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Dive into the research topics where Gary A. Rogers is active.

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Featured researches published by Gary A. Rogers.


Brain Research | 1994

A centrally active drug that modulates AMPA receptor gated currents.

Amy Arai; Markus Kessler; Peng Xiao; José Ambros-Ingerson; Gary A. Rogers; Gary Lynch

Systemic administration of the drug 1-(1,3-benzodioxol-5-ylcarbonyl)-piperidine (1-BCP) has been reported to enhance monosynaptic responses in the hippocampus in vivo and to improve spatial and olfactory memory in rats. The drugs mechanism of action was investigated in the present study using membrane patches excised from cultured hippocampal slices. The decay time of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor mediated inward currents was greatly increased by 1-BCP in a concentration dependent and reversible fashion; peak current was also enhanced but to a lesser degree. In vitro slice experiments indicated that the drug has parallel effects on the field EPSP. It is concluded that 1-BCP is a centrally active modulator of the AMPA receptor.


Journal of Cerebral Blood Flow and Metabolism | 1991

Rapid Feasibility Studies of Tracers for Positron Emission Tomography: High-Resolution PET in Small Animals with Kinetic Analysis

Martin Ingvar; Lars Eriksson; Gary A. Rogers; Sharon Stone-Elander; Lennart Widén

The development of methods for production of a radiotracer for use in human studies with positron emission tomography (PET) is often a time-consuming process of optimizing radiolabelling yields and handling procedures. Sometimes the radiotracer is not the original drug, but rather a derivative with unknown in vivo pharmacological properties. We have developed a fast and simple method of testing putative new PET tracers in vivo in small animals. The procedure has been validated in rats with different PET tracers with known kinetic and pharmacological properties ([2-18F]2-fluoro-2-deoxy-d-glucose, [N-methyl-11C]Ro 15-1788, and [15O]butanol). The tracer concentration in arterial blood was continuously measured to obtain the brain input function. Following image reconstruction of the scans, time–activity curves of selected regions of interest were generated. Estimations of CMRglc (1.0 ± 0.2 μmol g−1 min−1), CBF (1.4 ± 0.4 ml g−1 min−1) and transport rate constants for [N-methyl-11C]Ro 15-1788 (K1 = 0.44 ± 0.01 ml g−1 min−1 and k2 = 0.099 ± 0.005 min−1) as well as calculated first pass extraction (0.32 ±0.1) are in reasonable agreement with literature values. Small animal studies require minimal amounts of radioactivity and can be performed without sterility and toxicology tests. They may serve as a preliminary basis for radiation safety calculations because whole body scans can be performed even with a head scanner. The major advantage of this procedure in comparison to ex vivo autoradiography is that very few experiments are necessary to reliably determine the properties of the blood–brain barrier transport of the radiotracer and the possible whole brain receptor binding characteristics.


Neuroscience Letters | 1995

Enhanced glutamatergic neurotransmission facilitates classical conditioning in the freely moving rat.

Tracey J. Shors; Richard J. Servatius; Richard F. Thompson; Gary A. Rogers; Gary Lynch

Centrally active drugs that enhance alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-gated currents by increasing the amplitude and duration of fast, excitatory synaptic responses in the hippocampus have recently been described. The effects of the compound 1-(1,3-benzodioxol-5-ylcarbonyl) perperidine (BDP) on associative and non-associative aspects of the classically conditioned eyeblink response in the freely moving rat were examined. Rats injected with BDP blinked significantly more to an acoustic stimulus of 85 dB than did vehicle controls, indicating that the drug enhances alpha responding to discrete auditory cues. Using a less intense stimulus of 80 dB, rats injected with BDP did not exhibit alpha responding or pseudo-conditioning, yet learned the conditioned response at a facilitated rate. These results suggest that increasing excitatory neurotransmission enhances the processing of sensory information and may contribute to subsequent contingency detection.


Neuroscience Letters | 1992

Positron emission tomographic studies of central cholinergic nerve terminals

Lennart Widén; Lars Eriksson; Martin Ingvar; Stanley M. Parsons; Gary A. Rogers; Sharon Stone-Elander

The aim of this study was to develop a quantitative method for the study of cholinergic nerve terminals in vivo. An 18F-labeled analogue of vesamicol ([18F]FMV) that binds with high affinity to synaptic vesicles from Torpedo electric organ was synthesized and evaluated in vivo in rats and monkeys by positron emission tomography (PET). In rats, the tracer was rapidly cleared from the blood and highly extracted into the brain, where it was specifically and irreversibly bound. In monkeys, a specific binding of the tracer was observed in brain regions known to contain cholinergic nerve terminals. Preinjection of non-labeled vesamicol prevented the cerebral binding of [18F]FMV to a high affinity site in both species. Our results are a major step towards quantitative human in vivo studies of presynaptic cholinergic functions.


