Paul E. M. Phillips |
|
University of Washington School of Medicine Psychiatry and Behavioral Sciences Assistant ProfessorAppointed: 2004 University of Washington School of Medicine Pharmacology Joint Assistant ProfessorAppointed: 2004 |
Mailing AddressDepartment of Psychiatry and Behavioral Sciences Box 356560 University of Washington Seattle, Washington 98195-6560United States | Contact Informationpemp@u.washington.edu http://faculty.washington.edu/pemp |
Qualifications
Ph.D., University of London, Neuroscience, 1999.
B.Sc., University of Liverpool, Physiology, 1993.
Expertise and Research Interests
Rapid dopamine signaling; Presynaptic control of dopamine release
The nucleus accumbens had been proposed as an anatomical substrate of limbic-motor integration. It gathers information from midbrain dopaminergic neurons that are activated by salient sensory stimuli and from glutamatergic afferents from the amydala, hippocampus and prefrontal cortex that encode memory of prior responses, the emotional state and the context. This information is processed and, based on previous learning, an appropriate motor response to the stimulus is generated.
We are particularly interested in the dopaminergic input to the nucleus accumbens. Midbrain dopaminergic neurons burst fire in response to natural reinforcers or to stimuli that have been paired to their delivery. This has been presumed to result in a subsecond, transient increase in dopamine in several forebrain structures. Recently, we confirmed this by making direct chemical measurements of such changes during presentation of natural reinforcers, drug reinforcers or their paired cues. Increases in forebrain dopamine typically result in motor activation. In particular, increases in dopamine in the nucleus accumbens have been implicated in goal-directed movements. Using cocaine self-administration as a model of drug abuse, we provided the first direct evidence that phasic dopamine changes are temporally linked to, and can trigger drug-seeking behavior.
The associative information conveyed by phasically activated dopaminergic neurons is encoded from discrete sensory cues. In real world scenarios, rewards are predicted by a collection of cues and so it is desirable that their combined predictive value cues are effectively assessed. To do this, the response to an individual cue should adapt on presentation of multiple cues. Indeed, we find that if dopaminergic neurons are repeatedly activated with bursts of electrical stimulation, there is a large degree of variability in the amount of dopamine released for each burst. This is dictated by the history of stimulation (i.e., feedback control). In general, if bursts of stimulation are repeated close together in time, there is facilitation of the neurochemical response, but if stimulation persists the response becomes depressed. This may be desirable for the information encoding: if an animal receives several cues that a reward may be available it would be efficient to promote reward seeking above that for a single cue (since the probability of a reward being available would be higher), but conversely when the animal enters an environment that is rich with cues, the procurement of reward may not be such an ongoing priority for survival and he is able to ''tune out.'' In collaboration with Read Montague of Baylor College of Medicine, we have sought to understand the dynamics of this feedback. We have found that it can be accurately modeled using three dynamic components: short-lasting facilitation and both short- and long-lasting depression. We are currently determining the relative contributions of the physiological processes that inevitably underlie these components.
The nucleus accumbens had been proposed as an anatomical substrate of limbic-motor integration. It gathers information from midbrain dopaminergic neurons that are activated by salient sensory stimuli and from glutamatergic afferents from the amydala, hippocampus and prefrontal cortex that encode memory of prior responses, the emotional state and the context. This information is processed and, based on previous learning, an appropriate motor response to the stimulus is generated.
We are particularly interested in the dopaminergic input to the nucleus accumbens. Midbrain dopaminergic neurons burst fire in response to natural reinforcers or to stimuli that have been paired to their delivery. This has been presumed to result in a subsecond, transient increase in dopamine in several forebrain structures. Recently, we confirmed this by making direct chemical measurements of such changes during presentation of natural reinforcers, drug reinforcers or their paired cues. Increases in forebrain dopamine typically result in motor activation. In particular, increases in dopamine in the nucleus accumbens have been implicated in goal-directed movements. Using cocaine self-administration as a model of drug abuse, we provided the first direct evidence that phasic dopamine changes are temporally linked to, and can trigger drug-seeking behavior.
