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1.
Rationale
Alcohol and nicotine are commonly co-abused. Genetic correlations between responses to these drugs have been reported, providing evidence that common genes underlie the response to alcohol and nicotine. Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic dopamine system are important in mediating nicotine response, and several studies suggest that alcohol may also interact with these nAChRs.Objective
The aim of this study was to examine the role of nAChRs containing α7 or β2 subunits in ethanol consumption.Methods
A two-bottle choice paradigm was used to determine ethanol consumption in wild-type and nAChR subunit knockout mice. Challenge studies were performed using the α4β2 nAChR partial agonist varenicline.Results
Mice lacking the β2 subunit consumed a similar amount of ethanol compared to their wild-type siblings in an ethanol-drinking paradigm. In contrast, mice lacking the α7 nAChR receptor subunit consumed significantly less ethanol than wild-type mice but consumed comparable amounts of water, saccharin, and quinine. In C57BL/6J mice, varenicline dose-dependently decreased ethanol consumption with a significant effect of 2 mg/kg, without affecting water or saccharin consumption. This effect of varenicline was not reversed in mice lacking either the α7 or β2 subunit, providing evidence that nAChRs containing one of these subunits are not required for this effect of varenicline.Conclusions
This study provides evidence that α7 nAChRs are involved in ethanol consumption and supports the idea that pharmacological manipulation of nAChRs reduces ethanol intake. Additional nAChRs may also be involved in ethanol intake, and there may be functional redundancy in the nicotinic control of alcohol drinking. 相似文献2.
A A Feduccia J A Simms D Mill H Y Yi S E Bartlett 《British journal of pharmacology》2014,171(14):3420-3431
BACKGROUND AND PURPOSE
Varenicline, a neuronal nicotinic acetylcholine receptor (nAChR) modulator, decreases ethanol consumption in rodents and humans. The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via α4*-containing nAChRs in the ventral tegmental area (VTA). However, presynaptic nAChRs on dopaminergic terminals in the NAc have been shown to directly modulate dopaminergic signalling independently of neuronal activity from the VTA. In this study, we determined whether nAChRs in the NAc play a role in varenicline''s effects on ethanol consumption.EXPERIMENTAL APPROACH
Rats were trained to consume ethanol using the intermittent-access two-bottle choice protocol for 10 weeks. Ethanol intake was measured after varenicline or vehicle was microinfused into the NAc (core, shell or core-shell border) or the VTA (anterior or posterior). The effect of varenicline treatment on DA release in the NAc was measured using both in vivo microdialysis and in vitro fast-scan cyclic voltammetry (FSCV).KEY RESULTS
Microinfusion of varenicline into the NAc core and core-shell border, but not into the NAc shell or VTA, reduced ethanol intake following long-term ethanol consumption. During microdialysis, a significant enhancement in accumbal DA release occurred following systemic administration of varenicline and FSCV showed that varenicline also altered the evoked release of DA in the NAc.CONCLUSION AND IMPLICATIONS
Following long-term ethanol consumption, varenicline in the NAc reduces ethanol intake, suggesting that presynaptic nAChRs in the NAc are important for mediating varenicline''s effects on ethanol consumption. 相似文献3.
Rationale
Emerging evidence suggests that the ??4??2 form of the nicotinic acetylcholine receptor (nAChR) modulates the rewarding effects of alcohol. The nAChR ??4??2 subunit partial agonist varenicline (Chantix?), which is approved by the Food and Drug Administration for smoking cessation, also decreases ethanol consumption in rodents (Steensland et al., Proc Natl Acad Sci U S A 104:12518?C12523, 2007) and in human laboratory and open-label studies (Fucito et al., Psychopharmacology (Berl) 215:655?C663, 2011; McKee et al., Biol Psychiatry 66:185?C190 2009).Objectives
We present a randomized, double-blind, 16-week study in heavy-drinking smokers (n?=?64 randomized to treatment) who were seeking treatment for their smoking. The study was designed to determine the effects of varenicline on alcohol craving and consumption. Outcome measures included number of alcoholic drinks per week, cigarettes per week, amount of alcohol craving per week, cumulative cigarettes and alcoholic drinks consumed during the treatment period, number of abstinent days, and weekly percentage of positive ethyl glucuronide and cotinine screens.Results
Varenicline significantly decreases alcohol consumption (?? 2?=?35.32, p?0.0001) in smokers. Although varenicline has previously been associated with suicidality and depression, side effects were low in this study and declined over time in the varenicline treatment group.Conclusions
Varenicline can produce a sustained decrease in alcohol consumption in individuals who also smoke. Further studies are warranted to assess varenicline efficacy in treatment-seeking alcohol abusers who do not smoke and to ascertain the relationship between varenicline effects on smoking and drinking. 相似文献4.
