using recently standardized diagnostic criteria. METHODS: One thousand individuals older than 65 years were randomly sampled from a single general practice register; 272 participants underwent supine and upright carotid sinus massage with continuous heart rate and phasic blood pressure monitoring. Carotid sinus hypersensitivity was defined as asystole of 3 seconds or greater and/or a drop in systolic blood pressure of 50 mm Hg or greater. RESULTS: Carotid sinus hypersensitivity was present in 107 individuals (39%); 24% had asystole of 3 seconds or greater during carotid sinus massage; and 16% had symptoms (including syncope) with carotid sinus hypersensitivity. Age (odds ratio, 1.05; 95% confidence interval, 1.00-1.09) and male sex (odds ratio, 1.71; 95% confidence intervals, 1.04-2.82) were the only predictors of carotid sinus hypersensitivity. In 80 previously asymptomatic individuals, carotid sinus hypersensitivity was present in 28 (35%) and accompanied by symptoms in 10. The 95th percentile for carotid sinus massage response was 7.3 seconds' asystole and a 77-mm Hg drop in systolic blood pressure. CONCLUSIONS: Carotid sinus hypersensitivity is common in older persons, even those with no history of syncope, dizziness, or falls. The finding of a hypersensitive response should not necessarily preclude further investigation for other causes of syncope.

Accidental Falls↗

PubMed2006

Mouse Dach2 mutants do not exhibit gross defects in eye development or brain function.

Drosophila dachshund is a critical regulator of eye, brain, and limb formation. Vertebrate homologs, Dach1 and Dach2, are expressed in the developing retina, brain, and limbs, suggesting functional conservation of the dachshund/Dach gene family. Dach1 mutants die postnatally, but exhibit grossly normal development. Here we report the generation of Dach2 mutant mice. Although deletion of Dach2 exon 1 results in abrogation of RNA expression, Dach2 mutants are viable and fertile. Histochemical analysis reveals grossly normal Dach2 mutant eye development. In addition, a battery of neurological assays failed to yield significant differences in behavior between Dach2 mutants and controls. We discuss these findings in the light of published observations of DACH2 mutations in the human population. Finally, to test the functional conservation hypothesis, we generated Dach2; Dach1 double mutant mice. Dach double mutants die after birth, similar to Dach1 homozygotes. However, unlike Drosophila dachshund mutants that lack eyes and exhibit leg truncations, the eyes and limbs of Dach double mutants are present, suggesting differences between Dach and dachshund gene function during embryonic eye and limb formation.

Animals↗

PubMed2006

Melanin-concentrating hormone-1 receptor modulates neuroendocrine, behavioral, and corticolimbic neurochemical stress responses in mice.

Repeated exposure to stressful conditions is linked to the etiology of affective disorders. The melanin-concentrating hormone-1 receptor (MCHR1) may be a novel mechanism that is involved in the modulation of stress responses and affective states. The role of MCHR1 in neuroendocrine, behavioral, and neurochemical stress, and anxiety-related responses was examined by monitoring the effects of melanin-concentrating hormone (MCH) and the selective MCHR1 antagonist, GW3430, in inbred C57Bl/6NTac and MCHR1-knockout (KO) and wild-type (WT) mice. Intracerebroventricular injection of MCH increased plasma corticosterone, and produced anxiety-related responses in the elevated plus maze. The selective MCHR1 antagonist, GW3430, blocked the neuroendocrine and behavioral effects of MCH and produced anxiolytic-like effects by itself in animal models of anxiety. Moreover, KO mice had an anxiolytic-like phenotype in behavioral models of anxiety, and GW3430 had anxiolytic-like effects in WT, but not KO mice. Lastly, stressor-evoked acetylcholine release within the prefrontal cortex of inbred and WT mice, but not KO mice, was blocked by GW3430. We show that MCH elicits anxiety-like responses and that the effects of a selective MCHR1 antagonist and the phenotype of KO mice are consistent with anxiolytic-like action. Distinct behavioral, physiological, and neurochemical stress, and anxiety-related responses were selectively modulated by the MCHR1, and these actions may involve corticolimbic regulation of stress responsivity and anxiety.