The associative information conveyed by phasically activated dopaminergic neurons is encoded from discrete sensory cues. In real world scenarios, rewards are predicted by a collection of cues and so it is desirable that their combined predictive value cues are effectively assessed. To do this, the response to an individual cue should adapt on presentation of multiple cues. Indeed, we find that if dopaminergic neurons are repeatedly activated with bursts of electrical stimulation, there is a large degree of variability in the amount of dopamine released for each burst. This is dictated by the history of stimulation (i.e., feedback control). In general, if bursts of stimulation are repeated close together in time, there is facilitation of the neurochemical response, but if stimulation persists the response becomes depressed. This may be desirable for the information encoding: if an animal receives several cues that a reward may be available it would be efficient to promote reward seeking above that for a single cue (since the probability of a reward being available would be higher), but conversely when the animal enters an environment that is rich with cues, the procurement of reward may not be such an ongoing priority for survival and he is able to ''tune out.'' In collaboration with Read Montague of Baylor College of Medicine, we have sought to understand the dynamics of this feedback. We have found that it can be accurately modeled using three dynamic components: short-lasting facilitation and both short- and long-lasting depression. We are currently determining the relative contributions of the physiological processes that inevitably underlie these components.
Other Expertise
Rapid electrochemical detection of neurotransmitters
Keywords
COS Keywords:
Anatomy, Dopamine, Drugs or Drug Abuse, Neurochemistry, Neurophysiology, Neuroscience, Neurotransmitters, Physiology, Psychiatry, Psychology.Additional Terms:
Neuroeconomics, Reward.Languages
(Reading, Writing, Speaking)
English: (Fluent, Fluent, Fluent)
French: (Basic, Basic, Basic)
Memberships
International Brain Research Organization
Society for Electroanalytical Chemistry
Society for Neuroeconomics
Society for Neuroscience
Previous Positions
2004, Visiting Scholar,
University of Cambridge,
Biology,
Anatomy
2003-2004, Research Assistant Professor,
University of North Carolina at Chapel Hill,
College of Arts and Sciences,
Psychology
1999-2002, Postdoctoral Research Associate,
University of North Carolina at Chapel Hill,
College of Arts and Sciences,
Chemistry
1995-1999, Graduate Student,
University of London,
St. Bartholomew's and the Royal London School of Medicine and Dentistry,
Anesthetics Unit
Funding Received
- NIH/NIDA: Dynamic control of dopamine release in cocaine abuse, 2005 to 2007.
- NIH/NIDA: Overexpression of dopamine D1 and D2 receptors to study behaviors related to drug abuse, 2005 to 2007.
- Alcohol and Drug Abuse Institute: Subsecond dopamine release during acquisition of drug-taking behavior, 2005 to 2006.
- UW Royalty Research Fund: Miniaturized instrumentation for multisite, real-time dopamine detection in behaving animals, 2005 to 2006.
Publications
- Walton ME, Kennerley SW, Bannerman DM, Phillips PEM, Rushworth MFS (2006) Weighing up the benefits of work: Behavioral and neural analyses of effort-related decision making, Neural Networks, 19, 1302-1314
- Hnasko TS, Perez FA, Scouras AD, Stoll EA, Gale SD, Luquet S, Phillips PEM, Kremer EJ, Palmiter RD (2006) Cre-recombinase mediated restoration of nigrostriatal dopamine in a dopamine-deficient mouse reverses hypophagia and bradykinesia, Proceedings of the National Academy of Sciences of the United States of America, 103, 8858-8863
- Venton BJ, Seipel AT, Phillips PEM, Wetsel WC, Gitler D, Greengard P, Augustine GJ, Wightman RM (2006) Cocaine increases dopamine release by mobilization of a synapsin-dependent reserve pool, Journal of Neuroscience, 26, 3206-3209
- Vitaliano PP, Echeverria D, Yi J, Phillips PEM, Young H, Siegler IC (Sep 2005) Psychophysiological mediators of caregiver stress and differential cognitive decline., Psychology and Aging, 20 (3), 402-11
- Heien MLAV, Khan AS, Ariansen JL, Cheer JF, Phillips PEM, Wassum KM, Wightman RM (Jul 2005) Real-time measurement of dopamine fluctuations after cocaine in the brain of behaving rats., Proceedings of the National Acadamy of Sciences of the United States of America, 102 (29), 10023-8
- Stuber GD, Roitman MF, Phillips PEM, Carelli RM, Wightman RM, Rapid Dopamine Signaling in the Nucleus Accumbens During Contingent And