Rationale
Much evidence indicates that individuals use tobacco primarily to experience the psychopharmacological properties of nicotine. Varenicline, a partial ??4??2 nicotinic acetylcholine receptor (nAChR) agonist, is effective in reducing nicotine craving and relapse in smokers, suggesting that ??4??2 nAChRs may play a key role in nicotine dependence. In rats, the effect of varenicline on nicotine intake has only been studied with limited access to the drug, a model of the positive reinforcing effect of nicotine. Varenicline has not been tested on the increase in motivation to take nicotine in nicotine-dependent rats.Objectives
The present study evaluated the effects of varenicline on nicotine intake in rats with extended access to nicotine self-administration (23?h/day), a condition leading to the development of nicotine dependence. We hypothesized that varenicline??s effects on nicotine self-administration would be greater in rats with extended than limited access to the drug and after forced abstinence rather than during baseline self-administration.Results
Varenicline dose-dependently decreased nicotine self-administration in rats with limited (1?h/day) and extended (23?h/day) access. Despite an increased sensitivity to the motivational effects of abstinence on nicotine intake compared with limited-access rats, varenicline was equally effective in decreasing nicotine intake in dependent rats with extended access to nicotine.Conclusion
These results suggest that ??4??2 nAChRs are critical in mediating the positive reinforcing effects of nicotine but may not be a key element underlying the negative reinforcement process responsible for the increased nicotine intake after abstinence in dependent subjects. 相似文献5.
Rationale
Varenicline, a partial agonist at α4β2 nicotinic receptors (nAChRs) aids smoking cessation by reducing craving. Successful quitting may be associated with greater inhibitory control but the effectiveness of varenicline in this regard is unknown.Objectives
This study aimed to investigate the effect of varenicline on aspects of inhibitory control in smokers.Methods
A double-blind, placebo-controlled study investigating the effect of varenicline 1 mg (or matched placebo) in satiated and abstinent smokers. Tests included Rapid Visual Information Processing (RVIP), Stop-Signal (SS), Prospective Memory (PM) and the Cambridge Gambling Task (CGT).Results
Smoking enhanced RVIP accuracy and latency to respond. Varenicline did not alter RVIP performance, nor the effect of smoking, suggesting that these effects were unrelated to α4β2 nAChRs. Smoking increased the number of errors during SS and increased the stop latency, indicating that smoking decreased inhibitory control. Varenicline partially mimicked this effect of smoking but also reduced the smoking-induced increase, indicating a role for α4β2 nAChRs. Likewise, smoking increased the number of points bet following a win during CGT and varenicline blocked this effect. There was no effect of smoking or varenicline on PM target detection per se. However, smoking protected the target detection rate in the ongoing task when a concurrent intention was introduced. Varenicline improved response speed in both satiated and abstinent smokers.Conclusions
Some aspects of inhibitory control may be mediated by α4β2-related mechanisms and blockade of smoking-induced disinhibition may contribute towards the action of varenicline as an aid to smoking cessation. 相似文献6.
Rationale
Varenicline represents a new class of smoking cessation aids that has different mechanisms of action that are unique from bupropion or nicotine replacement therapies. An improved understanding of these mechanisms may lead to greater treatment success in quitting smoking.Objectives
We examined the effects of steady-state varenicline on attention and inhibitory control among adult treatment-seeking smokers.Methods
Adult smokers enrolled in a randomized clinical trial received either 4 weeks of pre-quit varenicline (n?=?31) or 3 weeks of placebo (n?=?26) followed by 1 week of standard varenicline treatment. Participants in the present work completed cognitive assessments at a baseline session (prior to treatment) and again 3 weeks later (during active treatment). At both sessions, participants completed the stop signal task to assess both lapses in attention and inhibitory control.Results
Analyses indicated that varenicline improved lapses in attention compared to placebo. There were no significant differences observed between groups at either session for inhibitory control.Conclusions
The present study demonstrated that varenicline improves lapses in attention among treatment-seeking smokers preparing to make a quit attempt. These findings suggest that the domain of attention may be a good candidate for larger studies of the role of improved cognition in understanding the mechanisms of varenicline treatment for smoking cessation. 相似文献7.