Acetylcholine↗

PubMed2005

The relationship of in vivo central CB1 receptor occupancy to changes in cortical monoamine release and feeding elicited by CB1 receptor antagonists in rats.

RATIONALE: Cannabinoid type 1 (CB(1)) receptor antagonists are reportedly effective in reducing food intake both preclinically and clinically. This may be due in part to their effects on monoamine release in the brain. The level of central CB(1) receptor occupancy underlying these neurobiological effects is unclear. OBJECTIVES: We explored the relationship between in vivo CB(1) receptor occupancy in the frontal cortex and changes in both monoamine release in the medial prefrontal cortex (mPFC) and feeding behavior in rats in response to two orally administered CB(1) receptor antagonists presently in clinical trials, SR141716A (rimonabant) and SLV319. METHODS: CB(1) receptor occupancy was measured using [(3)H] SR141716A, and these occupancies were related to potencies to mediate increases in dopamine (DA) and norepinephrine (NE) release measured with microdialysis and decreases in consumption of a highly palatable diet (HP). RESULTS: High receptor occupancy levels (>65%) were required to detect increases in monoamine release that were achieved with 3 and 10 mg/kg of SR141716A and 10 mg/kg of SLV319 for DA and 10 mg/kg of SR141716A for NE. Decreases in HP consumption were seen at occupancies higher than 65% for SR141716A that were achieved with 3 and 10 mg/kg. In contrast, decreases in HP consumption were seen at relatively low CB(1) receptor occupancies (11%) for SLV319. CONCLUSIONS: The occupancy method described here is an effective tool for interrelating central CB(1) receptor occupancy with neurobiological actions of CB(1) receptor antagonists and for furthering our understanding of the role of CB(1) receptors in central nervous system physiology and pathology.

Animals↗

PubMed2005

A therapeutic role for cannabinoid CB1 receptor antagonists in major depressive disorders.

Cannabinoid receptors in the CNS have been implicated in the control of appetite, cognition, mood and drug dependence. Recent findings support the hypothesis that cannabinoid CB1 receptor blockade might be associated with antidepressant and anti-stress effects. A novel potential antidepressant drug class based on this mechanism is supported by the neuroanatomical localization of CB1 receptors and signal transduction pathways that are involved in emotional responses, together with the antidepressant-like neurochemical and behavioral effects induced by CB1 receptor antagonists. Selective CB1 receptor antagonists are in development for the treatment of obesity and tobacco smoking, and could be tested for antidepressant efficacy because recent results of clinical studies suggest that they would also treat comorbid symptoms of depression such as cognitive deficiencies, weight gain, impulsivity and dependence disorders. Thus, CB1 receptor antagonism might constitute an integrated pharmacotherapeutic approach that impacts the affective, cognitive, appetitive and motivational neuronal networks involved in mood disorders.

Animals↗

PubMed2005

Genetic deletion of CB1 receptors improves non-associative learning.

Habituation (a form of non-associative learning) was measured by assessing locomotion in novel activity monitors in CB1 receptor knockout mice and juxtaposed to habituation measured in muscarinic M2, M4, and double M2/M4 receptor knockout mice. M2 and M2/M4, but not M4, receptor knockout mice appeared to have an impaired ability to habituate, whereas CB1 receptor knockout mice showed enhanced habituation compared to wild-type animals. We conclude that CB1 receptor gene invalidation improves habituation tentatively through an increase in cholinergic neurotransmission.

Analysis of Variance↗

PubMed2005

Effective analysis of genomic data.

High-throughput biotechnology has enabled genome-wide investigation of gene expression and has the potential to identify genes that have a role to play in focal cerebral ischemia, as well as many other interventions. The advent of this technology has also led to the generation of large amounts of expensive and complex expression data. One of the major problems with the generation of so much data is locating and extracting the relevant information to aid target identification and interpretation effectively and reliably. Statistical involvement is vital. Not only does it help to ensure effective extraction of information from the data, it also increases the likelihood that the data collected will embody the information about the differential expression of interest in the first place. The goal of this chapter is to recommend an effective process for investigating gene expression data. There are five stages in this process that we believe lead to reliable results when routinely applied to an expression dataset, once it has been appropriately generated and collected: (1) biological problem definition and design selection; (2) data examination, "preprocessing," and reexamination; (3) data analysis step I: screening for differentially expressed genes; (4) data analysis step II: verifying differential expression; and (5) biological verification, interpretation, and communication.

