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1.  Alcohol inhalation 
doi:10.1503/cmaj.131763
PMCID: PMC4081238  PMID: 24756624
2.  Screening and Treatment for Alcohol, Tobacco and Opioid Use Disorders: A Survey of Family Physicians across Ontario 
PLoS ONE  2015;10(4):e0124402.
Introduction
As a primary point of contact within the health care system, family physicians are able to play a vital role in identifying individuals with substance use disorders and connecting them to the appropriate treatment. However, there is very little data available on whether family physicians are actively screening for and treating substance use disorders. The objective of the current survey was to assess whether family physicians in Ontario are screening for alcohol, opioid and tobacco use disorders, using validated tools and providing treatment.
Methods
An online survey consisting of a series of 38 primarily close-ended questions was circulated to family physicians in Ontario. Rates of screening for alcohol, opioid and tobacco dependence, use of validated tools for screening, providing treatment for dependent individuals and the current barriers to the prescription of pharmacotherapies for these drug dependences were assessed.
Results
The use of validated screening tools was limited for all three substances. Screening by family physicians for the substance use disorders among adolescents was much lower than screening among adults. Pharmacotherapy was more commonly used as an intervention for tobacco dependence than for alcohol and opioid dependence. This was explained by the lack of knowledge among family physicians on the pharmacotherapies for alcohol and opioid dependence.
Conclusions
Findings from the current study suggest there is a need for family physicians to integrate screening for substance use disorders using validated tools into their standard medical practice. Furthermore, there is a need for increased knowledge on pharmacotherapies for alcohol and opioid use disorders. It is important to note that the low response rate is a major limitation to this study. One possible reason for this low response rate may be a lack of interest and awareness among family physicians on the importance of screening and treatment of substance use disorders in Ontario.
doi:10.1371/journal.pone.0124402
PMCID: PMC4414580  PMID: 25923976
3.  Dopamine D4 Receptors in Psychostimulant Addiction 
Since the cloning of the D4 receptor in the 1990s, interest has been building in the role of this receptor in drug addiction, given the importance of dopamine in addiction. Like the D3 receptor, the D4 receptor has limited distribution within the brain suggesting it may have a unique role in drug abuse. However, compared to the D3 receptor, few studies have evaluated the importance of the D4 receptor. This may be due, in part, to the relative lack of compounds selective for the D4 receptor; the early studies were mainly conducted in mice lacking the D4 receptor. In this review, we summarize the literature on the structure and localization of the D4 receptor before reviewing the data from D4 knockout mice that used behavioral models relevant to the understanding of stimulant use. Next, we present evidence from more recent pharmacological studies using selective D4 agonists and antagonists and animal models of drug seeking and taking. The data summarized here suggest a role for D4 receptors in relapse to stimulant use. Therefore, treatments based on antagonism of the D4 receptor may be useful treatments for relapse to nicotine, cocaine and amphetamine use.
doi:10.1016/B978-0-12-420118-7.00008-1
PMCID: PMC4410854  PMID: 24484981
amphetamine; cocaine; nicotine; smoking; dopamine; D4
4.  Role of the Endogenous Cannabinoid System in Nicotine Addiction: Novel Insights 
Several lines of evidence have shown that the endogenous cannabinoids are implicated in several neuropsychiatric diseases. Notably, preclinical and human clinical studies have shown a pivotal role of the cannabinoid system in nicotine addiction. The CB1 receptor inverse agonist/antagonist rimonabant (also known as SR141716) was effective to decrease nicotine-taking and nicotine-seeking in rodents, as well as the elevation of dopamine induced by nicotine in brain reward area. Rimonabant has been shown to improve the ability of smokers to quit smoking in randomized clinical trials. However, rimonabant was removed from the market due to increased risk of psychiatric side-effects observed in humans. Recently, other components of the endogenous cannabinoid system have been explored. Here, we present the recent advances on the understanding of the role of the different components of the cannabinoid system on nicotine’s effects. Those recent findings suggest possible alternative ways of modulating the cannabinoid system that could have implication for nicotine dependence treatment.
doi:10.3389/fpsyt.2015.00041
PMCID: PMC4373509  PMID: 25859226
cannabinoid system; nicotine; addiction; endogenous cannabinoids
5.  Elevation of Dopamine Induced by Cigarette Smoking: Novel Insights from a [11C]-(+)-PHNO PET Study in Humans 
Neuropsychopharmacology  2013;39(2):415-424.