Roel J. T. Mocking Stephany A. Wever C. Patrick Pflanz Abbie Pringle Elizabeth Parsons Sarah F. McTavish Phil J. Cowen Catherine J. Harmer Aart H. Schene 《Psychopharmacology》2014,231(1):143-148
Rationale
Varenicline is the most effective drug for smoking cessation, but its use decreased because of reports of depressogenic side effects. However, because smoking and smoking cessation on their own are associated with depression, it remains unclear whether reported depressogenic effects are attributable to varenicline, or to smoking, and/or smoking cessation themselves.Objectives
Previously, we observed no depressogenic effects of varenicline on a psychological level. In the present study, we aimed at investigating potential depressogenic effects of the partial nicotinergic acetylcholine receptor agonist varenicline on a biological level. A possible pathway would be an effect of varenicline on the hypothalamic–pituitary–adrenal (HPA) axis, considering the relation between the HPA axis and (1) the cholinergic system and (2) depression.Methods
In a randomized, double-blind design, we administered varenicline or placebo for 7 days (0.5 mg/day first 3 days, then 1 mg/day) to healthy never-smoking subjects, thereby eliminating bias by (previous) smoking status. We used repeated measures (before and after treatment) of the salivary free cortisol awakening response to measure HPA axis activity and flexibility.Results
Salivary cortisol data of 34 subjects were included in the analysis. Results showed no effect of varenicline on height (F 1,32?=?0.405; P?=?0.529) or shape (F 2,31?=?0.110; P?=?0.164) of the cortisol awakening response.Conclusions
Results do not suggest depressogenic effects of varenicline on the HPA axis. Although this does not preclude other biological depressogenic effects of varenicline, it seems that concerns about effects of varenicline on the HPA axis should not limit its potential to treat nicotine and related addictions. 相似文献8.
Joseph P. Schacht Raymond F. Anton Patrick K. Randall Xingbao Li Scott Henderson Hugh Myrick 《Psychopharmacology》2014,231(18):3799-3807
Rationale
The α4β2 nicotinic acetylcholine receptor partial agonist varenicline has been reported to reduce drinking among both heavy-drinking smokers and primary alcoholics, and this effect may be related to varenicline-mediated reduction of alcohol craving. Among smokers, varenicline has been reported to modulate cigarette cue-elicited brain activation in several reward-related areas.Objectives
This pilot study tested varenicline’s effects on drinking, alcohol craving, and alcohol cue-elicited activation of reward-related brain areas among non-treatment-seeking alcohol-dependent individuals.Methods
Thirty-five such individuals (mean age?=?30, 57 % male, 76 % heavy drinking days in the past month, 15 smokers) were randomized to either varenicline (titrated to 2 mg) or placebo for 14 days, and were administered an alcohol cue reactivity fMRI task on day 14. A priori regions of interest (ROIs) were bilateral and medial orbitofrontal cortex (OFC), right ventral striatum (VS), and medial prefrontal cortex (mPFC).Results
Despite good medication adherence, varenicline did not reduce heavy drinking days or other drinking parameters. It did, however, increase self-reported control over alcohol-related thoughts and reduced cue-elicited activation bilaterally in the OFC, but not in other brain areas.Conclusions
These data indicate that varenicline reduces alcohol craving and some of the neural substrates of alcohol cue reactivity. However, varenicline effects on drinking mediated by cue-elicited brain activation and craving might be best observed among treatment-seekers motivated to reduce their alcohol consumption. 相似文献9.
