Browsing by Author "Rose, Jed E"
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Item Open Access Amitifadine, a triple reuptake inhibitor, reduces self-administration of the opiate remifentanil in rats.(Psychopharmacology, 2020-06) Levin, Edward D; Wells, Corinne; Hawkey, Andrew; Holloway, Zade; Blair, Graham; Vierling, Alexander; Ko, Ashley; Pace, Caroline; Modarres, John; McKinney, Anthony; Rezvani, Amir H; Rose, Jed ERationale
A variety of neural systems are involved in drug addiction, and some of these systems are shared across different addictive drugs. We have found several different types of drug treatments that successfully reduce nicotine self-administration.Objectives
The current set of studies is the first in a series to determine if drug treatments that have been found to significantly reduce nicotine self-administration would reduce opiate self-administration.Methods
Amitifadine, a triple reuptake inhibitor of dopamine, norepinephrine, and serotonin, was assessed in female Sprague-Dawley rats to determine whether it significantly reduces remifentanil self-administration with either acute or chronic treatment.Results
Acutely, amitifadine doses of 5, 10, and 20 mg/kg each significantly reduced remifentanil self-administration. In a chronic study, repeated treatment with 10 mg/kg of amitifadine continued to reduce remifentanil self-administration, even after the cessation of treatment. However, amitifadine was not found to attenuate the rise in remifentanil self-administration with continued access. This study and our earlier one showed that the 10 mg/kg amitifadine dose did not significantly affect food motivated responding. Amitifadine did not attenuate remifentanil-induced antinociception as measured on the hot plate test but extended and maintained antinociceptive effects.Conclusions
These studies show the promise of amitifadine as a treatment for countering opiate self-administration for adjunctive use with opioids for analgesia. Further studies are needed to determine the possible efficacy of amitifadine for combating opiate addiction or preventing it in humans during adjunctive use with opioids for chronic pain.Item Open Access Chronic infusions of mecamylamine into the medial habenula: Effects on nicotine self-administration in rats.(Behavioural brain research, 2022-01) Levin, Edward D; Wells, Corinne; Slade, Susan; Johnson, Joshua; Petro, Ann; Rezvani, Amir H; Rose, Jed EThe habenula is an epithalamic structure through which descending connections go from the telencephalon to the brainstem, putting it in a key location to provide feedback control over the ascending projections from the brainstem to the telencephalon. The medial habenula has a high concentration of nicotinic receptors. We assessed the role of medial habenular nicotinic receptors for nicotine self-administration (SA) in female young adult Sprague-Dawley rats. The rats had bilateral chronic infusion cannulae placed into the medial habenula nucleus. Each cannula was connected to a slow delivery osmotic minipump to chronically infuse mecamylamine (100 µg/side/day) or vehicle for four consecutive weeks. The rats were tested for nicotine SA for the first two weeks of mecamylamine infusion. Then, they had one week of enforced abstinence, during which they had no access to the nicotine SA. Finally, they had one week of resumed nicotine SA access. There was a significantly differential mecamylamine effects in animals with lower and higher pretreatment baseline nicotine SA. Rats with lower baseline nicotine SA levels showed a nearly significant mecamylamine-induced reduction in SA while those with higher baseline levels of SA showed a significant mecamylamine-induced increase in nicotine SA. This study determined that medial habenular nicotinic receptors are important for nicotine reinforcement. Baseline level of performance makes a crucial difference for the involvement of habenular mechanisms in nicotine reinforcement with nicotinic activation being important for maintaining nicotine self-administration for those with lower levels of baseline self-administration and the opposite effect with subjects with higher levels of baseline self-administration.Item Open Access Chronic memantine decreases nicotine self-administration in rats.