Positron emission tomography (PET) has convincingly provided in vivo evidence that psychoactive drugs increase dopamine (DA) levels in human brain, a feature thought critical to their reinforcing properties. Some controversy still exists concerning the role of DA in reinforcing smoking behavior and no study has explored whether smoking increases DA concentrations at the D3 receptor, speculated to have a role in nicotine's addictive potential. Here, we used PET and [11C]-(+)-PHNO ([11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol) to test the hypothesis that smoking increases DA release (decreases [11C]-(+)-PHNO binding) in D2-rich striatum and D3-rich extra-striatal regions and is related to craving, withdrawal and smoking behavior. Ten participants underwent [11C]-(+)-PHNO scans after overnight abstinence and after smoking a cigarette. Motivation to smoke (smoking topography), mood, and craving were recorded. Smoking significantly decreased self-reported craving, withdrawal, and [11C]-(+)-PHNO binding in D2 and D3-rich areas (−12.0 and −15.3%, respectively). We found that motivation to smoke (puff rate) predicted magnitude of DA release in limbic striatum, and the latter was correlated with decreased craving and withdrawal symptoms. This is the first report suggesting that, in humans, DA release is increased in D3-rich areas in response to smoking. Results also support the preferential involvement of the limbic striatum in motivation to smoke, anticipation of pleasure from cigarettes and relief of withdrawal symptoms. We propose that due to the robust effect of smoking on [11C]-(+)-PHNO binding, this radiotracer represents an ideal translational tool to investigate novel therapeutic strategies targeting DA transmission.
doi:10.1038/npp.2013.209
PMCID: PMC3870776  PMID: 23954846
addiction and substance abuse; dopamine; imaging; clinical or preclinical; neurotransmitters; nicotine; PET; tobacco; ventral tegmental area; tobacco; PET; dopamine; ventral tegmental area; nicotine
6.  Recent methods for measuring dopamine D3 receptor occupancy in vivo: importance for drug development 
There is considerable interest in developing highly selective dopamine (DA) D3 receptor ligands for a variety of mental health disorders. DA D3 receptors have been implicated in Parkinson’s disease, schizophrenia, anxiety, depression, and substance use disorders. The most concrete evidence suggests a role for the D3 receptor in drug-seeking behaviors. D3 receptors are a subtype of D2 receptors, and traditionally the functional role of these two receptors has been difficult to differentiate. Over the past 10–15 years a number of compounds selective for D3 over D2 receptors have been developed. However, translating these findings into clinical research has been difficult as many of these compounds cannot be used in humans. Therefore, the functional data involving the D3 receptor in drug addiction mostly comes from pre-clinical studies. Recently, with the advent of [11C]-(+)-PHNO, it has become possible to image D3 receptors in the human brain with increased selectivity and sensitivity. This is a significant innovation over traditional methods such as [11C]-raclopride that cannot differentiate between D2 and D3 receptors. The use of [11C]-(+)-PHNO will allow for further delineation of the role of D3 receptors. Here, we review recent evidence that the role of the D3 receptor has functional importance and is distinct from the role of the D2 receptor. We then introduce the utility of analyzing [11C]-(+)-PHNO binding by region of interest. This novel methodology can be used in pre-clinical and clinical approaches for the measurement of occupancy of both D3 and D2 receptors. Evidence that [11C]-(+)-PHNO can provide insights into the function of D3 receptors in addiction is also presented.
doi:10.3389/fphar.2014.00161
PMCID: PMC4090596  PMID: 25071579
dopamine; occupancy; PET imaging; D3; D2
7.  Dopamine D3 Receptor Is Necessary for Ethanol Consumption: An Approach with Buspirone 
Neuropsychopharmacology  2014;39(8):2017-2028.
Mesolimbic dopamine (DA) controls drug- and alcohol-seeking behavior, but the role of specific DA receptor subtypes is unclear. We tested the hypothesis that D3R gene deletion or the D3R pharmacological blockade inhibits ethanol preference in mice. D3R-deficient mice (D3R−/−) and their wild-type (WT) littermates, treated or not with the D3R antagonists SB277011A and U99194A, were tested in a long-term free choice ethanol-drinking (two-bottle choice) and in a binge-like ethanol-drinking paradigm (drinking in the dark, DID). The selectivity of the D3R antagonists was further assessed by molecular modeling. Ethanol intake was negligible in D3R−/− and robust in WT both in the two-bottle choice and DID paradigms. Treatment with D3R antagonists inhibited ethanol intake in WT but was ineffective in D3R−/− mice. Ethanol intake increased the expression of RACK1 and brain-derived neurotrophic factor (BDNF) in both WT and D3R−/−; in WT there was also a robust overexpression of D3R. Thus, increased expression of D3R associated with activation of RACK1/BDNF seems to operate as a reinforcing mechanism in voluntary ethanol intake. Indeed, blockade of the BDNF pathway by the TrkB selective antagonist ANA-12 reversed chronic stable ethanol intake and strongly decreased the striatal expression of D3R. Finally, we evaluated buspirone, an approved drug for anxiety disorders endowed with D3R antagonist activity (confirmed by molecular modeling analysis), that resulted effective in inhibiting ethanol intake. Thus, DA signaling via D3R is essential for ethanol-related reward and consumption and may represent a novel therapeutic target for weaning.
