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.
Content source:
http://www.ohsu.edu/xd/education/schools/school-of-medicine/academic-programs/graduate-studies/faculty/grad-studies-faculty.cfm?facultyid=394