Sungwon Roh Susanne S. Hoeppner David Schoenfeld Catherine A. Fullerton Luke E. Stoeckel A. Eden Evins 《Psychopharmacology》2014,231(4):765-775
Rationale
Nicotinic acetylcholine receptors (nAChRs) have been implicated in the pathophysiology of cognitive deficits in the domains of attention and memory in schizophrenia. While nicotinic agonists and antagonists have been proposed as smoking cessation aids, few comparisons have been made of these agents on cognitive performance in individuals with schizophrenia.Objectives
This study investigated the acute effects of a nAChR antagonist, mecamylamine, and partial agonist, varenicline, on cognitive function in non-smokers with and without schizophrenia.Methods
Single oral doses of mecamylamine 10 mg, varenicline 1 mg, and placebo were administered 1 week apart in random order to adults with schizophrenia (n?=?30) and to healthy volunteers (n?=?41) in a double-blind, crossover design. The primary outcome of interest was sustained attention as assessed with hit reaction time variability (HRT-SD) on the identical pairs continuous performance test (CPT-IP).Results
Mecamylamine worsened performance on CPT-IP HRT-SD, a measure of attention, compared to varenicline in both groups. Performance on mecamylamine was worse than performance on both placebo and varenicline on several additional measures of attention, including CPT-IP hit reaction time (HRT) and random errors at various levels of task difficulty. There was a treatment by diagnosis interaction, such that mecamylamine worsened performance on CPT-IP 2-digit HRT, 3-digit random errors, and 4-digit hit rate compared to placebo and varenicline in participants with schizophrenia; effects not observed in controls.Conclusions
These findings support a role for nAChRs in attention and suggest that those with schizophrenia may be particularly sensitive to nAChR blockade. 相似文献10.
Luisa Ponzoni Daniela Braida Luca Pucci Donzelli Andrea Francesca Fasoli Irene Manfredi Roger L. Papke Clare Stokes Giuseppe Cannazza Francesco Clementi Cecilia Gotti Mariaelvina Sala 《Psychopharmacology》2014,231(24):4681-4693
Rationale
Cigarette smoking is one of the most serious health problems worldwide and people trying to stop smoking have high rates of relapse. Zebrafish (Danio rerio), by combining pharmacological and behavioral assays, is a promising animal model for rapidly screening new compounds to induce smoking cessation.Objectives
This study aims to identify possible acetylcholine nicotinic receptors (nAChRs) involved in mediating nicotine (NIC)-induced conditioned place preference (CPP) in zebrafish and investigate the effect of the CC4 and CC26 cytisine derivatives in reducing NIC-induced CPP.Methods
CPP was evaluated using a two-compartment chamber, and the zebrafish were given CC4 (0.001–5 mg/kg), CC26 (0.001–1 mg/kg), cytisine (0.1–2.5 mg/kg), and varenicline (1–10 mg/kg) alone or with NIC (0.001 mg/kg). Swimming activity was evaluated using a square observational chamber. The affinity of the nicotinic ligands for native zebrafish brain nAChRs was evaluated by binding studies using [3H]-Epibatidine (Epi) and [125I]-αBungarotoxin (αBgtx) radioligands, and their subtype specificity was determined by means of electrophysiological assay of oocyte-expressed α4β2 and α7 subtypes.Results
CC4 and CC26 induced CPP with an inverted U-shaped dose–response curve similar to that of NIC. However, when co-administered with NIC, they blocked its reinforcing or slightly aversive effect. Binding and electrophysiological studies showed that this effect was due to binding to high-affinity heteromeric but not α7-containing receptors.Conclusions
We have further characterized CC4 and identified a new compound (CC26) that may be active in inducing smoking cessation. Zebrafish is a very useful model for screening new compounds that can affect the rewarding properties of NIC. 相似文献11.
Lara A. Ray Kelly E. Courtney Dara G. Ghahremani Karen Miotto Arthur Brody Edythe D. London 《Psychopharmacology》2014,231(19):3843-3853
Rationale
Heavy-drinking smokers constitute a sizeable and hard-to-treat subgroup of smokers, for whom tailored smoking cessation therapies are not yet available.Objectives
The present study used a double-blind, randomized, 2?×?2 medication design, testing varenicline alone (VAR; 1 mg twice daily), low dose naltrexone alone (L-NTX; 25 mg once daily), varenicline plus naltrexone, and placebo for effects on cigarette craving and subjective response to alcohol and cigarettes in a sample (n?=?130) of heavy-drinking daily smokers (≥10 cigarettes/day).Methods
All participants were tested after a 9-day titration period designed to reach a steady state on the target medication. Testing was completed at 12 h of nicotine abstinence, after consuming a standard dose of alcohol (target breath alcohol concentration?=?0.06 g/dl) and after smoking the first cigarette of the day.Results
The combination of VAR?+?L-NTX was superior to placebo, and at times superior to monotherapy, in attenuating cigarette craving, cigarette and alcohol “high,” and in reducing ad-lib consumption of both cigarettes and alcohol during the 9-day medication titration period.Conclusions
These preliminary findings indicate that clinical studies of the combination of VAR?+?L-NTX for heavy drinkers trying to quit smoking are warranted and may ultimately improve clinical care for this sizeable and treatment-resistant subgroup of smokers. 相似文献12.