doi:10.1038/npp.2014.51
PMCID: PMC4059912  PMID: 24584330
8.  AM404 attenuates reinstatement of nicotine seeking induced by nicotine-associated cues and nicotine priming but does not affect nicotine- and food-taking 
Multiple studies suggest a pivotal role of the endocannabinoid system in the regulation of the reinforcing effects of various substances of abuse. Different approaches have been used to modulate endocannabinoid neurotransmission including the use of endogenous cannabinoid anandamide reuptake inhibitors. Previously, the effects of one of them, N-(4-hydroxyphenyl)-arachidonamide (AM404), have been explored in rodents trained to self-administer ethanol and heroin, producing some promising results. Moreover, AM404 attenuated the development and reinstatement of nicotine-induced conditioned place preference (CPP). In this study, we used the nicotine intravenous self-administration procedure to assess the effects of intraperitoneal administration of 0, 1, 3 and 10 mg/kg AM404 on nicotine-taking and food-taking behaviors under fixed-ratio and progressive-ratio schedules of reinforcement, as well as on reinstatement of nicotine-seeking induced by nicotine priming and by presentation of nicotine-associated cues. The ability of AM404 to produce place preference was also evaluated. AM404 did not produce CPP and did not modify nicotine-taking and food-taking behaviors. In contrast, AM404 dose-dependently attenuated reinstatement of nicotine-seeking behavior induced by both nicotine-associated cues and nicotine priming. Our results indicate that AM404 could be a potential promising therapeutic option for the prevention of relapse to nicotine-seeking in abstinent smokers.
doi:10.1177/0269881113477710
PMCID: PMC4058760  PMID: 23427192
Nicotine; nicotine taking; nicotine seeking; endocannabinoids; AM404
9.  Electrical Stimulation of the Insular Region Attenuates Nicotine-Taking and Nicotine-Seeking Behaviors 
Neuropsychopharmacology  2012;38(4):690-698.
Pharmacological inactivation of the granular insular cortex is able to block nicotine-taking and -seeking behaviors in rats. In this study, we explored the potential of modulating activity in the insular region using electrical stimulation. Animals were trained to self-administer nicotine (0.03 mg/kg per infusion) under a fixed ratio-5 (FR-5) schedule of reinforcement followed by a progressive ratio (PR) schedule. Evaluation of the effect of stimulation in the insular region was performed on nicotine self-administration under FR-5 and PR schedules, as well on reinstatement of nicotine-seeking behavior induced by nicotine-associated cues or nicotine-priming injections. The effect of stimulation was also examined in brain slices containing insular neurons. Stimulation significantly attenuated nicotine-taking, under both schedules of reinforcement, as well as nicotine-seeking behavior induced by cues and priming. These effects appear to be specific to nicotine-associated behaviors, as stimulation did not have any effect on food-taking behavior. They appear to be anatomically specific, as stimulation surrounding the insular region had no effect on behavior. Stimulation of brain slices containing the insular region was found to inactivate insular neurons. Our results suggest that deep brain stimulation to modulate insular activity should be further explored.
doi:10.1038/npp.2012.235
PMCID: PMC3572467  PMID: 23249816
insula; nicotine; self-administration; deep brain stimulation; rats; relapse; Addiction & Substance Abuse; Animal models; Behavioral Science; deep brain stimulation; Insula; Nicotine; Psychopharmacology; self-administration
10.  The endocannabinoid system: a new molecular target for the treatment of tobacco addiction 
Tobacco addiction is one of the leading preventable causes of mortality in the world and nicotine appears to be the main critical psychoactive component in establishing and maintaining tobacco dependence. Several lines of evidence suggest that the rewarding effects of nicotine, which underlie its abuse potential, can be modulated by manipulating the endocannabinoid system. For example, pharmacological blockade or genetic deletion of cannabinoid CB1 receptors reduces or eliminates many behavioral and neurochemical effects of nicotine that are related to its addictive potential.
This review will focus on the recently published literature about the role of the endocannabinoid system in nicotine addiction and on the endocannabinoid system as a novel molecular target for the discovery of medications for tobacco dependence.
PMCID: PMC3821699  PMID: 19128204
Addiction; tobacco dependence; nicotine; endocannabinoid system; CB1 receptors
11.  Varenicline decreases nicotine self administration and nicotine- and cue-induced reinstatement of nicotine-seeking behavior in rats when a long pretreatment time is used 
Effects of varenicline (Champix), a nicotinic partial agonist, were evaluated on subjective effects of nicotine (drug discrimination), motivation for nicotine taking (progressive-ratio schedule of intravenous nicotine self-administration) and reinstatement (cue-induced reinstatement of previously extinguished nicotine-seeking behavior). Effects on motor performance were assessed in rats trained to discriminate nicotine (0.4 mg/kg) from saline under a fixed-ratio (FR10) schedule of food delivery and in rats trained to respond for food under a progressive-ratio schedule. At short pretreatment times (5–40 min), varenicline produced full or high levels of partial generalization to nicotine’s discriminative-stimulus effects and disrupted responding for food, while there were low levels of partial generalization and no disruption of responding for food at 2- or 4-hour pretreatment times. Varenicline (1 and 3 mg/kg, 2-hour pretreatment time) enhanced discrimination of low doses of nicotine and to a small extent decreased discrimination of the training dose of nicotine. It also dose-dependently decreased nicotine-taking behavior, but had no effect on food-taking behavior under progressive-ratio schedules. Finally, varenicline significantly reduced the ability of a nicotine-associated cue to reinstate extinguished nicotine-seeking behavior. The ability of varenicline to reduce both nicotine-taking and nicotine-seeking behavior can contribute to its relatively high efficacy in treating human smokers.