Annals of the New York Academy of Sciences | 1987

Acetylcholine Transport: Fundamental Properties and Effects of Pharmacologic Agentsa

Stanley M. Parsons; Ben A. Bahr; Lawrence M. Gracz; Rose Kaufman; Wayne D. Kornreich; Lena Nilsson; Gary A. Rogers

Acetylcholine (ACh) is found in association with synaptic vesicle fractions obtained from mammalian brain, diaphragm and myenteric plexus, squid head ganglion, PC12 cells, and electric eel, catfish, and ray electric organs. Much well-known evidence supports the hypothesis that evoked release of ACh from nerve terminals occurs from the synaptic vesicle stores by means of calcium-dependent exocytosis. Thus, storage of ACh by the vesicles is an important step in cholinergic neurotransmission, and it is of fundamental importance that we understand this process. In particular, we would like to identify all of the enzymes, proteins, and small molecules which are involved, understand the electrical and osmotic transport relationships among the small molecules, and detexmine whether physiological regulation operates at this level of the cholinergic synapse. Progress on these molecular aspects of cholinergic vesicle function has been dacult until relatively recently. Biochemical studies are now possible, due in large measure to the efforts of Whittaker, Kelly, and co-workers, who demonstrated that one can isolate millipam quantities of highly purified homogeneously cholinergic synaptic vesicles from the electric organ of marine rays such as Torpedo.


Progress in Brain Research | 1993

Chapter 20: Acetylcholine transporter — vesamicol receptor pharmacology and structure

Stanley M. Parsons; Ben A. Bahr; Gary A. Rogers; Edward D. Clarkson; Krystyna Noremberg; Barry W. Hicks

Publisher Summary Acetylcholine (ACh) is stored by synaptic vesicles at about 100-fold higher concentration than present in the cytoplasm. As vesicular ACh is free in solution, energy input is required to establish the gradient of concentration. This is accomplished in a process having at least two macromolecular components that reside in the vesicular membrane. The first component is a proton-pumping ATPase known as a V-type ATPase. It pumps protons into the synaptic vesicle, thus acidifying the vesicle core to about pH 5.4. The enzyme is found in the vacuolar-type intracellular organelles, and it is evolutionally related to the mitochondria1 ATPase. The second component is the ACh transporter (AChT). It exchanges one or more vesicular protons for cytoplasmic ACh, thus accomplishing secondary active transport of ACh. The ACh exhibits a transport Michaelis dissociation constant (KM) of about 0.3 mM, which is less than the 4 mM that can be estimated for the concentration of ACh in the cytoplasm. Proton-exchanging transporters appear to account for vesicular storage of all of the classical neurotransmitters. As a class, these transporters are poorly characterized. A structure-activity study has demonstrated that the potency of vesamicol analogues, as assessed by inhibition of active transport, is highly dependent upon the structure of the analogue. This chapter reports the results of the recent ligand-interaction experiments that were directed toward making a choice between models 1 and 2, and toward the identification of the macromolecular structures of the AChT and VR.


Nuclear Medicine and Biology | 1994

18F-labelled vesamicol derivatives: Syntheses and preliminary in vivo small animal positron emission tomography evaluation

Gary A. Rogers; Sharon Stone-Elander; Martin Ingvar; Lars Eriksson; Stanley M. Parsons; Lennart Widén

As possible presynaptic tracers for cholinergic function in humans, three 18F-labelled vesamicol analogs were synthesized for use in positron emission tomography (PET): cis-[18F]-4-fluoromethylvesamicol (FMV), [18F]-N-fluoroacetamidobenzovesamicol (FAA) and [18F]-N-ethyl-N-fluoroacetamidobenzovesamicol (NEFA). Radiolabelling was accomplished using [18F]fluoride and the corresponding tosylates, the syntheses of which are also described. Yields were on the order of 40-60, 5 and 40-60%, respectively. Dynamic studies of the biodistribution in rats of [18F]FAA and [18F]NEFA using PET were compared with those previously reported for [18F]FMV. Due to probable rapid metabolism, [18F]FAA was considered unsuitable as a ligand for in vivo imaging. [18F]NEFA, similar to [18F]FAA, displayed a more moderate cerebral uptake than that of [18F]FMV (2 vs 20-30%). Pretreatment with vesamicol blocked the cerebral uptake, indicating a specific interaction with the vesamicol binding site. The biodistribution of high specific activity [18F]NEFA with time could be described with a three-compartmental model. The evaluation of [18F]NEFA as a tracer for cholinergic function is currently being pursued in monkeys and humans.


Journal of Neurochemistry | 1992

Binding and active transport of large analogues of acetylcholine by cholinergic synaptic vesicles in vitro.

