Charlie Norwood Veterans Administration Medical Center

Augusta, GA, United States

Charlie Norwood Veterans Administration Medical Center

Augusta, GA, United States
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Hall B.J.,Georgia Regents University | Hall B.J.,Charlie Norwood Veterans Administration Medical Center | Pearson L.S.,Charlie Norwood Veterans Administration Medical Center | Buccafusco J.J.,Georgia Regents University | Buccafusco J.J.,Charlie Norwood Veterans Administration Medical Center
Neuropharmacology | Year: 2010

The use-dependent, nicotinic acetylcholine receptor antagonist bis-(2,2,6,6-tetramethyl-4-piperidinyl) sebacate (BTMPS) was studied for its potential to reduce the self-administration of nicotine in rats, as well as to reduce context-induced recidivistic-like behavior after a six-week period of cessation. Rats were allowed to self-administer nicotine (FR1 schedule) inside an operant chamber with a response lever active on a 24 h basis for 14 days. After the self-administration phase, the rats were returned to standard maintenance cages for a period of six weeks. At the end of six weeks the rats were returned to the operant chambers for 7 days and lever responses were recorded under conditions identical to the original self-administration phase, except that lever responses were not rewarded. Daily administration (s.c.) of BTMPS produced a dose-dependent decrease in the self-administration of nicotine 55-80% compared to control animals, and significantly decreased context-induced lever responding initiated six weeks after cessation (35-78% reduction vs. controls). Decreasing the BTMPS regimen to administration once every 3 days was not effective in reducing nicotine self-administration, but lever responding induced during the return to the operant chambers 6 weeks later was significantly decreased (40% reduction vs. controls). Therefore BTMPS can selectively reduce both self-administration of nicotine and long-term recidivistic-like behavior depending upon the dose regimen. Since BTMPS does not evoke anti-nicotinic effects under normal physiological conditions, these data support a proof of concept for the safe use of such compounds in the treatment of tobacco abuse.

Middlemore-Risher M.L.,University of Georgia | Buccafusco J.J.,Georgia Regents University | Buccafusco J.J.,Charlie Norwood Veterans Administration Medical Center | Terry A.V.,University of Georgia | Terry A.V.,Georgia Regents University
Neurotoxicology and Teratology | Year: 2010

Organophosphates such as chlorpyrifos (CPF) are among the most commonly used pesticides in the world. Therefore, it is not surprising that measurable levels of organophosphates (including CPF) are found in over 50% of fresh fruits, vegetables and grains that we consume and that approximately 80% of adults in the US have detectable levels of CPF metabolites in their urine. It is well known that acute exposure to organophosphates can cause cognitive deficits; however, the effects of daily or intermittent contact with low levels of organophosphates (often reflective of environmental exposures) are not well understood. The objective of this study was to determine if repeated low-level exposures to CPF impaired the performance of the 5-Choice Serial Reaction Time Task (5C-SRTT), an animal model of sustained attention. Adult rats were trained to stably perform the 5C-SRTT, then treated with vehicle or CPF 18.0. mg/kg daily for 14 consecutive days or every other day for 30. days. Behavioral testing occurred daily during the CPF-exposure period and throughout a 30. day washout period to assess recovery. All CPF-treated animals exhibited deficits in percent correct, an increase in omissions and premature responses without signs of impaired motivation or overt toxicity. Deficits in 5C-SRTT accuracy were apparent well into the 30. day washout period despite significant recovery of cholinesterase activity. These results indicate that repeated exposures to relatively low levels of chlorpyrifos lead to protracted impairments of sustained attention and an increase in impulsive behaviors in rats. © 2010 Elsevier Inc.

Yin D.-M.,Georgia Regents University | Sun X.-D.,Georgia Regents University | Sun X.-D.,Southern Medical University | Bean J.C.,Georgia Regents University | And 10 more authors.
Journal of Neuroscience | Year: 2013

The trophic factor neuregulin 1 (Nrg1) and its receptor ErbB4 are schizophrenia candidate genes. NRG1-ErbB4 signaling was thought to regulate spine formation and function in a cell-autonomous manner. Yet, recent studies indicate that ErbB4 expression is largely restricted to GABAergic interneurons and is very low or absent in pyramidal cells. Here, we generated and characterized cell type-specific ErbB4 mutant and transgenic mice. Spine density and the number of excitatory synapses were unaltered by neither deletion nor overexpression of ErbB4 in pyramidal neurons. However, spine density and excitatory synapse number were reduced in PV-ErbB4-/- mice where ErbB4 was selectively ablated in parvalbumin-positive GABAergic interneurons. Concurrently, basal glutamate transmission was impaired in PV-ErbB4-/- mice, but not in mice where ErbB4 was deleted or overexpressed in pyramidal neurons. Our results demonstrate a role of ErbB4 in PV-positive interneurons for spine formation in excitatory neurons. © 2013 the authors.