doi:10.1017/S1461145711001398
PMCID: PMC3707493  PMID: 21939589
Varenicline; Nicotine; Progressive ratio schedule; Drug discrimination; Cue-induced reinstatement
12.  The potential role of dopamine D3 receptor neurotransmission in cognition 
Currently available treatments have limited pro-cognitive effects for neuropsychiatric disorders, such as schizophrenia, Parkinson’s disease and Alzheimer’s disease. The primary objective of this work is to review the literature on the role of dopamine D3 receptors in cognition, and propose dopamine D3 receptor antagonists as possible cognitive enhancers for neuropsychiatric disorders. A literature search was performed to identify animal and human studies on D3 receptors and cognition using PubMed, MEDLINE and EMBASE. The search terms included “dopamine D3 receptor” and “cognition”. The literature search identified 164 articles. The results revealed: (1) D3 receptors are associated with cognitive functioning in both healthy individuals and those with neuropsychiatric disorders; (2) D3 receptor blockade appears to enhance while D3 receptor agonism seems to impair cognitive function, including memory, attention, learning, processing speed, social recognition and executive function independent of age; and (3) D3 receptor antagonists may exert their pro-cognitive effect by enhancing the release of acetylcholine in the prefrontal cortex, disinhibiting the activity of dopamine neurons projecting to the nucleus accumbens or prefrontal cortex, or activating CREB signaling in the hippocampus. These findings suggest that D3 receptor blockade may enhance cognitive performance in healthy individuals and treat cognitive dysfunction in individuals with a neuropsychiatric disorder. Clinical trials are needed to confirm these effects.
doi:10.1016/j.euroneuro.2013.05.006
PMCID: PMC3748034  PMID: 23791072 CAMSID: cams3146
Dopamine D3 receptor; Cognition; Dopamine D3 receptor antagonist
13.  Nicotine-taking and nicotine-seeking in C57Bl/6J mice without prior operant training or food restriction 
Behavioural Brain Research  2012;230(1):34-39.
The ability to examine genetically engineered mice in a chronic intravenous (IV) nicotine self-administration paradigm will be a powerful tool for investigating the contribution of specific genes to nicotine reinforcement and more importantly, to relapse behavior. Here we describe a reliable model of nicotine-taking and -seeking behavior in male C57BL/6J mice without prior operant training or food restriction. Mice were allowed to self-administer either nicotine (0.03 mg/kg/infusion) or saline in 2-hr daily sessions under fixed ratio 1 (FR1) followed by FR2 schedules of reinforcement. In the nicotine group, a dose-response curve was measured after the nose-poke behavior stabilized. Subsequently, nose-poke behavior was extinguished and ability of cue presentations, priming injections of nicotine, or intermittent footshock to reinstate responding was assessed in both groups. C57BL/6J mice given access to nicotine exhibited high levels of nose-poke behavior and self-administered a high number of infusions as compared to mice given access to saline. After this acquisition phase, changing the unit-dose of nicotine resulted in a flat dose-response curve for nicotine-taking and subsequently reinstatement of nicotine-seeking behavior was achieved by both nicotine-associated light cue presentation and intermittent footshock. Nicotine priming injections only triggered significant reinstatement on the second consecutive day of priming. In contrast, mice previously trained to self-administer saline did not increase their responding under those conditions.. These results demonstrate the ability to produce nicotine-taking and nicotine-seeking behavior in naive C57BL/6J mice without both prior operant training and food restriction. Future work will utilize these models to evaluate nicotine-taking and relapsing behavior in genetically-altered mice.
doi:10.1016/j.bbr.2012.01.042
PMCID: PMC3310267  PMID: 22326373
nicotine; self-administration; seeking behavior; mice; relapse; dependence
14.  The anandamide transport inhibitor AM404 reduces the rewarding effects of nicotine and nicotine-induced dopamine elevations in the nucleus accumbens shell in rats 
British Journal of Pharmacology  2012;165(8):2539-2548.
BACKGROUND AND PURPOSE
The fatty acid amide hydrolase inhibitor URB597 can reverse the abuse-related behavioural and neurochemical effects of nicotine in rats. Fatty acid amide hydrolase inhibitors block the degradation (and thereby magnify and prolong the actions) of the endocannabinoid anandamide (AEA), and also the non-cannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). OEA and PEA are endogenous ligands for peroxisome proliferator-activated receptors alpha (PPAR-α). Since recent evidence indicates that PPAR-α can modulate nicotine reward, it is unclear whether AEA plays a role in the effects of URB597 on nicotine reward.
