University of Chicago Hospital

Innovation 1

One area of interest is to understand mechanisms underlying drug addiction and to find possible treatment. Drug addiction is a brain disease and one of the foremost public health problems in the U.S. and in the world. Memories of drug experience and drug-associated environmental cues can elicit drug seeking and taking behaviors. Relapse to drug-taking is the main obstacle to long-term treatment and cure for drug addiction in humans. Currently, there are few strategies for treating drug addiction. We have been investigating the key molecules including dopamine receptors and related intracellular mediators that are involved in reward-related learning and memory induced by drugs of abuse. We combine behavioral, genetic, anatomical and molecular biological methods. One major recent research project is mechanisms associated with reconsolidation of cocaine-induced reward memory. We found that D1 and D3 receptors and related signaling mechanisms play key roles in reconsolidation of cocaine memories in mice, and that these receptors may serve as novel targets for the treatment of cocaine abuse in humans. Another project is to understand how cocaine-induced memories can be extinguished. We found that several molecules including D1 and D3 receptors and the transcription factor c-fos mediate the extinction process and may serve as target to extinguish cocaine memories. A third project is to understand how methylation reprogram may influence the formation, reconsolidation and extinction of cocaine memories.

Innovation 2

The objective of our research is to determine whether drugs that elevate cyclic AMP (cAMP) accelerate recovery from anesthesia in humans. General anesthetics induce a coma-like state; recovery from anesthesia is passive and is due to the discontinuation of anesthetic. Problematically, recovery from anesthesia is somewhat random, dependent upon a variety of factors like age or genetics that are beyond the clinician’s control. Although “waking” from anesthesia can be relatively rapid, cognitive abilities are depressed for hours. In addition, some patients “wake” very slowly. It would be extremely beneficial to be able to time recovery from anesthesia in a reproducible manner and to have that recovery be complete. Our preliminary results, carried out in cultured PC12 cells and hippocampal neurons, suggested that general anesthetics inhibit neurotransmitter release. We hypothesized that inhibition of neurotransmitter release plays a key role in how anesthetics produce anesthesia in animals and humans Furthermore we hypothesized that drugs that reverse the inhibitory effects of anesthetics on the release machinery should reverse anesthesia. Historically, cAMP signaling has been shown to play a key role in synaptic function and plasticity. Elevating cAMP facilitates neurotransmitter release. We posited that elevating intracellular cAMP might alter anesthetic action by restoring neurotransmitter release. Three drugs that elevate [cAMP]i levels, were tested; these drugs were found to completely reverse the inhibitory effects of anesthetics on neurotransmitter release in in vitro studies. When tested, these same cAMP elevating drugs dramatically accelerated recovery from anesthesia in rats. The most effective drug tested to date was caffeine which dramatically accelerated recovery from anesthesia (isoflurane and propofol) at relatively modest concentrations. In addition to elevating [cAMP]i, caffeine also inhibits adenosine receptors. A2A receptors mediate caffeine’s arousal effects since knocking out this receptor or blocking it pharmacologically suppresses caffeine mediated arousal. It is possible that caffeine’s ability to inhibit adenosine receptors helps it to reverse anesthesia.