(European journal of pharmacology, 2019-10) Levin, Edward D; Wells, Corinne; Yao, Leah; Guo, Wendi; Nangia, Anica; Howard, Sarah; Pippen, Erica; Hawkey, Andrew B; Rose, Jed E; Rezvani, Amir HNeurobehavioral 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.Item Open Access Combination Lorcaserin and Nicotine Patch for Smoking Cessation Without Weight Gain.(Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 2020-08) Rose, Jed E; Davis, James MINTRODUCTION:This study explored the efficacy of combination lorcaserin and nicotine patch for smoking cessation treatment and prevention of postsmoking cessation weight gain. METHODS:We conducted a trial in which 61 adult daily smokers were asked to quit smoking using a combination of lorcaserin and nicotine patch. During the first 2 weeks of treatment prior to the quit day, participants were randomized to receive either lorcaserin (10 mg twice daily) plus nicotine patch (21 mg) or placebo plus nicotine patch (21 mg). Following this 2-week period, participants received both medications for 12 weeks. Outcomes included 4-week continuous smoking abstinence at the end of treatment (weeks 7-10 postquit attempt), weight change, ad libitum smoking, withdrawal symptoms, and ratings of cigarette reward. RESULTS:Biochemically confirmed continuous smoking abstinence from 7 to 10 weeks postquit attempt was 31.1% (90% confidence interval, 21.4%-40.8%). Participants who quit smoking showed no weight gain; in fact, mean weight change was minus 0.16 kg (SD = 3.27) over the study period. There was an unexpected but strong association (p = .006) between a decrease in sensory enjoyment of smoking and successful quit outcome on this regimen. During the prequit randomization period, lorcaserin versus placebo reduced the impact of smoking to relieve craving for cigarettes as well as the sensory enjoyment of smoking (p = .005). Adherence and tolerability to lorcaserin and nicotine patch was good. CONCLUSIONS:The combination of lorcaserin and nicotine patch was well tolerated, associated with a relatively high smoking abstinence rate, and effectively prevented weight gain associated with quitting smoking. IMPLICATIONS:This report provides an important contribution to the literature because it details evidence of a medication combination-lorcaserin and nicotine-that is effective for smoking cessation and for ameliorating weight gain associated with smoking cessation. For many smokers, postcessation weight gain is a major obstacle to quitting, and this medication combination provides a suitable treatment option for these smokers. CLINICAL TRIAL REGISTRATION:NCT02906644.Item Open Access Correction to: Amitifadine, a triple reuptake inhibitor, reduces self-administration of the opiate remifentanil in rats.(Psychopharmacology, 2021-04) Levin, Edward D; Wells, Corinne; Hawkey, Andrew; Holloway, Zade; Blair, Graham; Vierling, Alexander; Ko, Ashley; Pace, Caroline; Modarres, John; McKinney, Anthony; Rezvani, Amir H; Rose, Jed EOur article published in Psychopharmacology had a typographical error in the units of remifentanil infusion for selfadministration. The correct infusion dose of remifentanil is 0.3 µg/kg/infusion not 0.3 mg/kg/infusion.Item Open Access Dextromethorphan and bupropion reduces high level remifentanil self-administration in rats.(Pharmacology, biochemistry, and behavior, 2020-04) Blair, Graham; Wells, Corinne; Ko, Ashley; Modarres, John; Pace, Caroline; Davis, James M; Rezvani, Amir H; Rose, Jed E; Levin, Edward DOpiate 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.Item Open Access Prolonging the Reduction of Nicotine Self-Administration in Rats by Coadministering Chronic Nicotine With Amitifadine, a Triple Monoamine Reuptake Inhibitor With CYP2B6 Inhibitory Actions.(Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 2019-04-11) Levin, Edward D; Wells, Corinne; Slade, Susan; Lee, Michelle; McKinney, Anthony A; Rose, Jed E; Rezvani, Amir HINTRODUCTION:Existing treatments can aid tobacco smoking cessation, but they have low efficacy. Because there is a network of neural systems involved in tobacco addiction, combination treatments may provide greater efficacy. Chronic nicotine and amitifadine have each been shown to significantly reduce nicotine self-administration in rats. This study was conducted to determine if the combination of chronic nicotine with amitifadine, a triple monoamine reuptake inhibitor with CYP2B