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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  Inhibition of anandamide hydrolysis by URB597 reverses abuse-related behavioral and neurochemical effects of nicotine in rats 
Emerging evidence suggests that the rewarding, abuse-related effects of nicotine are modulated by the endocannabinoid system of the brain. For example, pharmacological blockade or genetic deletion of cannabinoid CB1 receptors can reduce or eliminate many abuse-related behavioral and neurochemical effects of nicotine. Furthermore, doses of Δ9-tetrahydrocannabinol (THC) and nicotine that are ineffective when given alone can induce conditioned place preference when given together. These previous studies have used systemically-administered CB1-receptor agonists and antagonists and gene deletion techniques, which affect cannabinoid CB1 receptors throughout the brain. A more functionally selective way to alter endocannabinoid activity is to inhibit fatty acid amide hydrolase (FAAH), thereby magnifying and prolonging the effects of only the endocannabinoid anandamide (AEA) when and where it is synthesized and released on demand. Here we combined behavioral and neurochemical approaches to evaluate whether the FAAH inhibitor cyclohexyl carbamic acid 3’-carbamoyl-3-yl ester (URB597) could alter the abuse-related effects of nicotine in rats. We found that URB597, at a dose (0.3 mg/kg) that had no behavioral effects by itself, prevented development of nicotine-induced conditioned place preference (CPP) and acquisition of nicotine self-administration. URB597 also reduced nicotine-induced reinstatement in both CPP and self-administration models of relapse. Furthermore, in vivo microdialysis showed that URB597 reduced nicotine-induced dopamine elevations in the nucleus accumbens shell, the terminal area of the brain’s mesolimbic reward system. These findings suggest that FAAH inhibition can counteract the addictive properties of nicotine and that FAAH may serve as a new target for development of medications for treatment of tobacco dependence.
doi:10.1124/jpet.108.142224
PMCID: PMC2663803  PMID: 18725543
21.  Effects of baclofen on conditioned rewarding and discriminative stimulus effects of nicotine in rats 
Neuroscience letters  2008;443(3):236-240.
Neurochemical studies suggest that baclofen, an agonist at GABAB receptors, may be useful for treatment of nicotine dependence. However, its ability to selectively reduce nicotine’s abuse-related behavioral effects remains in question. We assessed effects of baclofen doses ranging from 0.1 to 3 mg/kg on nicotine-induced conditioned place preferences (CPP), nicotine discrimination, locomotor activity and food-reinforced behavior in male Sprague Dawley rats. The high dose of baclofen (3 mg/kg) totally eliminated food-reinforced responding and significantly decreased locomotor activity. Lower doses of baclofen did not have nicotine-like discriminative effects in rats trained to discriminate 0.4 mg/kg nicotine from saline under a fixed-ratio 10 schedule of food delivery. Lower doses of baclofen also did not reduce discriminative-stimulus effects of the training dose of nicotine and did not significantly shift the dose-response curve for nicotine discrimination. Rats treated with the high 3 mg/kg dose of baclofen did not express nicotine-induced CPP. These experiments, along with previous reports that baclofen can reduce intravenous nicotine self-administration behavior, confirm the potential utility of baclofen as a tool for smoking cessation.
doi:10.1016/j.neulet.2008.07.074
PMCID: PMC2679513  PMID: 18682277
Conditioned place preferences – discrimination; Reward; Nicotine; Rats – GABA
22.  BLOCKING CANNABINOID CB1 RECEPTORS FOR THE TREATMENT OF NICOTINE DEPENDENCE: INSIGHTS FROM PRECLINICAL AND CLINICAL STUDIES 
Addiction biology  2008;13(2):239-252.
Tobacco use is one of the leading preventable causes of death in developed countries. Since existing medications are only partially effective in treating tobacco smokers, there is a great need for improved medications for smoking cessation. It has been recently proposed that cannabinoid CB1 receptor antagonists represent a new class of therapeutic agents for drug dependence, and, notably, nicotine dependence. Here, we will review current evidence supporting the use of this class of drugs for smoking cessation treatment. Preclinical studies indicate that nicotine exposure produces changes in endocannabinoid content in the brain. In experimental animals, Rimonabant (SR141716) and AM251, two cannabinoid CB1 receptor antagonists, block nicotine self-administration behavior, an effect that may be related to the blockade of the dopamine-releasing effects of nicotine in the brain. Rimonabant also seems efficacious in decreasing the influence of nicotine-associated stimuli over behavior, suggesting that it may act on two distinct neuronal pathways, those implicated in drug-taking behavior and those involved in relapse phenomena. The utility of Rimonabant has been evaluated in several clinical trials. It seems that Rimonabant is an efficacious treatment for smoking cessation, although its efficacy doesn’t exceed that of nicotine replacement therapy and its use may be limited by emotional side effects (nausea, anxiety and depression, mostly). Rimonabant also appears to decrease relapse rates in smokers. These findings indicate significant, but limited, utility of Rimonabant for smoking cessation.