Jadwiga Zalewska-Kaszubska Bartosz Bajer Dorota Gorska Dariusz Andrzejczak Wanda Dyr Przemysław Bieńkowski 《Psychopharmacology》2013,225(2):275-281
Rationale
Pharmacological treatment currently used for alcohol dependence is not sufficient for the all patients, and there is a crucial need to find more effective treatments. Recent studies indicate that topiramate is likely the most promising new medication for alcohol dependence. The rationale for topiramate as treatment for alcohol addiction is based on its multifaceted neurochemical activity that targets multiple neural pathways.Objectives
This study aims to assess the effect of repeated treatment with topiramate on voluntary alcohol intake and beta-endorphin plasma level in rats selectively bred for high alcohol preference.Methods
Initially, Warsaw high preferring rats (N?=?50) were given a 24-h/day free choice between a 10 % (v/v) alcohol solution and water for three consecutive weeks. Subsequently, rats were administered with topiramate (40 or 80 mg/kg b.w.) or vehicle for 14 days and ethanol intake was measured daily. Subsequently, we examined the effects of topiramate on plasma beta-endorphin levels, while alcohol was available and when it was not available for an extended period time.Results
We observed significantly increase in the levels of beta-endorphin in rats with free access to alcohol both in a topiramate- or vehicle-treated group. However, in topiramate-treated group, a voluntary consumption of alcohol diminished in comparison with the vehicle-treated rats.Conclusion
The results from this study indicated that topiramate reduces voluntary alcohol intake and support our previous findings that the increase of beta-endorphin level is responsible at least partly for the effectiveness of drugs in treating the alcohol addiction. 相似文献13.
14.
Rationale
The striatopallidal medium spiny neurons have been viewed as a final common path for drug reward, and the ventral pallidum (VP) as a convergent point for hedonic and motivational signaling. The medium spiny neurons are GABAergic, but they colocalize enkephalin.Objective
The present study investigated the role of the GABAergic mechanisms of the VP in ethanol consumption.Methods
The effects of bilateral microinjections of GABAA and GABAB receptor agonists and antagonists into the VP on voluntary ethanol consumption were monitored in alcohol-preferring Alko alcohol rats given 90 min limited access to ethanol in their home cages every other day. The influences of coadministration of GABA and opioid receptor modulators were also studied.Results
The GABAA receptor agonist muscimol (1–10 ng/site) decreased ethanol intake dose-dependently, while administration of the GABAA receptor antagonist bicuculline (10–100 ng) had an opposite effect. The GABAB receptor agonist baclofen (3–30 ng) also suppressed ethanol intake, but the GABAB receptor antagonist saclofen (0.3–3 μg) failed to modify it. Animals coadministered with bicuculline (30 ng) and baclofen (30 ng) consumed ethanol significantly less than those treated with bicuculline alone. Coadministration of the μ-receptor agonist D-Ala2,N-Me-Phe4,Glyol5-enkephalin (DAMGO, 0.1 μg) with bicuculline counteracted, whereas the μ-receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP, 1 μg) enhanced the bicuculline-induced increase of ethanol intake. When given alone, DAMGO decreased while CTOP increased ethanol intake.Conclusions
The study provides evidence for the ventral pallidal GABAergic mechanisms participating in the regulation of ethanol consumption and supports earlier work suggesting a role for pallidal opioidergic transmission in ethanol reward. 相似文献15.
