Jed Rose

Overview:

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.

Positions:

Professor in Psychiatry and Behavioral Sciences

Psychiatry & Behavioral Sciences, Addiction
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1978

University of California at San Diego

Grants:

Optimal Smoking Cessation Treatment in PTSD

Administered By
Psychiatry & Behavioral Sciences, Addiction
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Smoking & Anxiety In Posttraumatic Stress Disorder

Administered By
Psychiatry & Behavioral Sciences, Addiction
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Stress and Behavior in Health and Disease

Administered By
Psychiatry & Behavioral Sciences, Behavioral Medicine
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

The Effect of Smoking on Startle & PPI in PTSD

Administered By
Psychiatry & Behavioral Sciences, Addiction
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Novel Approach to Quantify Nicotinic Receptor Upregulation in Smokers

Administered By
Psychiatry & Behavioral Sciences, Addiction
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Publications:

Chronic memantine decreases nicotine self-administration in rats.

Neurobehavioral bases of tobacco addiction and nicotine reinforcement are complex, involving more than only nicotinic cholinergic or dopaminergic systems. Memantine is an NMDA glutamate antagonist used to improve cognitive function in people with Alzheimer's disease. Glutamate may be an important component of the reinforcing effects of nicotine, so memantine was evaluated as a potential smoking cessation aid. Two studies were conducted with adult female rats, one testing acute effects of memantine over a range of doses for changing nicotine self-administration and the other testing the chronic effects of memantine to reduce nicotine self-administration. Acute memantine injections slightly, but significantly, increased nicotine self-administration in a dose-related manner. In contrast, chronic memantine treatment significantly reduced nicotine self-administration. During the first day of memantine administration in the chronic study, nicotine self-administration was significantly elevated replicating the acute study. Starting in the second week of treatment there was a significant reduction of nicotine self-administration relative to controls. This was seen because memantine treatment prevented the increase in nicotine self-administration shown by controls. There even continued to be a memantine-induced lowered nicotine self-administration during the week after the cessation of memantine treatment. Memantine or other drugs affecting NMDA glutamate receptors may be useful aids to smoking cessation. Full efficacy for reducing nicotine self-administration was seen as the NMDA drug treatment is given chronically. Importantly, the effect persisted even after treatment is ended, indicating the high potential for NMDA glutamate receptors to impact nicotine addiction.
Authors
Levin, ED; Wells, C; Yao, L; Guo, W; Nangia, A; Howard, S; Pippen, E; Hawkey, AB; Rose, JE; Rezvani, AH
MLA Citation
Levin, Edward D., et al. “Chronic memantine decreases nicotine self-administration in rats..” Eur J Pharmacol, vol. 861, Oct. 2019. Pubmed, doi:10.1016/j.ejphar.2019.172592.
URI
https://scholars.duke.edu/individual/pub1404073
PMID
31421087
Source
pubmed
Published In
Eur J Pharmacol
Volume
861
Published Date
Start Page
172592
DOI
10.1016/j.ejphar.2019.172592

Bupropion-varenicline interactions and nicotine self-administration behavior in rats.