Computational Biology↗

PubMed2004

M4 muscarinic receptors regulate the dynamics of cholinergic and dopaminergic neurotransmission: relevance to the pathophysiology and treatment of related CNS pathologies.

Dopaminergic dysfunction is an important pathogenetic factor for brain pathologies such as Parkinson's disease, ADHD, schizophrenia, and addiction as well as for metabolic disorders and anorexia. Dopaminergic neurons projecting from the midbrain to forebrain regions, such as the nucleus accumbens and the prefrontal cortex, regulate motor and cognitive functions and coordinate the patterned response of the organism to sensory, affective, and rewarding stimuli. In this study, we showed that dopaminergic neurotransmission is highly dependent on M4 cholinergic muscarinic receptor function. Using in vivo microdialysis, we found elevated dopamine (DA) basal values and enhanced DA response to psychostimulants in the nucleus accumbens of M4 knockout mice. We also demonstrated impaired homeostatic control of cholinergic activity that leads to increased basal acetylcholine efflux in the midbrain of these animals. Thus, loss of M4 muscarinic receptor control of cholinergic function effectuates a state of dopaminergic hyperexcitability. This may be responsible for pathological conditions, in which appetitive motivation as well as affective and cognitive processing is impaired. We propose that M4 receptor agonists could represent an innovative strategy for the treatment of pathologies associated with hyperdopaminergia.

Acetylcholine↗

PubMed2004

Exposure to an elevated platform increases plasma corticosterone and hippocampal acetylcholine in the rat: reversal by chlordiazepoxide.

There is evidence that the septohippocampal cholinergic system is activated in response to stressful stimuli. In addition, prior studies indicate that stimulating the hippocampal cholinergic neurotransmission increases open arm exploration in the elevated plus-maze. This raises the possibility that exposing the rat to an elevated platform, which would be similar to confining the animal to the open arms of the plus-maze, would alter hippocampal acetylcholine levels. Results from the present study suggest that an elevated platform can be used as an animal model of stress in that exposure to the platform significantly increased plasma corticosterone levels. Importantly, exposure to a platform significantly increased hippocampal acetylcholine efflux. Interestingly, the increase in plasma corticosterone and hippocampal acetylcholine levels upon exposure to an elevated platform could be prevented by chlordiazepoxide at a dose that had no effect on basal hippocampal acetylcholine or plasma corticosterone levels. However, the elevated platform-induced increase in hippocampal acetylcholine could not be blocked by prior administration of buspirone. These results provide direct evidence for the importance of the hippocampal cholinergic system in stress and provide validation for the elevated platform as a model of stress.

Acetylcholine↗

PubMed2004

Expression and functions of the duodenal peptide secretin and its receptor in human lung.

The physiological role of the duodenal peptide secretin is as a potent stimulant of electrolyte and water movement in pancreatic and biliary epithelium, via activation of G protein-coupled secretin receptors (hSCTR). However, the distribution and potential function of hSCTR in human lung has not previously been addressed. Using real-time quantitative reverse transcriptase-polymerase chain reaction profiling, in situ hybridization, and immunohistochemistry, we demonstrated that the hSCTR is abundantly expressed within the distal regions of human lung (tertiary bronchus and parenchyma), with negligible expression detected in more proximal regions (trachea, primary, and secondary bronchus). Expression was observed predominantly on the basolateral membrane of the bronchial epithelial layer, with some expression also observed in bronchial smooth muscle. In primary cultures of human tertiary bronchial epithelial cells, secretin was demonstrated to potently stimulate channel-mediated Cl- efflux in a concentration-dependent manner. Secretin was also shown to cause concentration-dependent relaxation of human tertiary bronchial smooth muscle. In summary, these data demonstrate that secretin receptors are present in human lung, and that activation of these receptors with human secretin potently stimulates concentration-dependent Cl- efflux from bronchial epithelial cells and bronchorelaxation.