Christa M. Helms Andrew Rau Jessica Shaw Cara Stull Steven W. Gonzales Kathleen A. Grant 《Psychopharmacology》2014,231(8):1853-1861
Rationale
Consumption of alcohol begins during late adolescence in a majority of humans, and the greatest drinking occurs at 18–25 years then decreases with age.Objectives
The present study measured the differences in ethanol intake in relation to age at the onset of ethanol access among nonhuman primates to control for self-selection in humans and isolate age effects on heavy drinking.Methods
Male rhesus macaques were assigned first access to ethanol during late adolescence (n?=?8), young adulthood (n?=?8), or early middle age (n?=?11). The monkeys were induced to drink ethanol (4 %?w/v in water) in increasing doses (water then 0.5, 1.0, 1.5 g/kg ethanol) using a fixed-time (FT) 300-s schedule of food delivery, followed by 22 h/day concurrent access to ethanol and water for 12 months. Age-matched controls consumed isocaloric maltose–dextrin solution yoked to the late adolescents expected to be rapidly maturing (n?=?4).Results
Young adult monkeys had the greatest daily ethanol intake and blood-ethanol concentration (BEC). Only late adolescents escalated their intake (ethanol, not water) during the second compared to the first 6 months of access. On average, plasma testosterone level was consistent with age differences in maturation and tended to increase throughout the experiment more for control than ethanol-drinking adolescent monkeys.Conclusions
Young adulthood in nonhuman primates strongly disposes toward heavy drinking, which is independent of sociocultural factors present in humans. Ethanol drinking to intoxication during the critical period of late adolescence is associated with escalation to heavy drinking. 相似文献16.
Kuang-Chieh Hsueh Shu-Chun Hsueh Ming-Yueh Chou Lee-Fei Pan Ming-Shium Tu Andy McEwen Robert West 《Psychopharmacology》2014,231(14):2819-2823
Rationale
A network meta-analysis of randomized trials and real-world comparative studies strongly suggest that varenicline is more effective in aiding smoking cessation than single form nicotine replacement therapy (NRT). Modeling the health benefits attributable to this difference relies on extrapolation to lifetime cessation, but to date, follow-up has only extended to 12 months. Longer term follow-up data are helpful in checking these assumptions.Objectives
This study aimed to compare the sustained abstinence rates of smokers using varenicline versus nicotine patch in their quit attempt up to 36 months.Method
Five hundred eighty-seven smokers were recruited at Kaohsiung Veteran General Hospital between Feb 2006 and Aug 2009. Participants received counseling from a physician and received either varenicline (N?=?296) or the nicotine patch (N?=?291) for smoking cessation. Both varenicline and nicotine patch users could receive their medications for a maximum of 8 weeks. Participants were followed up by telephone at 3, 6, 12, and 36 months from the first visit. The primary outcome measure was self-reported sustained abstinence up to 36 months. Measures were also taken of smoking characteristics, cigarette dependence, and sociodemographic characteristics.Results
Multiple logistic regression of 36-month sustained abstinence on to medication adjusting for other baseline variables showed a significant advantage for varenicline, OR?=?7.94 (95 % CI 1.87–33.74).Conclusion
An 8-week course of varenicline appears to yield higher abstinence rate up to 3 years than a similar length course of nicotine transdermal patch in routine clinical practice where behavioral support is available. 相似文献17.
Amine Bahi Bassem Sadek Stephan J. Schwed Miriam Walter Holger Stark 《Psychopharmacology》2013,228(1):85-95
Rationale
Growing evidence supports a role for the central histaminergic system to have a modulatory influence on drug addiction in general and alcohol-use disorders in particular through histamine H3 receptors (H3R).Objective
In the present study, the effects of systemic injection of the newly synthesized H3R antagonist ST1283 on ethanol (EtOH) voluntary intake and EtOH-conditioned reward in mice have been investigated.Methods
Oral EtOH, saccharin, and quinine intake was assessed in a two-bottle choice paradigm using escalating concentrations of alcohol or tastant solutions. EtOH-induced place preference (CPP), EtOH-induced locomotor activity, and blood ethanol concentration (BEC) were also measured.Results
Following administration of the H3R antagonist (2.5, 5, and 10 mg/kg, i.p.), there was a significant dose-dependent decrease in alcohol consumption and preference. Importantly, vehicle- and ST1283 (5 mg/kg)-treated mice showed similar consumption and preference to increasing concentration of both sweet and bitter tastes. More interestingly, systemic administration of ST1283 inhibited EtOH-CPP and EtOH-enhanced locomotion. This inhibition was blocked when mice were pretreated with the selective H3R agonist R-(alpha)-methyl-histamine (10 mg/kg). Finally, vehicle- and ST1283-treated mice had similar BECs.Conclusion
Our results show that ST1283 may decrease voluntary EtOH consumption and EtOH-CPP by altering its reinforcing effects, suggesting a novel role for histamine signaling in regulation of alcoholism. Lastly, the results add to the growing literature on H3R modulation in the pharmacotherapy of EtOH addiction. 相似文献18.
