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Department of Psychiatry & Behavioral Sciences
Department of Pharmacology
Graduate Program in Neurobiology & Behavior
Graduate Program in Molecular & Cellular Biology
Center for Drug Addiction Research

pemp@washington.edu

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Paul graduated in Physiology from the University of Liverpool in 1993. He then joined the Neurotransmission Research Group in the Academic Department of Anaesthesia and Intensive Care at St Bartholomew's and the Royal London School of Medicine and Dentistry (University of London) where he completed his PhD in Neuroscience under the supervision of Jon Stamford. In 1999 he moved to the University of North Carolina at Chapel Hill to take up a postdoctoral position with Mark Wightman in the Department of Chemistry. After two years of collaboration with Gina Carelli in Psychology at UNC, in 2003 he was appointed to Research Assistant Professor in that department. Paul joined the faculty at the University of Washington in 2004.

Research interests

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 is 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 molecular processes that inevitably underlie these components.

Selected publications

Phillips PEM, Walton ME and Jhou TC (2007) Calculating utility: cost-benefit analysis by mesolimbic dopamine. Psychopharmacology 191, 483-495 • PDF

Phillips PEM and Wightman RM (2003) Critical guidelines for validation of the selectivity of in-vivo chemical microsensors. Trends in Analytical Chemistry 22, 509-514 • PDF

Phillips PEM, Stuber GD, Heien MLAV, Wightman RM and Carelli RM (2003) Subsecond dopamine release promotes cocaine seeking. Nature 422, 614-618 • PDF

Phillips PEM, Hancock PJ and Stamford JA (2002) The time window of autoreceptor-mediated inhibition of limbic and striatal dopamine release. Synapse 44, 15-22 • PDF

Phillips PEM and Stamford JA (2000) Differential recruitment of N-, P- and Q-type voltage-operated calcium channels in striatal dopamine release evoked by ‘regular’ and ‘burst’ firing patterns. Brain Research 884, 139-146 • PDF

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