doi:10.1111/j.1369-1600.2008.00113.x
PMCID: PMC2752688  PMID: 18482433
23.  QUELS FUTURS TRAITEMENTS POUR LA DEPENDANCE AU TABAC ET AU CANNABIS? 
RESUME
Plus de trois millions de morts sont attribués au tabagisme dans le monde par an, et l’usage de tabac est en progression dans les pays en voie de développement. L’usage de tabac est donc une des rares causes de mortalité qui augmente, avec une prévision de plus de 10 millions de morts par an dans 30–40 ans. Le cannabis ou marijuana est la drogue illicite la plus consommée dans le monde et il n’y a actuellement pas de traitement disponible. Bien que les systèmes dopaminergiques jouent un rôle central dans les effets renforçants des drogues, d’autres systèmes sont impliqués. Nous présentons ici des résultats récents obtenus avec des antagonistes des récepteurs cannabinoides CB1, des récepteurs D3 de la dopamine et des récepteurs opioïdes. Ces antagonistes qui modulent de façon directe ou indirecte la transmission dopaminergique cérébrale représentent des approches prometteuses pour le traitement du tabagisme ou de la dépendance au cannabis. Ces approches sont à valider dans des essais cliniques.
PMCID: PMC2744405  PMID: 18663981
TABAC; NICOTINE; CANNABIS; DEPENDANCE; TRAITEMENT
24.  Treatment of tobacco dependence: integrating recent progress into practice 
Tobacco use is one of the leading preventable causes of death in developed countries. Adoption of approaches that have demonstrated efficacy to improve the treatment of tobacco dependence are critical to reduce the health consequences of tobacco use. We summarize the latest epidemiologic data on tobacco use, the mechanisms that underlie tobacco dependence, and advances in pharmacotherapy and nonpharmacologic interventions available for the treatment of tobacco dependence. Specifically, we discuss the use of nicotine replacement therapy, bupropion and varenicline in primary care settings.
doi:10.1503/cmaj.070627
PMCID: PMC2072983  PMID: 18025429
25.  High Reinforcing Efficacy of Nicotine in Non-Human Primates 
PLoS ONE  2007;2(2):e230.
Although tobacco appears highly addictive in humans, there has been persistent controversy about the ability of its psychoactive ingredient nicotine to induce self-administration behavior in laboratory animals, bringing into question nicotine's role in reinforcing tobacco smoking. Because of ethical difficulties in inducing nicotine dependence in naïve human subjects, we explored reinforcing effects of nicotine in experimentally-naive non-human primates given access to nicotine for periods of time up to two years. Five squirrel monkeys with no experimental history were allowed to intravenously self-administer nicotine by pressing one of two levers. The number of presses on the active lever needed to obtain each injection was fixed (fixed-ratio schedule) or increased progressively with successive injections during the session (progressive-ratio schedule), allowing evaluation of both reinforcing and motivational effects of nicotine under conditions of increasing response cost. Over time, a progressive shift toward high rates of responding on the active lever, but not the inactive lever, developed. The monkeys' behavior was clearly directed toward nicotine self-administration, rather than presentation of environmental stimuli associated with nicotine injection. Both schedules of reinforcement revealed a high motivation to self-administer nicotine, with monkeys continuing to press the lever when up to 600 lever-presses were needed for each injection of nicotine. Thus, nicotine, by itself, in the absence of behavioral or drug-exposure history, is a robust and highly effective reinforcer of drug-taking behavior in a non-human primate model predictive of human behavior. This supports the use of nicotinic ligands for the treatment of smokers, and this novel preclinical model offers opportunities to test future medications for the treatment of nicotine dependence.
doi:10.1371/journal.pone.0000230
PMCID: PMC1794142  PMID: 17311094

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