EXPERIMENTAL APPROACH
A way to selectively increase endogenous levels of AEA without altering OEA or PEA levels is to inhibit AEA uptake into cells by administering the AEA transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404). To clarify AEA's role in nicotine reward, we investigated the effect of AM404 on conditioned place preference (CPP), reinstatement of abolished CPP, locomotor suppression and anxiolysis in an open field, and dopamine elevations in the nucleus accumbens shell induced by nicotine in Sprague-Dawley rats.
KEY RESULTS
AM404 prevented the development of nicotine-induced CPP and impeded nicotine-induced reinstatement of the abolished CPP. Furthermore, AM404 reduced nicotine-induced increases in dopamine levels in the nucleus accumbens shell, the terminal area of the brain's mesolimbic reward system. AM404 did not alter the locomotor suppressive or anxiolytic effect of nicotine.
CONCLUSIONS AND IMPLICATIONS
These findings suggest that AEA transport inhibition can counteract the addictive effects of nicotine and that AEA transport may serve as a new target for development of medications for treatment of tobacco dependence.
LINKED ARTICLES
This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7
doi:10.1111/j.1476-5381.2011.01467.x
PMCID: PMC3423245  PMID: 21557729
reward; tobacco dependence; nicotine; anandamide; AM404; conditioned place preference; reinstatement; microdialysis; dopamine
15.  Presentation of Smoking-Associated Cues Does Not Elicit Dopamine Release after One-Hour Smoking Abstinence: A [11C]-(+)-PHNO PET Study 
PLoS ONE  2013;8(3):e60382.
The presentation of drug-associated cues has been shown to elicit craving and dopamine release in the striatum of drug-dependent individuals. Similarly, exposure to tobacco-associated cues induces craving and increases the propensity to relapse in tobacco- dependent smokers. However, whether exposure to tobacco-associated cues elicits dopamine release in the striatum of smokers remains to be investigated. We hypothesized that presentation of smoking-related cues compared to neutral cues would induce craving and elevation of intrasynaptic dopamine levels in subregions of the striatum and that the magnitude of dopamine release would be correlated with subjective levels of craving in briefly abstinent tobacco smokers. Eighteen participants underwent two [11C]-(+)-PHNO positron emission tomography (PET) scans after one-hour abstinence period: one during presentation of smoking-associated images and one during presentation of neutral images. Smoking cues significantly increased craving compared to neutral cues on one, but not all, craving measures; however, this increase in craving was not associated with overall significant differences in [11C]-(+)-PHNO binding potential (BPND) (an indirect measure of dopamine release) between the two experimental conditions in any of the brain regions of interest sampled. Our findings suggest that presentation of smoking cues does not elicit detectable (by PET) overall increases in dopamine in humans after one-hour nicotine abstinence. Future research should consider studying smoking cue-induced dopamine release at a longer abstinence period, since recent findings suggest the ability of smoking-related cues to induce craving is associated with a longer duration of smoking abstinence.
doi:10.1371/journal.pone.0060382
PMCID: PMC3612056  PMID: 23555962
16.  Blockade of Dopamine D4 Receptors Attenuates Reinstatement of Extinguished Nicotine-Seeking Behavior in Rats 
Neuropsychopharmacology  2011;37(3):685-696.
Since cloning of the dopamine receptor D4 (DRD4), its role in the brain has remained unclear. It has been reported that polymorphism of the DRD4 gene in humans is associated with reactivity to cues related to tobacco smoking. However, the role of DRD4 in animal models of nicotine addiction has seldom been explored. In our study, male Long-Evans rats learned to intravenously self-administer nicotine under a fixed-ratio (FR) schedule of reinforcement. Effects of the selective DRD4 antagonist L-745,870 were evaluated on nicotine self-administration behavior and on reinstatement of extinguished nicotine-seeking behavior induced by nicotine-associated cues or by priming injections of nicotine. L-745,870 was also tested on reinstatement of extinguished food-seeking behavior as a control. In addition, the selective DRD4 agonist PD 168,077 was tested for its ability to reinstate extinguished nicotine-seeking behavior. Finally, L-745,870 was tested in Sprague Dawley rats trained to discriminate administration of 0.4 mg/kg nicotine from vehicle under an FR schedule of food delivery. L-745,870 significantly attenuated reinstatement of nicotine-seeking induced by both nicotine-associated cues and nicotine priming. In contrast, L-745,870 did not affect established nicotine self-administration behavior or reinstatement of food-seeking behavior induced by food cues or food priming. L-745,870 did not produce nicotine-like discriminative-stimulus effects and did not alter discriminative-stimulus effects of nicotine. PD 168,077 did not reinstate extinguished nicotine-seeking behavior. As DRD4 blockade by L-745,870 selectively attenuated both cue- and nicotine-induced reinstatement of nicotine-seeking behavior, without affecting cue- or food-induced reinstatement of food-seeking behavior, DRD4 antagonists are potential therapeutic agents against tobacco smoking relapse.