inhibitory effects, would reduce nicotine self-administration to a greater extent than either alone or placebo. METHODS:This study tested the combination of nicotine plus amitifadine in young adult female Sprague-Dawley rats self-administering nicotine (0.03 mg/kg/infusion). This combination was compared with each treatment alone and the vehicle during continuing nicotine self-administration as well as during resumption of self-administration after a week of enforced abstinence, modeling a quit attempt. Finally, we studied the residual effects of these therapies after discontinuation of treatment. RESULTS:Treatment with either chronic nicotine or amitifadine alone significantly reduced nicotine self-administration relative to controls. The combination of the treatments significantly enhanced this effect. After treatment withdrawal, all of the groups showed increases in nicotine self-administration, but only the combined treatment group remained significantly below control rates of nicotine self-administration. CONCLUSIONS:This study showed the promise of amitifadine as a possible new treatment for smoking cessation and suggested that amitifadine is more effective when given with chronic nicotine. The improved efficacy of the amitifadine and nicotine combination may be potentiated by amitifadine's inhibitory effects on CYP2B, which slows nicotine metabolism. IMPLICATIONS:This study replicated the effects that chronic nicotine or chronic amitifadine, a triple reuptake inhibitor, significantly reduces nicotine self-administration in rats. It extends those findings by showing that the combination of chronic nicotine plus amitifadine causes significantly greater reduction in nicotine self-administration than either drug treatment alone. The combination of chronic amitifadine and chronic nicotine also causes a persistent significant reduction in nicotine self-administration after the end of treatment. The amitifadine and nicotine treatment should be assessed in humans to determine whether this combination provides greater efficacy in smoking cessation than transdermal nicotine treatment alone.Item Open Access Pulmonary Delivery of Nicotine Pyruvate: Sensory and Pharmacokinetic Characteristics (vol 18, pg 385, 2010)(EXPERIMENTAL AND CLINICAL PSYCHOPHARMACOLOGY, 2011-02) Rose, Jed E; Turner, James E; Murugesan, Thangaraju; Behm, Frédérique M; Laugesen, MurrayItem Open Access Self-administration by female rats of low doses of nicotine alone vs. nicotine in tobacco smoke extract.(Drug and alcohol dependence, 2021-11) Levin, Edward D; Wells, Corinne; Pace, Caroline; Abass, Grant; Hawkey, Andrew; Holloway, Zade; Rezvani, Amir H; Rose, Jed EBackground
Nicotine has reinforcing effects, but there are thousands of other compounds in tobacco, some of which might interact with nicotine reinforcement.Aims
This rat study was conducted to determine if nicotine self-administration is altered by co-administration of the complex mixture of compounds in tobacco smoke extract (TSE).Methods
Female Sprague-Dawley rats were tested for self-administration of low doses of nicotine (3 or 10 µg/kg/infusion) at three different rates of reinforcement (FR1, FR3 and FR5) over three weeks either alone or together with the complex mixture of tobacco smoke extract (TSE).Results
Rats self-administering 3 µg/kg/infusion of nicotine alone showed a rapid initiation on an FR1 schedule, but declined with FR5. Rats self-administering nicotine in TSE acquired self-administration more slowly, but increased responding over the course of the study. With 10 µg/kg/infusion rats self-administered significantly more nicotine alone than rats self-administering the same nicotine dose in TSE. Rats self-administering nicotine alone took significantly more infusions with the 10 than the 3 µg/kg/infusion dose, whereas rats self-administering nicotine in TSE did not. Nicotine in TSE led to a significantly greater locomotor hyperactivity at a dose of 0.1 mg/kg compared to rats that received nicotine alone. Rats self-administering nicotine alone had significantly more responding on the active vs. inactive lever, but rats self-administering the same nicotine doses in TSE did not.Conclusions
Self-administration of nicotine in a purer form appears to be more clearly discriminated and dose-related than nicotine self-administered in the complex mixture of TSE.