Hall B.J.,Georgia Regents University | Hall B.J.,Charlie Norwood Veterans Administration Medical Center | Pearson L.S.,Charlie Norwood Veterans Administration Medical Center | Buccafusco J.J.,Georgia Regents University | Buccafusco J.J.,Charlie Norwood Veterans Administration Medical Center
Neuroscience Letters | Year: 2010

Withdrawal from cocaine use often is associated with anxiety and depressive states. In this study the use-dependent, nicotinic acetylcholine receptor antagonist bis-(2,2,6,6-tetramethyl-4-piperidinyl) sebacate (BTMPS) was studied for its ability to reduce these symptoms in two rat models of anxiety and depression. Rats were administered saline vehicle, or two escalating doses of cocaine, for a period of 5 days and they were evaluated during the period after cocaine discontinuation in the elevated plus maze (anxiety) and the forced swim test (affect). BTMPS (0.25, 0.5, or 0.75. mg/kg) was co-administered with saline or cocaine in the dependence phase. Withdrawal from cocaine administration alone resulted in reductions in both the time spent in the open arms of the elevated plus maze test, as well as entries into, and out of, the open arms of the maze. Withdrawal from cocaine also resulted in a reduction of escape behaviors, and the time to first immobility, in the forced swim test. Treatment with BTMPS produced a reversal of cocaine-induced anxiety-like behaviors in the elevated plus maze, including an increase (up to 68%) in time spent in the open arms of the maze and an increase in the number of crossings between open and enclosed arms. BTMPS also reduced depressive-like behaviors associated with the forced swim test, including up to a 62% increase in the time to first immobility and a 50% increase in escape behavior. These results provide proof of concept for the development and use of cholinergic compounds in the treatment of substance abuse. © 2010.

Garretson X.T.,Georgia State University | Teubner B.J.,Georgia State University | Grove K.L.,Oregon Health And Science University | Vazdarjanova A.,Georgia Regents University | And 3 more authors.
Journal of Neuroscience | Year: 2015

Peroxisome proliferator-activated receptor γ (PPARγ) is clinically targeted for type II diabetes treatment; however, rosiglitazone (ROSI), a PPARγ agonist, increases food intake and body/fat mass as side-effects. Mechanisms for these effects and the role of PPARγ in feeding are not understood. Therefore, we tested this role in Siberian hamsters, a model of human energy balance, and C57BL/6 mice. We tested the following: (1) how ROSI and/or GW9662 (2-chloro-5-nitro-N-phenylbenzamide;PPARγ antagonist) injected intraperitoneally or into the third ventricle (3V) affected Siberian hamster feeding behaviors; (2) whether food deprivation (FD) co-increases agouti-related protein (AgRP) and PPARγ mRNAexpression in Siberian hamsters and mice; (3) whether intraperitoneally administered ROSI increases AgRP andNPYin ad libitum-fed animals; (4) whether intraperitoneally administeredPPARγ antagonism blocks FD-induced increases in AgRP and NPY; and finally, (5) whether intraperitoneally administered PPAR γ modulation affects plasma ghrelin. Third ventricular and intraperitoneally administered ROSI increased food hoarding and intake for 7 d, an effect attenuated by 3V GW9662, and also prevented (intraperitoneal) FD-induced feeding. FD hamsters and mice increased AgRP within the arcuate hypothalamic nucleus with concomitant increases in PPAR γ exclusively within AgRP/NPY neurons. ROSI increased AgRP and NPY similarly to FD, and GW9662 prevented FD-induced increases in AgRP and NPY in both species. Neither ROSI nor GW9662 affected plasma ghrelin. Thus, we demonstrated that PPAR γ activation is sufficient to trigger food hoarding/intake, increase AgRP/NPY, and possibly is necessary for FD-induced increases in feeding and AgRP/NPY. These findings provide initial evidence that FD-induced increases in AgRP/NPY may be a direct PPARγ-dependent process that controls ingestive behaviors. ©2015 the authors.