Varenicline and bupropion each have been shown to significantly improve cessation of tobacco addiction in humans. They act through different mechanisms and the question about the potential added efficacy with their combined used has arisen. Preclinical animal models of nicotine addiction can help with the evaluation of this combined approach and what dose combinations of varenicline and bupropion may be useful for enhancing tobacco cessation. In this study, we investigated the interacting dose-effect functions of varenicline and bupropion in a rat model of nicotine self-administration. Young adult female Sprague-Dawley rats were allowed to self-administer nicotine in 1-h sessions under an FR1 reinforcement schedule. Varenicline (0.3, 1. 3 mg/kg) and bupropion (8.33, 25, 75 mg/kg) were administered alone or together 15 min before each session. The vehicle saline was the control. Higher doses of each drug alone reduced nicotine self-administration compared to control with reductions of 62% and 75% with 3 mg/kg varenicline and 75 mg/kg bupropion respectively. Lower dose varenicline which does not by itself reduce nicotine self-administration, significantly augmented bupropion effects. The 0.3 mg/kg varenicline dose combined with the 25 and 75 mg/kg bupropion doses caused greater reductions of nicotine self-administration than either dose of bupropion given alone. However, higher dose varenicline did not have this effect. Lower dose bupropion did not augment varenicline effects. Only the high bupropion dose significantly enhanced the varenicline effect. Likewise, combining 1 mg/kg varenicline with 75 mg/kg bupropion reduced self-administration to a greater extent than either dose alone. These results demonstrate that combination therapy with varenicline and bupropion may be more beneficial than monotherapy with either drug alone.
Authors
Hall, BJ; Slade, S; Wells, C; Rose, JE; Levin, ED
MLA Citation
Hall, Brandon J., et al. “Bupropion-varenicline interactions and nicotine self-administration behavior in rats..” Pharmacol Biochem Behav, vol. 130, Mar. 2015, pp. 84–89. Pubmed, doi:10.1016/j.pbb.2015.01.009.
URI
https://scholars.duke.edu/individual/pub1056398
PMID
25616031
Source
pubmed
Published In
Pharmacol Biochem Behav
Volume
130
Published Date
Start Page
84
End Page
89
DOI
10.1016/j.pbb.2015.01.009

Neuroanatomical evidence for a putative autocrine/paracrine signaling system involving nicotinic acetylcholine receptors, purinergic receptors, and nitric oxide synthase in the airways.

Nicotine in tobacco smoke is thought to stimulate sensory nerve fibers by receptors that are located on airway epithelial cells and on terminal branches of C-fiber afferents, but the exact neurochemical substrate that mediates the sensory effects of nicotine associated with cigarette smoking is not clear. ATP and nitric oxide (NO) have both been implicated in lung responsiveness to airborne chemicals such as nicotine. However, the neuroanatomical and functional relationships between nicotinic acetylcholine receptors (nAChRs), purinergic signaling, and NO are not known, and the main source of NO in the airways is not clear. In the present study, we performed RT-PCR to confirm the presence of mRNA for all three isoforms of nitric oxide synthase (NOS), neuronal (n-NOS), endothelial (e-NOS), and inducible (i-NOS), in the lung. Sequential double labeling was performed to assess the site of expression of the different NOS isoforms with respect to nAChRs and purinergic receptors (P2X3R) of the intrapulmonary airways. RT-PCR confirmed the presence of n-NOS, e-NOS, and i-NOS in the lung, and immunohistochemical studies verified their expression by epithelial cells at all levels of the intrapulmonary airways, including the terminal and respiratory bronchioles. Sequential double labeling demonstrated coexpression of n-NOS and/or i-NOS with nAChR- and P2X3R-expressing cells. These neuroanatomical findings suggest that bronchial epithelial cells may be a primary source of NO in the intrapulmonary airways and that the production and release of NO may be regulated by an autocrine/paracrine signaling system involving nAChRs and P2X3Rs.
Authors
Rose, JE; Dehkordi, O; Fatemi, M; Raghupathi, R; Millis, RM; Jayam-Trouth, A
MLA Citation
URI
https://scholars.duke.edu/individual/pub796393
PMID
22420037
Source
pubmed
Published In
J Neurosci Res
Volume
90
Published Date
Start Page
849
End Page
859
DOI
10.1002/jnr.22817

Hippocampal and striatal gray matter volume are associated with a smoking cessation treatment outcome: results of an exploratory voxel-based morphometric analysis.