doi:10.1038/npp.2011.245
PMCID: PMC3260983  PMID: 22030716
dopamine receptor D4; receptor antagonist; nicotine self-administration; reinstatement of nicotine-seeking behavior; tobacco smoking; relapse; addiction & substance abuse; animal models; dopamine; psychopharmacology; dopamine receptor; D4 receptor antagonist; nicotine self-administration; reinstatement of nicotine-seeking behavior; tobacco smoking
17.  The selective anandamide transport inhibitor VDM11 attenuates reinstatement of nicotine seeking behaviour, but does not affect nicotine intake 
British Journal of Pharmacology  2011;164(6):1652-1660.
BACKGROUND AND PURPOSE
The endocannabinoid system appears to play a pivotal role in mediating the rewarding and reinforcing effects of nicotine. Recent studies have shown that the inhibition of fatty acid amide hydrolase (FAAH) attenuates reinstatement of nicotine-seeking induced by nicotine priming and nicotine-associated cues. FAAH hydrolyses the endogenous endocannabinoid anandamide, as well as other non-cannabinoid ligands such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). As OEA and PEA can attenuate both nicotine-taking and nicotine-seeking behaviour, the specific role of anandamide remains unclear. In this study, we have tested the selective anadamide uptake inhibitor, VDM11, which elevates anandamide levels without affecting levels of OEA/PEA, on nicotine-taking and nicotine-seeking behaviour.
EXPERIMENTAL APPROACH
We used a nicotine intravenous self-administration model in rats to assess the effect of VDM11, given i.p., on nicotine taking using fixed and progressive ratio schedules of reinforcement as well as on reinstatement of nicotine-seeking induced by nicotine priming and nicotine-associated cues.
KEY RESULTS
VDM11 did not affect levels of responding for nicotine under fixed-ratio and progressive-ratio schedules of reinforcement. In contrast, VDM11 dose-dependently attenuated reinstatement of nicotine-seeking behaviour induced by nicotine-associated cues and nicotine priming.
CONCLUSIONS AND IMPLICATIONS
These results indicate that ligands elevating anandamide levels could have therapeutic value for preventing relapse into nicotine-seeking behaviour and should be tested in humans trying to quit smoking.
doi:10.1111/j.1476-5381.2011.01440.x
PMCID: PMC3230812  PMID: 21501143
nicotine; anandamide; cannabinoid; self-administration; VDM11
18.  Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors 
Biological psychiatry  2011;69(7):633-641.
Background
Recent findings indicate that inhibitors of fatty acid amide hydrolase (FAAH) counteract the rewarding effects of nicotine in rats. FAAH inhibition increases levels of several endogenous substances in the brain, including the endocannabinoid anandamide and the non-cannabinoid fatty-acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), which are ligands for alpha-type peroxisome proliferator-activated nuclear receptors (PPAR-α). Here, we evaluated whether directly-acting PPAR-α agonists can modulate reward-related effects of nicotine.
Methods
We combined behavioral, neurochemical and electrophysiological approaches to evaluate effects of the PPAR-α agonists WY14643 and methOEA (a long-lasting form of OEA) on: (1) nicotine self-administration in rats and squirrel monkeys; (2) reinstatement of nicotine-seeking behavior in rats and monkeys; (3) nicotine discrimination in rats; (4) nicotine-induced electrophysiological activity of VTA dopamine neurons in anesthetized rats; and (5) nicotine-induced elevation of dopamine levels in the nucleus accumbens shell of freely-moving rats.
Results
PPAR-α agonists dose-dependently decreased nicotine self-administration and nicotine-induced reinstatement in rats and monkeys, but did not alter food- or cocaine-reinforced operant behavior or the interoceptive effects of nicotine. PPAR-α agonists also dose-dependently decreased nicotine-induced excitation of dopamine neurons in the ventral tegmental area (VTA) and nicotine-induced elevations of dopamine levels in the nucleus accumbens shell of rats. The ability of WY14643 and methOEA to counteract the behavioral, electrophysiological, and neurochemical effects of nicotine was reversed by the PPAR-α antagonist MK886.
Conclusions
These findings indicate that PPAR-α might provide a valuable new target for anti-smoking medications.
doi:10.1016/j.biopsych.2010.07.009
PMCID: PMC2994947  PMID: 20801430
Nicotine; PPAR-α; reinstatement; reward; OEA; PEA; FAAH
19.  Effects of a Selective Cannabinoid CB2 Agonist and Antagonist on Intravenous Nicotine Self Administration and Reinstatement of Nicotine Seeking 
PLoS ONE  2012;7(1):e29900.