Bean J.C.,Georgia Regents University | Lin T.W.,Georgia Regents University | Sathyamurthy A.,Georgia Regents University | Liu F.,Georgia Regents University | And 6 more authors.
Journal of Neuroscience | Year: 2014

Neuregulin 1 (NRG1) and its receptor ErbB4 are schizophrenia risk genes. NRG1-ErbB4 signaling plays a critical role in neural development and regulates neurotransmission and synaptic plasticity. Nevertheless, its cellular targets remain controversial. ErbB4 was thought to express in excitatory neurons, although recent studies disputed this view. Using mice that express a fluorescent protein under the promoter of the ErbB4 gene, we determined in what cells ErbB4 is expressed and their identity. ErbB4 was widely expressed in the mouse brain, being highest in amygdala and cortex. Almost all ErbB4-positive cells were GABAergic in cortex, hippocampus, basal ganglia, and most of amygdala in neonatal and adult mice, suggesting GABAergic transmission as a major target of NRG1-ErbB4 signaling in these regions. Non-GABAergic, ErbB4-positive cells were present in thalamus, hypothalamus, midbrain, and hindbrain. In particular, ErbB4 is expressedinserotoninergicneurons of raphenuclei but not innorepinephrinergicneurons of thelocus ceruleus. Inhypothalamus, ErbB4 is present in neurons that express oxytocin. Finally, ErbB4 is expressed in a group of cells in the subcortical areas that are positive for S100 calcium binding protein β. These results identify novel cellular targets of NRG1-ErbB4 signaling. © 2014 the authors.

Prakash R.,Charlie Norwood Veterans Administration Medical Center | Prakash R.,University of Georgia | Li W.,Charlie Norwood Veterans Administration Medical Center | Li W.,Georgia Regents University | And 7 more authors.
Stroke | Year: 2013

Background and Purpose-Pre-existing diabetes mellitus worsens brain functionality in ischemic stroke. We have previously shown that type 2 diabetic rats exhibit enhanced dysfunctional cerebral neovascularization and when these rats are subjected to cerebral ischemic reperfusion injury develop hemorrhagic transformation and greater neurological deficits. However, our knowledge of vascular and functional plasticity during the recovery phase of diabetic stroke is limited. This study tested the hypothesis that vascular repair is impaired in the poststroke period in diabetes mellitus, and this is associated with poor sensorimotor and cognitive function. We further hypothesized that glycemic control prevents impaired vascularization and improves functional outcome in diabetes mellitus. Methods-Vascularization was assessed in the ipsilateral and contralateral hemispheres in control, diabetes mellitus and diabetes mellitus plus metformin groups 14 days after ischemic reperfusion injury, as well as in respective sham controls. Three-dimensional reconstruction of the fluorescein isothiocyanate (FITC)-stained vasculature was achieved by confocal microscopy, and stereological parameters, including vascular volume and surface area, were measured. Astrogliosis was determined by glial fibrillary acidic protein staining. The relative rates of sensorimotor recovery, cognitive decline, and spontaneous activity were assessed. Results-Vascular density in the peri-infarct area was significantly reduced in diabetes mellitus, whereas there was reparative neovascularization in control rats. Astroglial swelling and reactivity were more pronounced in diabetic stroke compared with control stroke. Diabetes mellitus blunted sensorimotor recovery and also exacerbated anxiety-like symptoms and cognitive deficits. Glycemic control started after stroke partially prevented these changes. Conclusions-Diabetes mellitus impairs poststroke reparative neovascularization and impedes the recovery. Glycemic control after stroke can improve neurovascular repair and improve functional outcome. © 2013 American Heart Association, Inc.

Weinberger P.M.,Georgia Regents University | Merkley M.A.,Georgia Regents University | Khichi S.S.,Georgia Regents University | Lee J.R.,Charlie Norwood Veterans Administration Medical Center | And 3 more authors.
Laryngoscope | Year: 2010