Bronchi↗

PubMed2004

EP4 prostanoid receptor-mediated vasodilatation of human middle cerebral arteries.

1. Dilatation of the cerebral vasculature is recognised to be involved in the pathophysiology of migraine. Furthermore, elevated levels of prostaglandin E(2) (PGE(2)) occur in the blood, plasma and saliva of migraineurs during an attack, suggestive of a contributory role. In the present study, we have characterised the prostanoid receptors involved in the relaxation and contraction of human middle cerebral arteries in vitro. 2. In the presence of indomethacin (3 microm) and the TP receptor antagonist GR32191 (1 microM), PGE(2) was found to relax phenylephrine precontracted cerebral arterial rings in a concentration-dependent manner (mean pEC(50) 8.0+/-0.1, n=5). 3. Establishment of a rank order of potency using the EP(4)>EP(2) agonist 11-deoxy PGE(1), and the EP(2)>EP(4) agonist PGE(1)-OH (mean pEC(50) of 7.6+/-0.1 (n=6) and 6.4+/-0.1 (n=4), respectively), suggested the presence of functional EP(4) receptors. Furthermore, the selective EP(2) receptor agonist butaprost at concentrations <1 microM failed to relax the tissues. 4. Blockade of EP(4) receptors with the EP(4) receptor antagonists AH23848 and EP(4)A caused significant rightward displacements in PGE(2) concentration-response curves, exhibiting pA(2) and pK(B) values of 5.7+/-0.1, n=3, and 8.4, n=3, respectively. 5. The IP receptor agonists iloprost and cicaprost relaxed phenylephrine precontracted cerebral arterial rings (mean pEC(50) values 8.3+/-0.1 (n=4) and 8.1+/-0.1 (n=9), respectively). In contrast, the DP and FP receptor agonists PGD(2) and PGF(2 alpha) failed to cause appreciable relaxation or contraction at concentrations of up to 30 microm. In the absence of phenylephrine contraction and GR32191, the TP receptor agonist U46619 caused concentration-dependent contraction of cerebral artery (mean pEC(50) 7.4+/-0.3, n=3). 6. These data demonstrate the presence of prostanoid EP(4) receptors mediating PGE(2) vasodilatation of human middle cerebral artery. IP receptors mediating relaxation and TP receptors mediating contraction were also functionally demonstrated.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2003

Drosophila retinal homeobox (drx) is not required for establishment of the visual system, but is required for brain and clypeus development.

The possibility that mechanisms of retinal determination may be similar between vertebrates and Drosophila has been supported by the observations that Pax6/eyeless genes are necessary and sufficient for retinal development. These studies suggest that the function of other gene families, operating during early eye development, might also be conserved. One candidate is the retinal homeobox (Rx) family of transcription factors. Vertebrate Rx is expressed in the prospective eye and forebrain and is required for eye morphogenesis, retinal precursor appearance, and normal forebrain development, indicating that it is an essential regulator of early eye and brain formation. Here, we test the hypothesis that Drosophila Rx (drx) is required for adult and larval eye development. We have isolated a drx null allele and demonstrate that the mutant compound eye and larval visual system is not detectably abnormal. However, we find that drx is required for development of a central brain structure, the ellipsoid body, suggesting that Rx function in the brain may be conserved. Finally, we characterize a novel anterior head phenotype and demonstrate that drx is required for clypeus development. Thus, our data suggest that drx may be required for the regulation of genes involved in brain morphogenesis and clypeus precursor development. We propose that differences in insect and vertebrate eye development may be explained by changes in gene regulation and/or the tissue of origin for eye precursor cells.

Alleles↗

PubMed2003

The CB1 receptor antagonist SR141716A selectively increases monoaminergic neurotransmission in the medial prefrontal cortex: implications for therapeutic actions.

