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Biomedical subjects

David R Hill

Publications and source records attributed to David R Hill.

12 recordsLinked to original sources
PubMed2005

Regionally selective and dose-dependent effects of the ampakines Org 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by 14C-2-deoxyglucose autoradiography.

AMPA receptor potentiating drugs (e.g. ampakines) enhance glutamatergic neurotransmission, and may have potential therapeutic consequences in CNS disorders. The neuroanatomical basis of action for these compounds is at present unclear. This study aimed to identify the effects of two novel ampakines, Org 26576 and Org 24448, on local cerebral glucose use (LCGU) in the mouse. C57BL/6J mice received Org 26576 (0.1, 1, 10 mg/kg i.p.) or Org 24448 (3, 10, 30 mg/kg i.p.) or vehicle and LCGU was assessed using 14C-2-deoxyglucose autoradiography. Both compounds produced dose-dependent increases in LCGU with specific regional activation at low doses. Org 26576 (1 mg/kg) produced significant increases in 9 of the 43 areas examined, including the anteroventral and laterodorsal thalamus, cingulate cortex, dentate gyrus and CA3 subfield of the hippocampus. Org 24448 (3 mg/kg) produced significant increases in LCGU in 4 of the 43 regions examined, including the dorsal raphe nucleus, medial lateral habenula, CA1 subfield of the hippocampus and median forebrain bundle. Furthermore, the increases in LCGU observed with both Org 26576 (10 mg/kg) and Org 24448 (10 mg/kg) were blocked by pre-treatment with the AMPA receptor antagonist NBQX (10 mg/kg). These data demonstrate that both Org 26576 and Org 24448 produce dose-dependent AMPA receptor mediated increases in LCGU and provide an anatomical basis suggestive that these drugs may be of use in the treatment of conditions such as depression or schizophrenia.

Animals↗
PubMed2005

Comparison of alterations in c-fos and Egr-1 (zif268) expression throughout the rat brain following acute administration of different classes of antidepressant compounds.

The majority of immediate-early gene (IEG) studies focus on a few key brain regions associated with the class of psychoactive compound being studied. Recently, using a meta-analysis of the c-fos literature, we demonstrated the utility of c-fos profiling to classify such compounds. The present study examined acute delivery of a range of antidepressant classes; fluoxetine, imipramine, LiCl, and mirtazapine. The dual aims were to study the IEG profiles of these varying classes of antidepressants throughout the rat brain and to compare the utility of c-fos or Egr-1 as IEGs to classify clinically efficacious antidepressants. All antidepressants increased c-fos mRNA in the central amygdala, as previously shown, while c-fos was also increased in the anterior insular cortex and significantly decreased within the septum. Although acute antidepressant administration altered c-fos expression in a number of brain regions, Egr-1 expression was only significantly altered in the central amygdala, suggesting that Egr-1 may not be as useful a marker to investigate acute antidepressant treatment. The fact that these drugs, including the previously unclassified antidepressant mirtazapine, share a number of common loci of activation, which are implicated by human and animal studies in depression, adds further support to the use of IEG mapping to classify psychoactive compounds.

Acetylcholinesterase↗
PubMed2003

Acute oral dexamethasone administration reduces levels of orphan GPCR glucocorticoid-induced receptor (GIR) mRNA in rodent brain: potential role in HPA-axis function.

Glucocorticoid-induced receptor (GIR) is an orphan G-protein-coupled receptor (GPCR) with predominant expression in brain and thymus. More specifically, high levels of GIR expression have been described in brain regions of mouse, rat and human including limbic forebrain and hypothalamic regions, suggesting a role for GIR in memory, cognition, stress, reward or the control of emotion. Previous in vitro studies performed in murine thymocytes demonstrated an induction of GIR following dexamethasone treatment, suggesting the potential in vivo regulation of GIR by glucocorticoids. Glucocorticoids have been implicated in a number of disorders. In this study we employed in situ hybridisation with semi-quantitative image analysis to assess the level of GIR expression in mouse brain following acute dexamethasone administration. GIR was highly expressed in the nucleus accumbens, striatum, olfactory tubercle and nuclei of the hypothalamus. Three hours following acute dexamethasone treatment (0.05 mg/kg, p.o.), levels of GIR mRNA were found to be significantly decreased in striatum (25%, P<0.05), nucleus accumbens (19%, P<0.05), olfactory tubercle (19%, P<0.05) and CA2 sub-region of the hippocampus (30%, P<0.05) compared with vehicle. Significant decreases in GIR expression were also observed in hypothalamic nuclei including the dorsomedial (48%, P<0.05) and ventrolateral (58%, P<0.05) part of the ventromedial hypothalamic nuclei, dorsomedial hypothalamic nuclei (39%, P<0.01) and arcuate nucleus (54%, P<0.05), compared with vehicle. These data demonstrate the in vivo regulation of GIR in response to glucocorticoids and suggest a potential role for GIR in mediating the response to altered levels of glucocorticoids in disease states.

Administration, Oral↗
PubMed2003

Giardia intestinalis.

PURPOSE OF REVIEW: Giardia intestinalis (syn. duodenalis or lamblia) is one of the most common intestinal parasites in the world, with an estimated 2.8 x 10(6) infections per year in humans, and it contributes to diarrhea and nutritional deficiencies in children in developing regions. The wide prevalence of Giardia and its unique place in evolutionary biology have led to ongoing research. RECENT FINDINGS: Research into the basic biology of Giardia has highlighted some of its unique properties as an 'early-branching' eukaryote. Although Giardia do not contain mitochondria, they have developed pathways to perform some mitochondrial functions. Investigations into encystation and excystation have identified new gene products that are important in cyst wall formation, and signal transduction events that occur during excystation. The ability to transfect Giardia stably will lead to an improved understanding of its development and metabolism. Molecular typing of G. intestinalis isolates indicates that most animal parasites are not associated with human infection. Insights into immunology have helped define the role of IL-6 in the early control of murine giardiasis, and the contributions of IgA in controlling infection. Further studies of giardiasis in poorly nourished children in developing regions supports an important contributing role of Giardia in stunting and cognitive impairment. Finally, new diagnostic assays using antigen detection are being evaluated and a new agent, nitazoxanide, has been approved in the USA for the treatment of giardiasis and cryptosporidiosis in children. SUMMARY: Research into the biology of Giardia should increase knowledge about protist differentiation and will complement studies in other biological systems. Continued study of the role of Giardia in chronic diarrhea and malnutrition in developing regions will help focus strategies to improve childhood growth and nutrition.

Animals↗