John Williams, Ph.D.
After earning his Ph.D. in Pharmacology from Loyola University in 1979, John Williams worked as a research scientist at the Max-Planck Institute in Munich and at Loyola University School of Medicine. He then spent five years as a research scientist in Biological Sciences at the Massachusetts Institute of Technology. In 1987, he became an assistant staff scientist at the Vollum Institute and rose to the position of senior scientist in 1996. He holds a concurrent appointment in the Department of Physiology and Pharmacology in the School of Medicine. Williams earned his B.S. from St. Lawrence University and his M.S. from the State University of New York at Potsdam.
Summary of Current Research
John Williams and colleagues investigate the early events that lead to the development of tolerance to opioids. Opioids such as morphine are important therapeutic compounds used for the management of pain. The primary problem with the use of opioids is the development of tolerance, where higher doses of morphine are required to achieve the same effect. One ongoing project is the study of opioid actions on neurons in the locus coeruleus. Opioids bind to mu opioid receptors found on locus coeruleus neurons and result in the activation of an inwardly rectifying potassium conductance. Recent work has shown that even a brief treatment with a potent opioid agonist results in a transient decrease in the ability to activate the receptor (desensitization). This desensitization is thought to be one of the earliest steps leading to the long-term decrease in receptor sensitivity found with long-term morphine treatment. A current project focuses on the mechanisms that underlie this desensitization and its reversal.
Another brain area under study is the ventral tegmental area (VTA). This region contains dopamine cells that are an important component of the endogenous reward pathway in the brain. Many abused drugs (cocaine, amphetamine, opioids, nicotine) act in this area to increase the release or presence of dopamine in the extracellular space. Both psychostimulants and opioids cause a presynaptic inhibition of GABA inhibitory postsynaptic potentials in dopamine cells, thus increasing their excitability and causing the release of dopamine. Although glutamate is best known as an excitatory transmitter, it also causes slow inhibitory postsynaptic potentials (IPSPs) in dopamine cells through activation of a metabotropic glutamate receptor. Psychostimulants block the IPSP mediated by glutamate, while leaving the excitatory postsynaptic potential in place. Thus, psychostimulants can increase dopamine release in the brain by several different mechanisms.
Recent studies have focused on the release of dopamine from within the VTA. The regulation of dopamine release is one of the cornerstones in the understanding of the endogenous reward pathway. Studies have focused on the identification of an IPSP mediated by dopamine in this area. This synaptic potential is the first of its kind and offers the opportunity to study the basic mechanisms that control dopamine release as well as the direct actions of drugs of abuse on this key transmitter. One observation resulting from this work is the realization that the pool of dopamine used for synaptic transmission is very labile. Dopamine release can be increased or decreased rapidly after treatment with a variety of drugs. Among the drugs that increase dopamine release is L-DOPA, an agent used commonly for patients with Parkinson’s disease. The mechanisms that regulate synaptic release of dopamine may help explain the actions of certain therapeutic drugs as well as the long-term effects of drugs of abuse.
Vaaga CE, Yorgason JT, Williams JT, Westbrook GL. (2017) Presynaptic gain control by endogenous cotransmission of dopamine and GABA in the olfactory bulb. J. Neurophysiol. 117:1163-1170.
Yorgason JT, Zeppenfeild DM, Williams JT. (2017) Cholinergic interneurons underlie spontaneous dopamine release in nucleus accumbens. J. Neurosci. 37:2086-2096.
Kramer PF, Williams JT. (2016) Calcium release from stores inhibits GIRK. Cell Reports 17:3246-3255.
Gantz SC, Robinson BG, Buck DC, Bunzow JR, Neve RL, Williams JT, Neve KA. (2015) Distinct regulation of dopamine D2S and D2L autoreceptor signaling by calcium. eLife 4:e09358.
Gantz SC, Levitt ES, Llamosas N, Neve KA, Williams JT. (2015) Depression of serotonin synaptic transmission by the dopamine precursor L-DOPA. Cell Reports 12:944-954.
Levitt ES, Abdala AP, Paton JF, Bissonnette JM, Williams JT. (2015) Mu opioid receptor activation hyperpolarizes respiratory-controlling Kölliker-Fuse neurons and suppresses post-inspiratory drive. J. Physiol. 593:4453-4469.
Birdsong WT, Arttamangkul S, Bunzow JR, Williams JT. (2015) Agonist binding and desensitization of the mu-opioid receptor is modulated by phosphorylation of the C-terminal tail domain. Mol. Pharm. 88:816-824.
Kramer PF, Williams JT. (2015) Cocaine decreases metabotropic glutamate receptor mGluR1 currents in dopamine neurons by activating mGluR5. Neuropsychopharmacology 40:2418-2424.
Arttamangkul S, Birdsong W, Williams JT. (2014) Does PKC activation increase the homologous desensitization of mu-opioid receptor? Br. J. Pharmacol. 172:583-592.