Objectives/Hypothesis: Mortality for black males with head and neck squamous cell carcinoma (HNSCC) is twice that of white males or females. Human papillomavirus (HPV)-active HNSCC, defined by the concurrent presence of high-risk type HPV DNA and host cell p16INK4a expression, is associated with decreased mortality. We hypothesized that prevalence of this HPV-active disease class would be lower in black HNSCC patients compared to white patients. Study Design: Multi-institutional retrospective cohort analysis. Methods: Real-time polymerase chain reaction was used to evaluate for high-risk HPV DNA presence. Immunohistochemistry for p16INK4a protein was used as a surrogate marker for HPV oncoprotein activity. Patients were classified as HPV-negative (HPV DNA-negative, p16INK4a low), HPV-inactive (HPV DNA-positive, p16INK4a low), and HPV-active (HPV DNA-positive, p16INK4a high). Overall survival and recurrence rates were compared by Fisher exact test and Kaplan-Meier analysis. Results: There were 140 patients with HNSCC who met inclusion criteria. Self-reported ethnicity was white (115), black (25), and other (0). Amplifiable DNA was recovered from 102/140 patients. The presence of HPV DNA and the level of p16INK4a expression were determined, and the results were used to classify these patients as HPV-negative (44), HPV-inactive (33), and HPV-active (25). Patients with HPV-active HNSCC had improved overall 5-year survival (59.7%) compared to HPV-negative and HPV-inactive patients (16.9%) (P = .003). Black patients were less likely to have HPV-active disease (0%) compared to white patients (21%) (P = .017). Conclusions: The favorable HPV-active disease class is less common in black than in white patients with HNSCC, which appears to partially explain observed ethnic health disparities. © 2010 The American Laryngological, Rhinological and Otological Society, Inc.

Singh N.,Georgia Regents University | Gurav A.,Georgia Regents University | Sivaprakasam S.,Georgia Regents University | Brady E.,Georgia Regents University | And 9 more authors.
Immunity | Year: 2014

Commensal gut microflora and dietary fiber protect against colonic inflammation and colon cancer through unknown targets. Butyrate, a bacterial product from fermentation of dietary fiber in the colon, has been implicated in this process. GPR109A (encoded by Niacr1) is a receptor for butyrate in the colon. GPR109A is also a receptor for niacin, which is also produced by gut microbiota and suppresses intestinal inflammation. Here we showed that Gpr109a signaling promoted anti-inflammatory properties in colonic macrophages and dendritic cells and enabled them to induce differentiation of Treg cells and IL-10-producing Tcells. Moreover, Gpr109a was essential for butyrate-mediated induction of IL-18 incolonicepithelium. Consequently, Niacr1-/- mice were susceptible to development of colonic inflammation and colon cancer. Niacin, a pharmacological Gpr109a agonist, suppressed colitis and colon cancer in a Gpr109a-dependent manner. Thus, Gpr10a has an essential role in mediating the beneficial effects of gut microbiota and dietary fiber in colon. © 2014 Elsevier Inc.

Barik A.,Georgia Regents University | Lu Y.,Georgia Regents University | Sathyamurthy A.,Georgia Regents University | Bowman A.,Georgia Regents University | And 6 more authors.
Journal of Neuroscience | Year: 2014

The neuromuscular junction (NMJ) is a synapse between motor neurons and skeletal muscle fibers, and is critical for control of muscle contraction. Its formation requires neuronal agrin that acts by binding to LRP4 to stimulate MuSK. Mutations have been identified in agrin, MuSK, and LRP4 in patients with congenital myasthenic syndrome, and patients with myasthenia gravis develop antibodies against agrin, LRP4, and MuSK. However, it remains unclear whether the agrin signaling pathway is critical for NMJ maintenance because null mutation of any of the three genes is perinatal lethal. In this study, we generated imKO mice, a mutant strain whose LRP4 gene can be deleted in muscles by doxycycline (Dox) treatment. Ablation of the LRP4 gene in adult muscle enabled studies of its role in NMJ maintenance. We demonstrate that Dox treatment of P30 mice reduced muscle strength and compound muscle action potentials. AChR clusters became fragmented with diminished junctional folds and synaptic vesicles. The amplitude and frequency of miniature endplate potentials were reduced, indicating impaired neuromuscular transmission and providing cellular mechanisms of adult LRP4 deficiency. We showed that LRP4 ablation led to the loss of synaptic agrin and the 90 kDa fragments, which occurred ahead of other prejunctional and postjunctional components, suggesting that LRP4 may regulate the stability of synaptic agrin. These observations demonstrate that LRP4 is essential for maintaining the structural and functional integrity of the NMJ and that loss of muscle LRP4 in adulthood alone is sufficient to cause myasthenic symptoms. © 2014 the authors.

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