Douglas Jones, PhD

Assistant Professor


   Midwestern University
   Arizona College of Osteopathic Medicine
   Department of Pharmacology
   Agave 214
   19555 N 59th Ave
   Glendale, Arizona, 85308
   Office: (623) 572-3713
   e-mail: djones@midwestern.edu

EDUCATION

BS Psychology University of Kansas 1992
MS Medicinal Chemistry and Molecular Pharmacology Purdue University 2000
PhD Toxicology/Pharmacology University of Texas 2004

RESEARCH

In general, my research interests include the potential adverse effects that environmental toxicants (pesticides, endocrine disrupters, heavy metals) have on the brain and behavior. Currently, the major focus of my work is a project examining the role of muscarinic receptor uncoupling in Alzheimer's disease (AD). A secondary project will focus on the effects of specific toxins on muscarinic receptor uncoupling and cholinergic degeneration. The hallmark neuropathology of AD consists of 1) accumulation of Ab, 2) formation of neurofibrillary tau tangles, 3) and the degeneration of cholinergic neurons. Cholinergic dysfunction in AD is associated with the disruption of muscarinic receptor function. Although cholinesterase inhibitors, the major treatment of AD, alleviate some of the cognitive deficits in AD the effectiveness is limited by a number of factors including continuing degeneration of cholinergic neurons and the uncoupling of muscarinic receptors from their g-proteins and the cell signaling cascade. For this reason, new therapeutic strategies such as directly targeting post-synaptic muscarinic receptors, specifically M1, are actively being investigated. M1mAChRs are heavily distributed in the cerebral cortex and hippocampus where they play a major role in learning and memory as well as the regulation of cognition. Several reports have indicated a reduction in high affinity agonist binding and an uncoupling of the M1 receptor from its g-protein and secondary signaling mechanisms, including PLC, in AD patients. The extent of muscarinic impairment correlates with the degree of amyloid plaque formation and the stage of associated cognitive changes. Finally, Ab caused a reduction in M1 receptor levels and downstream proteins, suggesting that it may exaggerate cholinergic dysfunction.

Exposure to pesticides, including DDT, has been associated with the development of AD. DDT is a colorless, tasteless and almost odorless organochloride known for its insecticidal properties. It was widely used in agriculture in the US until it was banned in 1972 although it is still used in other countries. Although banned from use in the US for 40 plus years, due its long half-life and high degree of lipophilicity, DDT and its metabolites persist in nature and have a tendency to bioaccumulate in mammals. Consequently, depending on patterns of international DDT use and trade, it is possible that dietary exposure levels may actually increase over time (Agency for Toxic Substances and Diseases Registry; ATSDR). Following neonatal exposure to DTT animals displayed permanent changes in muscarinic receptors and behavior. Finally, recent studies report elevated levels of DDT metabolites in the brain and plasma of AD subjects.  

Research projects

Aim 1: To investigate the effects of Aβ and DDT on muscarinic M1 receptor uncoupling in an in-vitro cell model, human neuroblastoma cells (SH-5YSY).

Muscarinic receptor uncoupling may be exaggerated with increased amyloid precursor protein (APP695) levels; hence, comparisons will be made between cells with normal APP695 expression and cells that overexpress APP695. The hypothesis being tested is that exposure to Aβ or DDT will induce uncoupling of the M1 receptor from its g-protein signaling mechanisms and alter proteins involved in receptor coupling and internalization.

Aim 2: To characterize muscarinic M1 receptor uncoupling and the effects of DDT in an animal model of AD (3xTg-AD mice).

In addition we will begin studies on the effects of DDT exposure on this uncoupling. Levels of Aβ accumulation will be correlated to uncoupling of M1 receptors and alterations in protein markers. The hypothesis being studied is that 3xTg-AD mice will demonstrate increased signs of M1 receptor uncoupling as they age.  In addition, we suspect that exposure to DDT will exaggerate uncoupling.                
   

SELECTED PUBLICATIONS

Regulation of CART peptide expression by CREB in the rat nucleus accumbens in vivo. Rogge GA, Jones DC, Green T, Nestler E, Kuhar MJ. Brain Res. 2009 Jan 28;1251:42-52. doi: 10.1016/j.brainres.2008.11.011. Epub 2008 Nov 14. PMID: 19046951

The effects of environmental neurotoxicants on the dopaminergic system: A possible role in drug addiction. Jones DC, Miller GW. Biochem Pharmacol. 2008 Sep 1;76(5):569-81. doi: 10.1016/j.bcp.2008.05.010. Epub 2008 May 20. Review. PMID: 18555207

CART receptor binding in primary cell cultures of the rat nucleus accumbens. Jones DC, Kuhar MJ. Synapse. 2008 Feb;62(2):122-7. PMID: 18000808

The CART (cocaine- and amphetamine-regulated transcript) system in appetite and drug addiction. Vicentic A, Jones DC. J Pharmacol Exp Ther. 2007 Feb;320(2):499-506. Epub 2006 Jul 13. Review. PMID:16840648

CART peptides as modulators of dopamine and psychostimulants and interactions with the mesolimbic dopaminergic system. Hubert GW, Jones DC, Moffett MC, Rogge G, Kuhar MJ.Biochem Pharmacol. 2008 Jan 1;75(1):57-62. Epub 2007 Jul 26. Review. PMID: 17854774

The role of CART in the reward/reinforcing properties of psychostimulants. Jaworski JN, Jones DC. Peptides. 2006 Aug;27(8):1993-2004. Review. PMID: 16766084

Cocaine-amphetamine-regulated transcript expression in the rat nucleus accumbens is regulated by adenylyl cyclase and the cyclic adenosine 5'-monophosphate/protein kinase a second messenger system. Jones DC, Kuhar MJ. J Pharmacol Exp Ther. 2006 Apr;317(1):454-61. Epub 2005 Dec 1. PMID:16322355

Serotonergic neurotoxic metabolites of ecstasy identified in rat brain. Jones DC, Duvauchelle C, Ikegami A, Olsen CM, Lau SS, de la Torre R, Monks TJ. J Pharmacol Exp Ther. 2005 Apr;313(1):422-31. Epub 2005 Jan 5. PMID:15634943

The role of metabolism in 3,4-(+)-methylenedioxyamphetamine and 3,4-(+)-methylenedioxymethamphetamine (ecstasy) toxicity. Monks TJ, Jones DC, Bai F, Lau SS. Ther Drug Monit. 2004 Apr;26(2):132-6. Review. PMID:15228153

Thioether metabolites of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine inhibit human serotonin transporter (hSERT) function and simultaneously stimulate dopamine uptake into hSERT-expressing SK-N-MC cells. Jones DC, Lau SS, Monks TJ. J Pharmacol Exp Ther. 2004 Oct;311(1):298-306. Epub 2004 May 28. PMID:15169827

Cyanide enhancement of dopamine-induced apoptosis in mesencephalic cells involves mitochondrial dysfunction and oxidative stress. Jones DC, Prabhakaran K, Li L, Gunasekar PG, Shou Y, Borowitz JL, Isom GE. Neurotoxicology. 2003 Jun;24(3):333-42. PMID:12782099

The metabolism and toxicity of quinones, quinonimines, quinone methides, and quinone-thioethers. Monks TJ, Jones DC. Curr Drug Metab. 2002 Aug;3(4):425-38. Review. PMID:12093358