CURRENT RESEARCH INTERESTS

I am interested in the molecular basis for neurobehavioral disorders, especially posttraumatic stress disorder and alcoholism. The long-term aim of my research is to identify drug targets for the treatment of these disorders. This aim can only be achieved by understanding the molecular mechanisms by which these disorders arise and are maintained. I use a combination of molecular, behavioral, genetic and pharmacological approaches.

Posttraumatic Stress Disorder (PTSD)

PTSD can be modeled in rodents by examining the extinction of conditioned fear. Protein kinase C (PKC) is a family of intracellular signaling molecules. I have found that transgenic mice lacking the epsilon isoform of PKC (PKCε) exhibit a profound deficit in the extinction of conditioned fear. PKCε-null mice show other behavioral deficits relevant to PTSD such as impaired reversal learning. Funded by a PTSD New Investigator grant from the U.S. Department of Defense, I am determining the anatomical site of action of PKCε using lentiviral-vector mediated RNA-interference. I am also examining whether treatment with PKCε activators can accelerate the extinction of conditioned fear, a translational project aimed at developing treatments for PTSD.

Alcoholism

Using preclinical models, I have identified the N-type calcium channel as a therapeutic target for the treatment of alcoholism. The N-type calcium channel is a presynaptic voltage-gated calcium channel that controls neurotransmitter release. The abundance of the N-type calcium channel is increased by chronic ethanol exposure. I examined the ethanol phenotype of transgenic mice lacking functional N-type calcium channels and found that these mice have a very unusual ethanol phenotype; they are very resistant to the acute effects of ethanol but show reduced alcohol consumption. They also display reduced anxiety-like behavior. I obtained, from our collaborators at Neuromed Pharmaceuticals (Vancouver, BC), a novel inhibitor of N-type calcium channels (NP078585) that is suitable for in vivo use. I found that NP078585 potently reduces responding in multiple animal models of alcoholism and anxiety. We are currently assessing whether N-type calcium channel inhibitors can reduce craving for other drugs of abuse, as well as localizing the anatomical site of action for N-type calcium channels using microinjection and RNAi.

I completed my Ph.D. in Biochemistry and Molecular Biology at the University of Leeds, UK, in 2001. I received my postdoctoral training at the University of California, San Francisco in the laboratory of Dr. Robert O. Messing.

SELECTED PUBLICATIONS

1. Newton PM, Orr CJ. Wallace MJ, Shin H-S, Messing RO. Deletion of N-type calcium channels blocks ethanol reward and reduces ethanol consumption in mice. J. Neurosci. 24:9862-9869, 2004.
2. Newton PM, Watson JA, Wolowacz R, Wood, EJ. 2004. Macrophages restrain contraction of an in vitro wound healing model. Inflammation 28 (4): 207-214.
3. Newton PM, Tully K, McMahon T, Connolly J, Dadgar J, Treistman SM, Messing RO. Chronic ethanol exposure induces an N-type calcium channel splice variant with altered channel kinetics. FEBS Lett. 579:671-676, 2005.
4. Newton, PM. and Messing RO. Intracellular signaling pathways that regulate behavioral responses to ethanol. Pharmacol. Ther. 109: 227-237, 2005.
5. Wallace MJ, Newton PM, Oyasu M, McMahon T, Chou W-H, Connolly J, Messing RO. Acute functional tolerance to ethanol mediated by protein kinase C. Neuropsychopharmacology 32 (1): 127-136 2007.
6. Newton PM, Kim JA, McGeehan AM, Paredes JP, Chu K, Wallace MJ, Roberts AJ, Hodge CW and Messing RO. Increased response to morphine in mice lacking protein kinase C epsilon. Genes Brain Behav 2007 6(4):329-38.
7. Newton PM and Messing R.O. Increased sensitivity to the aversive effects of ethanol in PKC null mice revealed by place conditioning. Behav Neurosci 2007 121(2):439-42.
8. Newton PM and Ron D. PKC Homeostasis and alcohol addiction. Pharmacol Res 2007 Jun;55(6):570-7.
9. Qi ZH, Song M, Wallace MJ, Wang D, Newton PM, McMahon T, Zhang C, Shokat KM, Messing RO. Protein kinase C epsilon regulation of GABAA receptors revealed using chemical genetics. J Biol Chem 2007. 282(45):33052-63.
10. Newton PM, McGeehan AJ, Zeng L, Wang V, Connolly J, Wallace MJ, Kim CK, Shin HS, Belardetti F, Snutch TP and Messing RO. A Blocker of N- and T-type voltage-gated calcium channels attenuates ethanol-induced intoxication, place-preference, sef-administration and relapse. J Neurosci 28;11712-11719.
11. Lesscher HMB, Wallace, MJ, Zeng L, Wang V, Deitchman JKD, Messing RO and Newton PM. 2008. Amygdala protein kinase C epsilon controls alcohol consumption. In review.