Dynamic Neuropharmacology in Parkinson’s Disease and Aging
Dr. Gerhardt’s laboratory focuses on studies of the dopamine and glutamate neurotransmitter systems in animal models of Parkinson’s disease. For these studies, his lab uses both the 6-hydroxydopamine-treated rat model and the MPTP-treated primate model of Parkinson’s disease. Using his microsensor techniques, Dr. Gerhardt’s lab has investigated the release and uptake of dopamine in the striatum and substantia nigra of the normal and parkinsonian brain. A major finding from these studies is that there is a severe disruption of dopamine regulation in the parkinsonian brain. This disruption of the control of dopamine may relate to some of the movement problems seen in this CNS disease. His laboratory is currently investigating the use of growth factors, such as GDNF, to restore function to damaged dopamine neurons. His laboratory has recently shown that GDNF can restore function to damaged dopamine neurons in rats and monkeys. This formed the basis for the Morris K. Udall Parkinson’s Disease Center of Excellence, which has evolved into the Brain Restoration Center.
Another area of research in his laboratory involves studies of movement abnormalities in aging. Such studies are performed in the striatum and substantia nigra of young and aged Fischer 344 rats, and in young and aged nonhuman primates. His recent studies have shown that dopamine synapses change in their ability to regulate neurotransmitter release through changes in the dopamine transporter. This lack of regulation or change in the regulation of neurotransmitter signaling may account for some of the motor abnormalities that are seen in aged animals and humans.
A major research area of Dr. Gerhardt’s laboratory is the dynamics of neurotransmitter function in the central nervous system. In order to perform such studies, his lab develops microsensors (5-30 microns) and instrumentation for the rapid, sensitive, and spatially resolved measurement of neurotransmitters and neuromodulators, such as dopamine, norepinephrine, serotonin, nitric oxide, and glutamate. A major goal of these studies is to understand neurotransmitter signaling in biological systems. This forms the basis for the Center for Microelectrode Technology.
Stanford JA and Gerhardt GA. Aged F344 rats exhibit altered electrophysiological activity in locomotor-unrelated but not locomotor-related striatal neurons. Neurobio Aging 25:509-515, 2004.
Moxon, K.A., Leiser S., Gerhardt GA and Chapin J.K. Ceramic-based multisite electrode arrays for chronic single-neuron recording. IEEE Transaction on Biomedical Engineering 51(4):647-656, 2004.
Salvatore MF, Zhang J-L, Large DM, Wilson PE, Gash CR, Thomas TD, Haycock, JW, Bing G, Stanford JA, Gash DM and Gerhardt GA. Striatal GDNF administration increases tyrosine hydroxylase phosphorylation in the rat striatum and substantia nigra. J Neurochem 90(1):245-254, 2004.
Zuch CL, David D, Ujhelyi L, Hudson JL, Gerhardt GA, Kaplan PL and Bickford PC. Beneficial effects of intraventricularly administered BMP-7 following a striatal 6-hydroxydopamine lesion. Brain Res 1010:10-16, 2004.
Parikh V, Sarter M, Bruno JP, Pomerleau F, Huettl P, and Gerhardt GA. Amperometric measurement of extracellular choline: A method for the detection of rapid changes in cholinergic transmission. Eur J Neurosci. 20(6):1545-54., 2004.
Maswood N, Young J, Tilmont E, Zhang Z, Gash DM, Gerhardt GA, Grondin R, Yi A, Roth GS, Lane MA, Carson R, Cohen RM, Mouton PM, Mattson MP, Ingram DK. Caloric restriction increases GDNF levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson’s disease. PNAS, 101(52):18171-18176, 2004.
Nickell J, Pomerleau F, Allen J and Gerhardt GA. Aged related changes in the dynamics of potassium-evoked l-glutamate release in the striatum of Fischer 344 rats. J Neural Transm. 112(1):87-96, 2004.
Zaman V, Nelson ME, Gerhardt GA and Rohrer B. Neurodegenerative alterations in the nigrostriatal system of trkB hypomorphic mice. Exp. Neurol. 190(2):337-46, 2004.
Burmeister JJ, Palmer M and Gerhardt GA. L-lactate measures in brain tissue with ceramic-based multisite microelectrodes. Biosensors and Bioelectronics 20:1772-1779, 2005.
Daws LC, Montanez S, Owens WA, Gould GG, Frazer A, Toney GM and Gerhardt GA. Transport mechanisms governing serotonin clearance in vivo revealed by high speed chronoamperometry. J Neurosci Meth 143(1):49-62, 2005.
Glaser PEA, Currier TD, Joyce BM, Castellanos FX and Gerhardt GA. In vivo electrochemical studies of d-amphetamine and d,l-amphetamine-induced dopamine release in the rat striatum and nucleus accumbens core. Psychopharmacology (in press), 2005.
Slevin JT, Gerhardt GA, Smith CD, Gash DM, Kryscio R, and Young AB. Unilateral Intraputamenal GDNF improves bilateral motor functions in patients with Parkinson’s disease. J Neurosurg 102:216-222, 2005.
Gash DM, Zhang Z, Ai Y, Grondin R and Gerhardt GA. Intranigral GDNF infusion: VTA and nigral restoration in parkinsonian monkeys. Annals of Neurology (in press), May 17, 2005.
Ferreira NR, Ledo A, Frade JG, Gerhardt GA, Laranjinha J, and Barbosa RM. Electrochemical measurement of endogenously-produced nitric oxide in brain slices using nafion/o-phenylenediamine modified carbon fiber microelectrodes. Analytica Chimica Acta (in press), 2005.
Salvatore MF, Fisher B, Surgener SP, Gerhardt GA, and Roualut T. Neurochemical investigations of dopamine neunal systems in iron-regulatory protein 2 (IRP-2) knockout mice. Mol. Brain Res. (in press), 2005.