Edward D. Clarkson; Gary A. Rogers; Stanley M. Parsons

Abstract: A previous structure‐activity investigation of acetylcholine (ACh) revealed a positive correlation between additional hydrophobic bulk and increased potency for inhibition of active transport of [3H]ACh by synaptic vesicles isolated from the electric organ of Torpedo. In the current study, several ACh analogues that are significantly larger than previously studied “false transmitters” were synthesized in the tritiated form by chemical means and tested for active transport. These are analogue 14 [(±)‐(cis,trans)‐1‐benzyl‐1‐methyl‐3‐acetoxypyrrolidinium iodide], analogue 15 [(±)‐1,1‐dimethyl‐3‐benzoyloxypyrrolidinium iodide], and analogue 16/17 [(±)‐(cis,trans)‐ 1‐benzyl‐1‐methyl‐3‐benzoyloxypyrrolidinium iodide]. These analogues place significant additional hydrophobic bulk on one or the other (analogues 14 and 15) or both (analogue 16/17) of the two pharmacophores of a small, conformationally constrained analogue of ACh. [3H]Analogue 14 and [3H]analogue 15 are actively transported, with Vmax values the same as or less than that of ACh, depending on the vesicle preparation. The observation that Vmax is the same for an analogue and ACh in some vesicle preparations suggests that the rate‐limiting step does not involve ACh bound to the transporter. [3H]‐Analogue 16/17 is actively transported very poorly. Km values for ACh and for transported ACh analogues vary by up to two‐ to threefold in different vesicle preparations. The ACh transporter is much less selective for transported substrates than anticipated.


Annual Reports in Medicinal Chemistry | 1993

Chapter 26. In Vivo Diagnostics for Alzheimer's Disease Based on the Acetylcholine Transporter

Stanley M. Parsons; Gary A. Rogers

Publisher Summary This chapter discusses the ACh transporter (AChT). The chapter also discusses the current status of efforts to develop ligands for the AChT that can be used in single photon emission computed tomography (SPECT) or positron emission tomography (PET) to map the density of cholinergic nerve terminals in living human brain. Degeneration of cholinergic terminals in the hippocampus and frontal cortex are among the earliest deficits in this neurodegenerative disease. A sensitive in vivo diagnostic that determines the functional status and/or density of cholinergic nerve terminals in brain might provide a means to detect the onset of Alzheimers disease before cognitive deficits occur. An early diagnostic probably must probe a concentrated target found only in the cholinergic presynapse. The characteristic function of cholinergic nerve terminals, which constitutes about 6% of the cortical terminals in mammalian brain, is to synthesize and release acetylcholine (ACh). The sodium-dependent high affinity choline uptake transporter in the cytoplasmic membrane, choline acetyltransferase in the cytoplasm, and the ACh transporter in the membrane of synaptic vesicles are key proteins in the synthesis and release of ACh. Among the proteins that carry out presynaptic metabolism of ACh, AChT complex has the most highly developed pharmacology. A potent family of compounds that binds allosterically to the AChT is known. Most of the compounds are relatively easily synthesized and many of them exhibit favorable pharmacokinetics in vivo. Despite the various shortcomings of the available analogs, the utility of the vesamicol family for the visualization of cholinergic nerve terminals has been demonstrated. Thus, this approach to the diagnosis of Alzheimers disease has great promise, but better ligands are needed. Because of its modularity, the chemical structure of vesamicol is amenable to extensive structure–activity analysis.


Neurochemical Research | 2003

Specificity of the Rat Vesicular Acetylcholine Transporter

Myung Hee Kim; Mei Lu; Gary A. Rogers; Stanley M. Parsons; Louis B. Hersh

The protein kinase A–deficient PC12 cell line PC12A123.7 lacks both choline acetyltransferase and the vesicular acetylcholine transporter. This cell line has been used to establish a stably transfected cell line expressing recombinant rat vesicular acetylcholine transporter that is appropriately trafficked to small synaptic vesicles. Acetylcholine is transported by the rat vesicular acetylcholine transporter at a maximal rate of 1.45 nmol acetylcholine/min/mg protein and exhibits a Km for transport of 2.5 mM. The transporter binds vesamicol with a Kd of 7.5 nM. The ability of structural analogs of acetylcholine to inhibit both acetylcholine uptake and vesamicol binding was measured. The results demonstrate that like Torpedo vesicular acetylcholine transporter, the mammalian transporter can bind a diverse group of acetylcholine analogs.

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Gary Lynch

University of California

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Lena Nilsson

University of California

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Lars Eriksson

Karolinska University Hospital

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Sharon Stone-Elander

Karolinska University Hospital

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Barry W. Hicks

University of California

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Ben A. Bahr

University of California

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