Amir H. Rezvani Susan Slade Cori Wells Ann Petro Lawrence Lumeng Ting-Kai Li Yingxian Xiao Milton L. Brown Mikell A. Paige Brian E. McDowell Jed E. Rose Kenneth J. Kellar Edward D. Levin 《Psychopharmacology》2010,211(2):161-174
Rationale
Manipulations of nicotinic cholinergic receptors have been shown to influence both alcohol and nicotine intake. Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a novel compound that potently and selectively desensitizes α4β2 nicotinic receptors with only modest receptor activation.Objectives
The goal of the present study was to examine the effects of sazetidine-A on alcohol and nicotine self-administration in alcohol-preferring (P) rats.Methods
P rats were given the choice of water or alcohol. Once stable baselines were established, the acute (0, 0.1, 0.3, 1, and 3 mg/kg, s.c.) and chronic (3 mg/kg for 10 days) effects of sazetidine-A on alcohol intake were assessed. Naltrexone (2.5 mg/kg) served as a positive control. The effect of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on saccharin (0.2%) preference was also assessed. In addition, the acute effects of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on alcohol intake after alcohol deprivation were evaluated. In another experiment, the effects of sazetidine-A (0, 1, or 3 mg/kg) on IV nicotine self-administration in P and NP rats were assessed.Results
Sazetidine-A caused a dose-dependent reduction in alcohol intake. Chronic sazetidine-A also effectively reduced alcohol intake until the seventh day of treatment, when partial tolerance appeared to develop. In the post-deprivation study, sazetidine-A significantly reduced alcohol intake and preference. Sazetidine-A at 3 mg/kg significantly reduced nicotine self-administration in both lines.Conclusions
Sazetidine-A significantly reduced alcohol and nicotine intake in P rats that self-administer higher levels of both drugs. Sazetidine-A may hold promise for the treatment of alcohol and nicotine addiction. 相似文献19.
Jesse S. Rodriguez Colin S. Cunningham Fernando B. Moura Pauline Ondachi F. Ivy Carroll Lance R. McMahon 《Psychopharmacology》2014,231(23):4455-4466
Rationale
Receptor mechanisms underlying the in vivo effects of nicotinic acetylcholine receptor (nAChR) drugs need to be determined to better understand possible differences in therapeutic potential.Objective
This study compared the effects of agonists that are reported either to differ in intrinsic activity (i.e., efficacy) at α4β2 nAChR in vitro or to have in vivo effects consistent with differences in efficacy. The drugs included nicotine, varenicline, cytisine, epibatidine, and three novel epibatidine derivatives: 2′-fluoro-3′-(4-nitrophenyl)deschloroepibatidine (RTI-7527-102), 2′-fluorodeschloroepibatidine (RTI-7527-36), and 3′-(3″-dimethylaminophenyl)-epibatidine (RTI-7527-76).Methods
Mice discriminated nicotine base (1 mg/kg base) from saline; other mice were used to measure rectal temperature.Results
In the nicotine discrimination assay, the maximum percentage of nicotine-appropriate responding varied: 92 % for nicotine, 84 % for epibatidine, 77 % for RTI-7527-36, and 71 % for varenicline and significantly less for RTI-7527-76 (58 %), RTI-7527-102 (46 %), and cytisine (33 %). Each drug markedly decreased rectal temperature by as much as 12?ºC. The rank-order potency in the discrimination and hypothermia assays was epibatidine?>?RTI-7527-36?>?nicotine?>?RTI-7527-102?>?varenicline?=?cytisine?=?RTI-7527-76. The nAChR antagonist mecamylamine (3.2 mg/kg) antagonized the discriminative stimulus effects of epibatidine and RTI-7527-102, as well as the hypothermic effects of every drug except cytisine. The β2-subunit selective nAChR antagonist dihydro-β-erythroidine (DHβE; up to 10 mg/kg) antagonized hypothermic effects but less effectively so than mecamylamine.Conclusions
The marked hypothermic effects of all drugs except cytisine are due in part to agonism at nAChR containing β2-subunits. Differential substitution for the nicotine discriminative stimulus is consistent with differences in α4β2 nAChR efficacy; however, collectively the current results suggest that multiple nAChR receptor subtypes mediate the effects of the agonists. 相似文献20.