Over the last decade there have been significant advances in the discovery and understanding of the cannabinoid system along with the development of pharmacologic tools that modulate its function. Characterization of the crosstalk between nicotine addiction and the cannabinoid system may have significant implications on our understanding of the neurobiological mechanisms underlying nicotine dependence. Two types of cannabinoid receptors (CB1 and CB2) have been identified. CB1 receptors are expressed in the brain and modulate drug taking and drug seeking for various drugs of abuse, including nicotine. CB2 receptors have been recently identified in the brain and have been proposed to play a functional role in mental disorders and drug addiction. Our objective was to explore the role of CB2 receptors on intravenous nicotine self administration under two schedules of reinforcement (fixed and progressive ratio) and on nicotine seeking induced by nicotine priming or by nicotine associated cues. For this, we evaluated the effects of various doses of the selective CB2 antagonist AM630 (1.25 to 5 mg/kg) and CB2 agonist AM1241 (1 to 10 mg/kg) on these behavioral responses in rats. Different groups of male Long Evans rats were trained to lever press for nicotine at a unit dose of 30 µg/kg/infusion. Subsequently, animals were randomized using a Latin-square design and injected with either AM1241 or AM630 using a counterbalanced within subject design. Administration of the CB2 ligands did not affect either nicotine-taking nicotine-seeking behavior. Our results do not support the involvement of CB2 receptors in nicotine-taking or nicotine-seeking behavior.
doi:10.1371/journal.pone.0029900
PMCID: PMC3266883  PMID: 22291896
21.  Noradrenergic α1 Receptors as a Novel Target for the Treatment of Nicotine Addiction 
Neuropsychopharmacology  2010;35(8):1751-1760.
Nicotine is the main psychoactive ingredient in tobacco and its rewarding effects are considered primarily responsible for persistent tobacco smoking and relapse. Although dopamine has been extensively implicated in the rewarding effects of nicotine, noradrenergic systems may have a larger role than previously suspected. This study evaluated the role of noradrenergic α1 receptors in nicotine and food self-administration and relapse, nicotine discrimination, and nicotine-induced dopamine release in the nucleus accumbens in rats. We found that the noradrenergic α1 receptor antagonist prazosin (0.25–1 mg/kg) dose dependently reduced the self-administration of nicotine (0.03 mg/kg), an effect that was maintained over consecutive daily sessions; but did not reduce food self-administration. Prazosin also decreased reinstatement of extinguished nicotine seeking induced by either a nicotine prime (0.15 mg/kg) or nicotine-associated cues, but not food-induced reinstatement of food-seeking, and decreased nicotine-induced (0.15 mg/kg) dopamine release in the nucleus accumbens shell. However, prazosin did not have nicotine-like discriminative effects and did not alter the dose-response curve for nicotine discrimination. These findings suggest that stimulation of noradrenergic α1 receptors is involved in nicotine self-administration and relapse, possibly via facilitation of nicotine-induced activation of the mesolimbic dopaminergic system. The findings point to α1 adrenoceptor blockade as a potential new approach to the treatment of tobacco dependence in humans.
doi:10.1038/npp.2010.42
PMCID: PMC3055474  PMID: 20357760
nicotine; noradrenergic α1 receptors; prazosin; dopamine; self-administration; relapse; Addiction & Substance Abuse; Dopamine; Animal models; Neuropharmacology; nicotine; dopamine; noradrenergic a1 receptors; self-administration; prazosin
22.  The future of endocannabinoid-oriented clinical research after CB1 antagonists 
Psychopharmacology  2009;205(1):171-174.
Great interest has been shown by the medical community and the public in the cannabinoid CB1 receptor antagonists, such as rimonabant, for treatment of obesity, metabolic syndrome, and possibly drug addiction. This novel class of drug has therapeutic potential for other disorders, as the endocannabinoid system is involved in various health conditions. However, rimonabant, the first clinically available member of this class of drugs, has been linked to increased risk of anxiety, depression, and suicidality. Due to those risks, the European Medicines Agency (EMEA) called for its withdrawal from the market in October, 2008. Shortly after this decision, several pharmaceutical companies (Sanofi-aventis, Merck, Pfizer, Solvay) announced they would stop further clinical research on this class of drug. Here, we provide an overview of those events and make several suggestions for continuing such clinical research, while safeguarding the safety of patients and clinical trial subjects.
doi:10.1007/s00213-009-1506-7
PMCID: PMC2695840  PMID: 19300982
Rimonabant; CB1 receptor antagonist; pharmacotherapy; safety; drug dependence; addiction; obesity
23.  Baseline expression of α4 β2* nicotinic acetylcholine receptors predicts motivation to self-administer nicotine 
Biological psychiatry  2008;65(8):714-716.
Background
Marked inter-individual differences in vulnerability to nicotine dependence exist, but factors underlying such differences are not well understood. The midbrain α4β2* subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediation of the reinforcing effects of nicotine responsible for dependence. However, no study has been performed evaluating the impact of inter-individual differences in midbrain nAChR levels on motivation to self-administer nicotine.