Noncontingent Cocaine Administration., Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology., 30(5), 853-63, May 2005
- Lavin A, Nogueira L, Lapish CC, Wightman RM, Phillips PEM, Seamans JK, Mesocortical Dopamine Neurons Operate in Distinct Temporal Domains Using
Multimodal Signaling., The Journal of Neuroscience : the Official Journal of the Society for Neuroscience., 25(20), 5013-23, May 2005
- Cheer JF, Wassum KM, Heien MLAV, Phillips PEM, Wightman RM, Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats, The Journal of Neuroscience : the Official Journal of the Society for Neuroscience., 24(18), 4393-400, May 2004
- Phillips PEM, Wightman RM, Extrasynaptic dopamine and phasic neuronal activity, Nature Neuroscience, 7(3), 199; author reply 19, Mar 2004
- Montague PR, McClure SM, Baldwin PR, Phillips PEM, Budygin EA, Stuber GD, Kilpatrick MR, Wightman RM, Dynamic gain control of dopamine delivery in freely moving animals, The Journal of Neuroscience : the Official Journal of the Society for Neuroscience., 24(7), 1754-9, Feb 2004
- Roitman MF, Stuber GD, Phillips PEM, Wightman RM, Carelli RM, Dopamine operates as a subsecond modulator of food seeking, The Journal of Neuroscience : the Official Journal of the Society for Neuroscience., 24(6), 1265-71, Feb 2004
- Venton BJ, Zhang H, Garris PA, Phillips PEM, Sulzer D, Wightman RM, Real-time decoding of dopamine concentration changes in the caudate-putamen during tonic and phasic firing, Journal of Neurochemistry, 87(5), 1284-95, Dec 2003
- Heien MLAV, Phillips PEM, Stuber GD, Seipel AT, Wightman RM, Overoxidation of carbon-fiber microelectrodes enhances dopamine adsorption and increases sensitivity, The Analyst, 128(12), 1413-9, Dec 2003
- Phillips PEM, Wightman RM, Critical guidelines for validation of the selectivity of in-vivo chemical microsensors, Trends in Analytical Chemistry, 22(9), 509-514, 01 Sep 2003
- Phillips PEM, Stuber GD, Heien MLAV, Wightman RM, Carelli RM, Subsecond dopamine release promotes cocaine seeking, Nature, 422(6932), 614-8, Apr 2003
- Garris PA, Budygin EA, Phillips PEM, Venton BJ, Robinson DL, Bergstrom BP, Rebec GV, Wightman RM, A role for presynaptic mechanisms in the actions of nomifensine and haloperidol, Neuroscience, 118(3), 819-29, 2003
- Phillips PEM, Robinson DL, Stuber GD, Carelli RM, Wightman RM, Real-time measurements of phasic changes in extracellular dopamine concentration in freely moving rats by fast-scan cyclic voltammetry, Methods in Molecular Medicine, 79, 443-64, 2003
- Phillips PEM, Johns JM, Lubin DA, Budygin EA, Gainetdinov RR, Lieberman JA, Wightman RM, Presynaptic dopaminergic function is largely unaltered in mesolimbic and mesostriatal terminals of adult rats that were prenatally exposed to cocaine, Brain Research, 961(1), 63-72, Jan 2003
- Phillips PEM, Hancock PJ, Stamford JA, Time window of autoreceptor-mediated inhibition of limbic and striatal dopamine release, Synapse (new York, N.y.), 44(1), 15-22, Apr 2002
- Budygin EA, Phillips PEM, Wightman RM, Jones SR, Terminal effects of ethanol on dopamine dynamics in rat nucleus accumbens: an in vitro voltammetric study, Synapse (new York, N.y.), 42(2), 77-9, Nov 2001
- Robinson DL, Phillips PEM, Budygin EA, Trafton BJ, Garris PA, Wightman RM, Sub-second changes in accumbal dopamine during sexual behavior in male rats, Neuroreport, 12(11), 2549-52, Aug 2001
- Budygin EA, Phillips PEM, Robinson DL, Kennedy AP, Gainetdinov RR, Wightman RM, Effect of acute ethanol on striatal dopamine neurotransmission in ambulatory rats, The Journal of Pharmacology and Experimental Therapeutics, 297(1), 27-34, Apr 2001
- Phillips PEM, Stamford JA, Differential recruitment of N-, P- and Q-type voltage-operated calcium channels in striatal dopamine release evoked by 'regular' and 'burst' firing, Brain Research, 884(1--2), 139-46, Nov 2000
- Schulte D, Callado LF, Davidson C, Phillips PEM, Roewer N, Schulte am Esch J, Stamford JA, Propofol decreases stimulated dopamine release in the rat nucleus accumbens by a mechanism independent of dopamine D2, GABAA and NMDA receptors, British Journal of Anaesthesia, 84(2), 250-3, Feb 2000
- Phillips PEM, Stamford JA, Voltammogram 'landscapes' aid detection and identification of in vivo electrochemical signals, 11(5), 301-307, May 1999
- Lipton P, Aitken PG, Dudek FE, Eskessen K, Espanol MT, Ferchmin PA, Kelly JB, Kreisman NR, Landfield PW, Larkman PM, et al., Making the best of brain slices: comparing preparative methods, Journal of Neuroscience Methods, 59(1), 151-6, Jun 1995
Profile Details
Last Updated: 8/30/2007
COS Expertise ID #1121505
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