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About Us : Faculty : Newton

Thomas F. Newton, Ph.D.
Associate Professor in Residence, Division of Adult Psychiatry, UCLA Department of Psychiatry and Biobehavioral Sciences
Senior Research Scientist, Cousins Center for Psychoneuroimmunology, UCLA Neurpsychiatric Institute

Research Interests

Following completion of post-doctoral training in psychobiology, I focused on the study of neurobiology using quantitative electroencephalography (QEEG). Initially, I focused on studies of HIV and described EEG power and coherence abnormalities in subjects with advanced HIV disease (Newton et al 1994a; Newton et al 1994b). Subsequently, I explored potential associations between HIV-related changes in these measures and changes in brain metabolic activity, using positron emission tomography (PET). I then began to extend and expand this work into the area of substance abuse, initially using QEEG and PET to evaluate smokers (Newton et al 1998; Newton et al 1997) and stimulant users. I and co-workers have recently shown that methamphetamine dependence is associated with QEEG abnormalities and with impairment on a range of neuropsychological tests (Kalechstein et al 2003; Newton et al 2003a); other papers show that these electrophysiological and functional measures are highly intercorrelated (Newton et al in press; Newton et al 2004; Newton et al 2003b). Supported by a K08 award, I have completed and am finalizing analysis of a study evaluating neurochemical abnormalities in methamphetamine dependence, using 11C-WIN 35,428 PET to assess dopamine transporter (DAT) availability. Methamphetamine-dependent participants showed reduced DAT availability (20% reduction for caudate and 18% reduction for putamen, compared to non-drug-using comparison subjects). I believe these neurobiological changes have critical implications for better understanding (and developing treatments for) methamphetamine dependence, but I also believe that it is likely that they are not the entire story, as will be discussed more fully below. My research career has been predominantly committed to patient-oriented research and will remain so, as indicated below in Section C and in the Research Plan.

As noted above, I believe that these neurobiological changes reflect only part of the story. The effects of stress on the course of stimulant dependence have generally been overlooked or ignored. Preclinical research has shown that exposure to a variety of stressors is associated with reinstatement of extinguished drug-seeking behavior, as exemplified by the reinstatement model of relapse (Le and Shaham 2002; Shaham et al 2000; Shaham and Stewart 1994; Shaham and Stewart 1995). In addition, chronic stress as modeled by early maternal deprivation is associated with higher rates of drug self-administration in monkeys (Higley et al 1991; Higley et al 1993) and in rats (Kosten et al 2000), and chronic stress has been shown to alter the effects of acute stress in humans (Irwin et al 1991; Pike et al 1997) . I propose to utilize support from this award to obtain additional training in order to the acquire skills and experience needed to carry out research investigating the physiologic and behavioral effects of acute and chronic stress in methamphetamine dependence, as described in the Research Plan below I believe that my current abilities and knowledge will be significantly complemented by the addition of these skills, and that this will facilitate my overall goal, which is to utilize findings from comprehensive, interdisciplinary research to develop effective treatments for stimulant abuse disorders.

Current Research Projects

Current projects include studies assessing bupropion and selegiline for the treatment of methamphetamine dependence. Several projects are just getting underway. These include assessment of the effects of aripiprazole, a dopamine D2 partial agonist on drug-seeking behavior and effects of disulfiram on response to cocaine. These are particularly exciting because dopamine partial agonists have been shown to reduce drug-seeking behavior in rodents. Disulfiram (used in the past for alcoholism treatment) is also of great interest because the compound also inhibits dopamine-beta-hydroxylase, the enzyme converting dopamine to norepinephrine. Inhibition of this enzyme leads to enhanced brain dopamine, which has been shown to reduce drug-seeking behavior. Just funded are two grant with more direct relevance to PNI. One, a 3-year project, will evaluate how perindopril pretreatment alters the effects of methamphetamine. Perindopril (an ACE inhibitor that is a treatment for hypertension) also inhibits enkephalinase and enhances opiate neurotransmission. The second, entitled “Stress Effects in Methamphetamine Dependence” is a career award to evaluate the contribution of PNI relevant measures to methamphetamine dependence.