1. In order to explore potential therapeutic implications of cannabinoid antagonists, the effects of the prototypical cannabinoid antagonist SR141716A on monoamine efflux from the medial prefrontal cortex and the nucleus accumbens of the rat were investigated by in vivo microdialysis. 2. SR141716A moderately increased serotonin efflux and concentrations of its metabolite 5-HIAA, both in the medial prefrontal cortex and the nucleus accumbens, and increased norepinephrine, dopamine and their metabolites in the medial prefrontal cortex. In contrast, it had no effect on norepinephrine, dopamine and their metabolites in the nucleus accumbens. 3. At the same doses, SR141716A increased acetylcholine efflux in the medial prefrontal cortex, in agreement with previous studies; contrary to the effects in cortex, SR141716A had no effect on acetylcholine efflux in the nucleus accumbens. 4. The efficacy of SR141716A in the psychostimulant-induced hyperlocomotion and the forced swimming paradigms was also explored in mice. SR141716A attenuated phenylcyclidine- and d-amphetamine-induced hyperlocomotion, without affecting locomotor activity when administered alone, and decreased immobility in the forced swimming test. 5. These results suggest that the cortical selectivity in the release of catecholamines, dopamine in particular, induced by the cannabinoid antagonist SR141716A, its procholinergic properties, together with its mild stimulatory effects on serotonin and norepinephrine efflux make similar compounds unique candidates for the treatment of psychosis, affective and cognitive disorders.

Animals↗

PubMed2003

Gastric emptying and control of ingestion in preweanling rat pups.

In adult rats, the rate of gastric emptying is modulated by properties of the diet, including its caloric content and osmotic properties. In developing pups, there is little known about the modulation of gastric emptying, despite evidence that volume of gastric contents may play a significant role in modulating intake in young rats. The present experiments examined gastric emptying of oral infusions of corn oil emulsions or glucose solutions in pups aged 6 or 15 days of age and their effects on independent ingestion. The results demonstrated that pups as young as 6 days of age modulate the rate of gastric emptying in response to changes in the concentration of a corn oil or glucose diet. However, oral infusions of corn oil emulsions failed to produce differences in subsequent intake of a milk diet, while oral infusions of a glucose diet did suppress subsequent intake. Taken together, the results support different ontogenetic courses for the development of mechanisms modulating gastric emptying of lipid versus carbohydrate diets, and suggest that gastric fill plays a limited role in modulation of intake in young pups.

Animals↗

PubMed2002

Dach1, a vertebrate homologue of Drosophila dachshund, is expressed in the developing eye and ear of both chick and mouse and is regulated independently of Pax and Eya genes.

We have cloned a chick homologue of Drosophila dachshund (dac), termed Dach1. Dach1 is the orthologue of mouse and human Dac/Dach (hereafter referred to as Dach1). We show that chick Dach1 is expressed in a variety of sites during embryonic development, including the eye and ear. Previous work has demonstrated the existence of a functional network and genetic regulatory hierarchy in Drosophila in which eyeless (ey, the Pax6 orthologue), eyes absent (eya), and dac operate together to regulate Drosophila eye development, and that ey regulates the expression of eya and dac. We find that in the developing eye of both chick and mouse, expression domains of Dach1 overlap with those of Pax6, a gene required for normal eye development. Similarly, in the developing ear of both mouse and chick, Dach1 expression overlaps with the expression of another Pax gene, Pax2. In the mouse, Dach1 expression in the developing ear also overlaps with the expression of Eya1 (an eya homologue). Both Pax2 and Eya1 are required for normal ear development. Our expression studies suggest that the Drosophila Pax-eya-dac regulatory network may be evolutionarily conserved such that Pax genes, Eya1, and Dach1 may function together in vertebrates to regulate neural development. To address the further possibility that a regulatory hierarchy exists between Pax, Eya, and Dach genes, we have examined the expression of mouse Dach1 in Pax6, Pax2 and Eya1 mutant backgrounds. Our results indicate that Pax6, Pax2, and Eya1 do not regulate Dach1 expression through a simple linear hierarchy.

Amino Acid Sequence↗