RATIONALE: Compared to nonsmokers, smokers exhibit a number of potentially important differences in regional brain structure including reduced gray matter (GM) volume and/or density in areas including frontal and cingulate cortices, thalamus, and insula. However, associations between brain structure and smoking cessation treatment outcomes have not been reported. OBJECTIVES: In the present analysis we sought to identify associations between regional GM volume--as measured by voxel-based morphometry (VBM)--and a smoking cessation treatment outcome (point prevalence abstinence at 4 weeks). METHODS: Adult smokers underwent high-resolution anatomical MRI scanning prior to an open label smoking cessation treatment trial. VBM was conducted in SPM5 using the DARTEL algorithm and relapser vs. quitter groups were compared using independent sample t tests (p < 0.001, uncorrected). Analyses controlled for potentially confounding factors including years smoked, cigarettes per day, total intracranial volume (TIV), and sex. RESULTS: Of 18 smokers, 8 achieved a 4-week point prevalence abstinence, confirmed by CO level (<or=8 ppm). After controlling for all covariates, compared to relapsers, quitters had significantly higher GM volume in the left putamen and right occipital lobe, while also significantly lower GM volume in bilateral hippocampus and right cuneus. CONCLUSIONS: These preliminary results suggest that maintaining smoking abstinence is associated with higher pre-quit brain volume in regions that subserve habit learning and visual processing, and lower brain volume in regions that subserve long-term memory processes and visual information processing. Future, large-scale studies can determine whether brain structure variables can serve as clinically useful predictors of smoking cessation treatment outcome.
Authors
Froeliger, B; Kozink, RV; Rose, JE; Behm, FM; Salley, AN; McClernon, FJ
MLA Citation
Froeliger, Brett, et al. “Hippocampal and striatal gray matter volume are associated with a smoking cessation treatment outcome: results of an exploratory voxel-based morphometric analysis..” Psychopharmacology (Berl), vol. 210, no. 4, July 2010, pp. 577–83. Pubmed, doi:10.1007/s00213-010-1862-3.
URI
https://scholars.duke.edu/individual/pub731025
PMID
20424827
Source
pubmed
Published In
Psychopharmacology (Berl)
Volume
210
Published Date
Start Page
577
End Page
583
DOI
10.1007/s00213-010-1862-3

Ketanserin, a 5-HT2 receptor antagonist, decreases nicotine self-administration in rats.

Nicotine intake constitutes a principal mechanism for tobacco addiction. In addition to primary effects on nicotinic acetylcholine receptors, nicotine has cascading effects, which may also underlie its neurobehavioral actions. Nicotine induces serotonin (5-HT) release, which has not classically been thought to be involved in tobacco addiction as dopamine has. However, addiction can be characterized more as a disorder of compulsion than a disorder of enjoyment. 5-HT mechanisms play key roles in compulsive disorders. Nicotine-induced 5-HT release may be a key to tobacco addiction. Ketanserin, a 5-HT2a and 5-HT2c receptor antagonist, significantly attenuates nicotine effects on attention and memory. These studies were conducted to determine if ketanserin would reduce nicotine self-administration in rats. Male Sprague-Dawley rats (N=12) were given initial food pellet training and then 10 sessions of nicotine self-administration training (0.03 mg/kg/infusion, i.v.). Then the rats were administered ketanserin (1 or 2 mg/kg, s.c.) or the saline vehicle. Ketanserin (2 mg/kg) significantly decreased nicotine self-administration. This did not seem to be due to sedative or amnestic effects of ketanserin. In a second study, the effects of repeated administration of 2 mg/kg ketanserin (N=11) vs. saline injections (N=10) were examined. In the initial phase, the acute effectiveness of ketanserin in significantly reducing nicotine self-administration was replicated. The effect became attenuated during the following several sessions, but the significant effect became re-established during the final phases of this two-week study. 5-HT mechanisms play critical roles in the maintenance of nicotine self-administration. Better understanding of those roles may help lead to new 5-HT-based treatments for tobacco addiction.
Authors
Levin, ED; Slade, S; Johnson, M; Petro, A; Horton, K; Williams, P; Rezvani, AH; Rose, JE
MLA Citation
Levin, Edward D., et al. “Ketanserin, a 5-HT2 receptor antagonist, decreases nicotine self-administration in rats..” Eur J Pharmacol, vol. 600, no. 1–3, Dec. 2008, pp. 93–97. Pubmed, doi:10.1016/j.ejphar.2008.10.016.
URI
https://scholars.duke.edu/individual/pub783776
PMID
18950618
Source
pubmed
Published In
Eur J Pharmacol
Volume
600
Published Date
Start Page
93
End Page
97
DOI
10.1016/j.ejphar.2008.10.016