Dextromethorphan and bupropion reduces high level remifentanil self-administration in rats.
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2020-04
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Abstract
Opiate addiction has risen substantially during the past decade. New treatments to combat opiate addiction are sorely needed. The current study was conducted to determine the acute individual and interactive effects of bupropion and dextromethorphan in a rat model of opiate self-administration using the short-acting synthetic opioid remifentanil. Both of these drugs have been found to reduce self-administration of nicotine. Bupropion and dextromethorphan and their combination had differential effects depending on whether the rats showed higher or lower baseline remifentanil self-administration. The rats with higher initial remifentanil self-administration showed a significant decrease in remifentanil self-administration with bupropion or dextromethorphan treatment, compared to the vehicle control condition. This decrease in self-remifentanil administration was most pronounced when combination of the higher doses of bupropion and dextromethorphan were administered. In contrast, the rats with lower baseline remifentanil self-administration showed the opposite effect of drug treatment with an increase in remifentanil self-administration with bupropion treatment compared to the vehicle control condition. Dextromethorphan had no significant effect inthis group. This study shows that combination bupropion and dextromethorphan affects remifentanil self-administration in a complex fashion with differential effects on low and high baseline responders. In subjects with high baseline remifentanil self-administration, bupropion and dextromethorphan treatment significantly reduced self-administration, whereas in subjects with low baseline remifentanil self-administration, bupropion increased remifentanil self-administration and dextromethorphan had no discernible effect. This finding suggests that combination bupropion-dextromethorphan should be tested in humans, with a focus on treating people with high-level opiate use.
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Blair, Graham, Corinne Wells, Ashley Ko, John Modarres, Caroline Pace, James M Davis, Amir H Rezvani, Jed E Rose, et al. (2020). Dextromethorphan and bupropion reduces high level remifentanil self-administration in rats. Pharmacology, biochemistry, and behavior, 193. p. 172919. 10.1016/j.pbb.2020.172919 Retrieved from https://hdl.handle.net/10161/20571.
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Scholars@Duke
James Davis
Dr. James Davis is a practicing physician of Internal Medicine, and serves as the Medical Director for Duke Center for Smoking Cessation, Director of the Duke Smoking Cessation Program and Co-Director of the Duke-UNC Tobacco Treatment Specialist Credentialing Program. His research focuses on development of new pharmaceutical treatments for smoking cessation. He is principal investigator on several trials including a study on “adaptive” smoking cessation and several trials on new medications for smoking cessation. The new medications leverage more novel neurobiological mechanisms - NMDA receptor antagonism, nicotinic receptor antagonism, which impact addiction-based learning and cue response. Additionally, Dr. Davis serves as co-investigator on trials on lung cancer screening, e-cigarettes, minor nicotine alkaloids, imaging trials, lung function trials and others. Dr. Davis leads the Duke Smoke-Free Policy Initiative, is co-author on a national tobacco dependence treatment guideline, and provides training in tobacco dependence treatment for the Duke School of Medicine, Duke Internal Medicine, Family Practice and Psychiatry residency programs.
Jed Eugene Rose
We are pursuing three main lines of research:
1) Brain imaging of the effects of nicotine and cigarette smoking: We have used Positron Emission Tomography (PET) methods to analyze regional cerebral blood flow responses to nicotine, administered either intravenously or inhaled in cigarettes. Our aim is to identify brain substrates mediating the addictive properties of nicotine. Preliminary results have shown alterations in the pattern of regional cerebral blood flow, involving frontal cortex, amygdala and other brain regions. We will continue to delineate the similarities and differences between the effects of nicotine and other drugs on regional brain activity, and plan to monitor the changes in response to nicotine after smoking cessation with nicotine antagonist treatment.
2) Analysis of airway sensory components of smoking reinforcement: We have continued the study the role of sensorimotor aspects of cigarette smoking in relieving craving for cigarettes and regulating smoke intake. We completed a study of the effects of intravenous nicotine presented alone or in combination with the sensorimotor aspects of smoking using de-nicotinized cigarette smoke. Craving for cigarettes was relieved more effectively by the de-nicotinized smoke than by the intravenous nicotine. Current studies underway at the Clinical Research Unit will further investigate the subjective effects of i.v. nicotine and de-nicotinized cigarette smoke, using a wider range of nicotine doses. Possible predictors of clinical outcome following nicotine skin patch treatment will be identified based on acute responses to the pharmacologic effects of nicotine in the laboratory.
We are also continuing to further the clinical application of these findings by developing substitutes that provide the airways sensory effects of smoking (e.g. citric acid aerosol).
3) Agonist/antagonist combination treatment for drug dependence: In a double blind smoking cessation trial using mecamylamine, a nicotinic antagonist, in combination with nicotine skin patches, we found that addition of the antagonist substantially increases smoking abstinence throughout the 1 year follow-up. Two additional studies that we conducted support the view that pre-treatment with mecamylamine prior to smoking cessation may be a critical factor in achieving high success rates. By blocking reinforcing effects of nicotine, smoking behavior may be partially extinguished, thereby facilitating subsequent smoking cessation. We recently completed a Phase II FDA trial evaluating a transdermal patch delivering nicotine and mecamylamine, which replicated our previous results. It is anticipated that an NDA pertaining to the new skin patch will be submitted in 1997. Continuing studies in our program will determine the optimal dose and duration of treatment. We also have initiated studies to extend this approach to the treatment of other drug dependencies, including cocaine.
Edward Daniel Levin
Dr. Levin is Chief of the Neurobehavioral Research Lab in the Psychiatry Department of Duke University Medical Center. His primary academic appointment is as Professor in the Department of Psychiatry and Behavioral Sciences. He also has secondary appointments in the Department Pharmacology and Cancer Biology, the Department of Psychological and Brain Sciences and the Nicholas School of the Environment at Duke. His primary research effort is to understand basic neural interactions underlying cognitive function and addiction and to apply this knowledge to better understand cognitive dysfunction and addiction disorders and to develop novel therapeutic treatments.
The three main research components of his laboratory are focused on the themes of the basic neurobiology of cognition and addiction, neurobehavioral toxicology and the development of novel therapeutic treatments for cognitive dysfunction and substance abuse. Currently, our principal research focus concerns nicotine. We have documented the basic effects of nicotine on learning memory and attention as well as nicotine self-administration. We are continuing with more mechanistic studies in rat models using selective lesions, local infusions and neurotransmitter interaction studies. We have found that nicotine improves memory performance not only in normal rats, but also in rats with lesions of hippocampal and basal forebrain connections. We are concentrating on alpha7 and alpha4beta2 nicotinic receptor subtypes in the hippocampus, amygdala , thalamus and frontal cortex and how they interact with dopamine D1 and D2 and glutamate NMDA systems with regard to memory and addiction. I am also conducting studies on human cognitive behavior. We have current studies to assess nicotine effects on attention, memory and mental processing speed in schizophrenia, Alzheimer's Disease and Attention Deficit Hyperactivity Disorder. In the area of neurobehavioral toxicology, I have continuing projects to characterize the adverse effects of prenatal and adolescent nicotine exposure. Our primary project in neurobehavioral toxicology focuses on the cognitive deficits caused by the marine toxins. The basic and applied aims of our research complement each other nicely. The findings concerning neural mechanisms underlying cognitive function help direct the behavioral toxicology and therapeutic development studies, while the applied studies provide important functional information concerning the importance of the basic mechanisms under investigation.
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