Higley JD, Hasert MF, Suomi SJ, Linnoila M (1991): Nonhuman primate model of alcohol abuse: effects of early experience, personality, and stress on alcohol consumption. Proc Natl Acad Sci U S A 88:7261-5.

Higley JD, Thompson WW, Champoux M, et al (1993): Paternal and maternal genetic and environmental contributions to cerebrospinal fluid monoamine metabolites in rhesus monkeys (Macaca mulatta). Arch Gen Psychiatry 50:615-23.

Irwin M, Brown M, Patterson T, Hauger R, Mascovich A, Grant I (1991): Neuropeptide Y and natural killer cell activity: findings in depression and Alzheimer caregiver stress. Faseb J 5:3100-7.

Kalechstein AD, Newton TF, Green M (2003): Methamphetamine dependence is associated with neurocognitive impairment in the initial phases of abstinence. J Neuropsychiatry Clin Neurosci 15:215-20.

Kosten TA, Miserendino MJ, Kehoe P (2000): Enhanced acquisition of cocaine self-administration in adult rats with neonatal isolation stress experience. Brain Res 875:44-50.

Le A, Shaham Y (2002): Neurobiology of relapse to alcohol in rats. Pharmacol Ther 94:137.

Newton TF, Cook IA, Holschneider DP, Rosenblatt MR, Lindholm JE, Jarvik MM (1998): Quantitative EEG effects of nicotine replacement by cigarette smoking. Neuropsychobiology 37:112-6.

Newton TF, Cook IA, Kalechstein AD, et al (2003a): Quantitative EEG Abnormalities in Recently Abstinent

Methamphetamine Dependent Individuals. Clinical Neurophysiology 114:410-415.

Newton TF, Kalechstein AD, Duran S, VanSluis N, Ling W (in press): Methamphetamine Abstinence Syndrome: Preliminary Findings. American Journal on Addictions.

Newton TF, Kalechstein AD, Hardy DJ, et al (2004): Association between quantitative EEG and neurocognition in methamphetamine-dependent volunteers. Clin Neurophysiol 115:194-8.

Newton TF, Kalechstein AD, Tervo KE, Ling W (2003b): Irritability following abstinence from cocaine predicts euphoric effects of cocaine administration. Addictive Behaviors 28:817-821.

Newton TF, Khalsa-Denison ME, Gawin FH (1997): The face of craving? Facial muscle EMG and reported craving in abstinent and non-abstinent cocaine users. Psychiatry Res 73:115-8.

Newton TF, Leuchter AF, Miller EN, Weiner H (1994a): Quantitative EEG in patients with AIDS and asymptomatic HIV infection. Clinical Electroencephalography 25:18-25.

Newton TF, Leuchter AF, Walter DO, et al (1994b): Electroencephalographic coherence in AIDS. Psychiatry Research 54:1-11.

Pike JL, Smith TL, Hauger RL, et al (1997): Chronic life stress alters sympathetic, neuroendocrine, and immune responsivity to an acute psychological stressor in humans. Psychosom Med 59:447-57.

Shaham Y, Erb S, Stewart J (2000): Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res Brain Res Rev 33:13-33.

Shaham Y, Stewart J (1994): Exposure to mild stress enhances the reinforcing efficacy of intravenous heroin self-administration in rats. Psychopharmacology (Berl) 114:523-7.

Shaham Y, Stewart J (1995): Stress reinstates heroin-seeking in drug-free animals: an effect mimicking heroin, not withdrawal. Psychopharmacology (Berl) 119:334-41.

Recent Grants

Clinical Research Education for Drug Abuse Professionals

Principle Investigator: T. F. Newton

Agency: National Institute on Drug Abuse

Type: R25DA014593 Period: 9/02-6/07

This is a research training program that serves to train professionals in the methods and procedures associated with performing clinical trials.

Clinical Trials Operations

Principle Investigator: T. Newton

Agency: National Institute on Drug Abuse

Type: N01DA-0-8804 Period: 2/00-2/05

This contract supports a laboratory for inpatient medication studies and a clinical trials program. The inpatient medication study component utilized cocaine and amphetamine challenge approaches to access pharmacodynamic interactions with potential medication treatment for drug dependence.