Methods
Baseline levels of α4β2* nAChRs were measured using 2-[18F]fluoro-A-85380 (2-FA) and positron emission tomography (PET) in five squirrel monkeys. Motivation to self-administer nicotine was subsequently measured using a progressive-ratio (PR) schedule of reinforcement.
Results
Greater motivation to self-administer nicotine was associated with lower levels of midbrain nAChRs.
Conclusions
The results suggest that level of expression of nAChRs is a contributing factor in the development of nicotine dependence. Similarly, it has been previously shown that low levels of dopamine D2 receptors (DRD2) are associated with a higher preference for psychostimulant use in humans and non-human primates. Together, results from these PET studies of dopaminergic and nicotinic cholinergic transmission suggest that an inverse relationship between the availability of receptors that mediate reinforcement and the motivation to take drugs exists across different neurotransmitter systems.
doi:10.1016/j.biopsych.2008.09.036
PMCID: PMC2687082  PMID: 19095220
positron emission tomography; non-human primates; nicotinic receptors; nicotine self-administration; in vivo binding
24.  Effects of chronic caffeine exposure on adenosinergic modulation of the discriminative-stimulus effects of nicotine, methamphetamine and cocaine in rats 
Psychopharmacology  2008;203(2):355-367.
Rationale
Adenosine receptors are involved in cocaine and methamphetamine discrimination and exposure to caffeine can affect behavioral effects of nicotine in rats.
Objectives
Here we investigated the relative involvement of adenosine A1 and A2A receptors in nicotine, cocaine and methamphetamine discrimination, before and/or during chronic caffeine exposure.
Methods
The non-selective adenosine antagonist caffeine, the A1-receptor antagonist CPT and the A2A-receptor antagonist MSX-3 were evaluated in rats trained to discriminate 0.4 mg/kg nicotine from saline under a fixed-ratio schedule of food delivery. Effects of antagonists were then compared in rats discriminating nicotine, methamphetamine or cocaine during chronic caffeine exposure in their drinking water.
Results
Caffeine, CPT and MSX-3 partially generalized to nicotine and shifted nicotine dose-response curves leftwards. During chronic caffeine exposure, however, all three ligands failed to generalize to nicotine and failed to shift nicotine dose-response curves. In previous experiments, CPT and MSX-3 partially generalized to methamphetamine and cocaine and shifted dose-response curves leftwards. In the present experiments, CPT neither generalized nor shifted dose-response curves for methamphetamine or cocaine during chronic caffeine exposure. However, MSX-3 partially generalized to both psychostimulants and shifted their dose-response curves leftwards. Caffeine partially generalized to cocaine, but not methamphetamine, and shifted both dose-response curves leftwards.
Conclusions
Both adenosine A1 and A2A receptors are capable of modulating the discriminative-stimulus effects of nicotine. Chronic caffeine exposure produces complete tolerance to both A1- and A2A-mediated effects in nicotine-trained rats. In contrast, chronic caffeine exposure produces tolerance to adenosine A1-mediated, but not A2A-mediated, effects in methamphetamine- and cocaine-trained rats.
doi:10.1007/s00213-008-1270-0
PMCID: PMC2656400  PMID: 18688601
Adenosine A1 receptor; adenosine A2A receptor; caffeine; cocaine; drug discrimination; methamphetamine; nicotine; rats
25.  Effects of nicotine in experimental animals and humans: an update on addictive properties 
Tobacco use through cigarette smoking is the leading preventable cause of death in the developed world. Nicotine, a psychoactive component of tobacco, appears to play a major role in tobacco dependence, but reinforcing effects of nicotine have often been difficult to demonstrate directly in controlled studies with laboratory animals or human subjects. Here we update our earlier review published in Psychopharmacology (Berl) in 2006 on findings obtained with various procedures developed to study dependence-related behavioral effects of nicotine in experimental animals and humans. Results obtained with drug self-administration, conditioned place preference, subjective reports of nicotine effects and nicotine discrimination indicate that nicotine can function as an effective reinforcer of drug-seeking and drug-taking behavior both in experimental animals and humans under appropriate conditions. Interruption of chronic nicotine exposure produces ratings of drug withdrawal and withdrawal symptoms that may contribute to relapse. Difficulties encountered in demonstrating reinforcing effects of nicotine under some conditions, relative to other drugs of abuse, may be due to weaker primary reinforcing effects of nicotine, to aversive effects produced by nicotine, or to a more critical contribution of environmental stimuli to the maintenance of drug-seeking and drug-taking behavior with nicotine than with other drugs of abuse. Several recent reports suggest that other chemical substances inhaled along with nicotine in tobacco smoke may play a role in sustaining smoking behavior. However, conflicting results have been obtained with mice and rats and these findings have not yet been validated in non-human primates or human subjects. Taken together, these findings suggest that nicotine acts as a typical drug of abuse in experimental animals and humans under appropriate situations.
doi:10.1007/978-3-540-69248-5_12
PMCID: PMC2687081  PMID: 19184655

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