Principle Investigator: T. Newton

Agency: National Institute on Drug Abuse

Type: N01DA 3 8824 (Ling) Period: 9/30/02- 2005

This contract complements N01DA-0-8804 noted above, which expires in 2005. It supports a series of human laboratory studies in addition to clinical trials and other activities.

Medication Development Unit for Stimulant Dependence

Principle Investigator: T. Newton (human laboratory studies component)

Agency: National Institute on Drug Abuse

Type: P50 DA012755 (Shoptaw) Period: 8/99-8/04, renewed 9/04-9/09
The Medication Development Unit (MDU), in Los Angeles, is dedicated to rapidly evaluating potential pharmacotherapeutic agents for the treatment of cocaine and methamphetamine abuse and dependence.

Cocaine Dependence: EEG Sleep and Cytokines

Principle Investigator: M. Irwin

Agency: NIH/NHLBI

Perindopril-Methamphetamine Interaction Study

Principle Investigator: T. Newton

Agency: NIH/NIDA

Type: R21DA017182 Period: 9/30/03-9/29/06

This study will deteremine effects of perindopril pretratment on the subjective and cardiovascular effects of perindopril, a CNS-penetrating ACE inhibitor.

PENDING

Asses. Stress Effects in Methamphetamine Dependence

Agency: NIH/NIDA Period: Pending

Type: K24 DA17754

This career award will provide salary support with the goal of improving understanding of the effects of stress on drug taking behavior.

Recent Publications

Kalechstein AD, Newton TF, Green M (2003): Methamphetamine dependence is associated with neurocognitive impairment in the initial phases of abstinence. J Neuropsychiatry Clin Neurosci; 15(2):215-20

Newton TF, Kalechstein AD, Tervo KE, Ling W. Irritability Following Abstinence from Cocaine Predicts Euphoric Effects of Cocaine Administration . Addictive Behaviors, (2003) 28:817-821.

Newton TF, Cook IA, Kalechstein AD, Duran S, Monroy F, Ling W, Leuchter AF (2003): Quantitative EEG Abnormalities in Recently Abstinent Methamphetamine Dependent Individuals. Clinical Neurophysiology 114:410-415.

Newton TF, Kalechstein AD, Duran S, VanSluis N, Ling W (2003): Methamphetamine Abstinence Syndrome: Preliminary Findings. American Journal on Addictions In press.

Kalechstein AD, Newton TF, van Gorp WG (in press): Neurocognitive functioning is associated with employment status: a quantitative review. Journal of Clinical and Experimental Neuropsychology.

Houtsmuller EJ, Notes LD, Newton T, Van Sluis N, Chiang N, Elkashef A, Bigelow GE (2003): Transdermal selegiline and intravenous cocaine: safety and interactions. Psychopharmacology (Berl). 172(1): 31-40.

Newton TF, Kalechstein AD, Hardy DJ, Cook IA, Nestor L, Ling W, Leuchter AF Houtsmuller EJ, Notes LD, Newton T, Van Sluis N, Chiang N, Elkashef A, Bigelow GE: Transdermal selegiline and intravenous cocaine: safety and interactions. Psychopharmacology (Berl) 2003: Association between quantitative EEG and neurocognition in methamphetamine-dependent volunteers. Clin Neurophysiol; 115(1):194-8

London ED, Simon SL, Berman SM, Mandelkern MA, Lichtman AM, Bramen J, Shinn AK, Miotto K, Learn J, Dong Y, Matochik JA, Kurian V, Newton T, Woods R, Rawson R, Ling W: Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers. Arch Gen Psychiatry 2004; 61(1):73-84

Contact Information

Thomas F. Newton, Ph.D.
Psychiatry and Biobehavioral Sciences
Box 951759, A7-372 NPI
Los Angeles, CA 90095-1759
Phone: (310) 267-0159
Fax: (310) 267-0162
E-mail: [email protected]

 

 

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