New Insights in the Involvement of the Endocannabinoid System and Natural Cannabinoids in Nicotine Dependence.

Nicotine, the main psychoactive component in tobacco smoke, plays a major role in tobacco addiction, producing a high morbidity and mortality in the world. A great amount of research has been developed to elucidate the neural pathways and neurotransmitter systems involved in such a complex addictive behavior. The endocannabinoid system, which has been reported to participate in the addictive properties of most of the prototypical drugs of abuse, is also implicated in nicotine dependence. This review summarizes and updates the main behavioral and biochemical data involving the endocannabinoid system in the rewarding properties of nicotine as well as in nicotine withdrawal and relapse to nicotine-seeking behavior. Promising results from preclinical studies suggest that manipulation of the endocannabinoid system could be a potential therapeutic strategy for treating nicotine addiction.

The Role of Peroxisome Proliferator-Activated Receptor in Addiction: A Novel Drug Target.

The peroxisome proliferator activated receptors (PPARs) are a superfamily of well-recognized ligand-binding nuclear receptors comprising three isoforms: PPARα, PPARγ, and PPARß/δ. In response to endogenous lipid messengers, PPARs trigger the transcription of genes related to a wider spectrum of physiological phenomena, including fatty acid oxidation, inflammation, adipogenesis, among many others. Thus, the importance of PPARs as putative protective therapy in health issues has increased the interest of studying these nuclear receptors, including the management of neurodegenerative disorders, multiple sclerosis, and likely addiction. In recent years, several pieces of evidence from animal models have demonstrated the promising role of PPARs as a critical element for interventions in addictive behaviors by reducing the reinforcing properties of addictive substances such as alcohol. However, there is a lack of data in the scope and has so far been unexplored the function of PPARs in additional drugs such as cannabis, opioids, methamphetamine, or cocaine. A similar scenario has been found for the management of binge-type eating disorders. Thus, here we review recent advances in understanding the relevance of the PPAR controlling addiction.

A non-hallucinogenic psychedelic analogue with therapeutic potential.

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

Accelerated habitual learning resulting from L-dopa exposure in rats is prevented by N-acetylcysteine.

Instrumental actions are initially goal-directed and driven by their associated outcome. However, with repeated experience habitual actions develop which are automated and efficient, as they are instead driven by antecedent stimuli. Dopamine is thought to facilitate the transition from goal-directed to habitual actions. This idea has been largely derived from evidence that psychostimulants accelerate the development of habitual actions. In the current study, we examined the impact of L-dopa (levodopa or L-dihydroxyphenylalanine), which also potentiates dopamine activity, on habitual learning. L-dopa was systemically administered prior to training rats to press a lever for a food outcome. When tested, L-dopa exposed animals were insensitive to changes in the value of the food outcome, and hence demonstrated accelerated habitual behavioral control compared to control animals that remained goal directed. We also showed that when N-acetylcysteine (NAC), an antioxidant and regulator of glutamate activity, was co-administered with L-dopa, it prevented the transition to habitual behavior; an effect demonstrated previously for cocaine. Therefore, this study establishes similarities between L-dopa and psychostimulants in both the development and prevention of habitual actions, and supports the notion that excess dopamine potentiates habitual learning. This finding extends the limited existing knowledge of the impact of L-dopa on learning and behavior, and has implications for neurological disorders where L-dopa is the primary treatment.

Red-hot chili receptors: A systematic review of TRPV1 antagonism in animal models of psychiatric disorders and addiction.

Transient Receptor Potential Vanilloid 1 (TRPV1) channels are non-selective cationic polymodal receptors gated by several different chemical and physical stimuli. TRPV1 receptors are distributed in several brain areas and interact with important neurotransmitter systems linked to mental disorders, such as endocannabinoid and opioid systems. The increasing number of results obtained in this field has recently attracted growing attention to these receptors as potential targets for the treatment of different psychiatric conditions. To review the available results on this topic, we searched on PubMed, Embase and Science Direct databases up to May 2020 using the following search string: "TRPV1", thus including a total of 48 studies. The results, still limited to preclinical studies, suggest that TRPV1 antagonism could represent a potential mechanism for the treatment of depression and anxiety, as well as for opioids, methamphetamine and cocaine addiction. Few available results consider schizophrenia-like behaviours, suggesting an intriguing role of TRPV1 receptors in the neurobiology of major psychoses. Single studies report the effectiveness of TRPV1 antagonists in animal models of obsessive-compulsive disorder and fibromyalgia. Future preclinical and clinical studies are required to shed further light on the feasibility of the use of TRPV1 modulators in psychopharmacology.

Hypodopaminergia and "Precision Behavioral Management" (PBM): It is a Generational Family Affair.

BACKGROUND/AIMS: This case series presents the novel Genetic Addiction Risk Score (GARS®) coupled with a customized pro-dopamine regulator matched to polymorphic reward genes having a hypodopaminergic risk. METHODS: The proband is a female with a history of drug abuse and alcoholism. She experienced a car accident under the influence and voluntarily entered treatment. Following an assessment, she was genotyped using the GARS, and started a neuronutrient with a KB220 base indicated by the identified polymorphisms. She began taking it in April 2018 and continues. RESULTS: She had success in recovery from Substance Use Disorder (SUD) and improvement in socialization, family, economic status, well-being, and attenuation of Major Depression. She tested negative over the first two months in treatment and a recent screening. After approximately two months, her parents also decided to take the GARS and started taking the recommended variants. The proband's father (a binge drinker) and mother (no SUD) both showed improvement in various behavioral issues. Finally, the proband's biological children were also GARS tested, showing a high risk for SUD. CONCLUSION: This three-generation case series represents an example of the impact of genetic information coupled with an appropriate DNA guided "Pro-Dopamine Regulator" in recovery and enhancement of life.

Lorcaserin: A review of its preclinical and clinical pharmacology and therapeutic potential.

The selective 5-HT2C receptor agonist lorcaserin, in conjunction with lifestyle modification, was approved by the FDA in 2012 for weight management. It has been marketed in the US as Belviq® since 2013. This article provides a review of the preclinical and clinical pharmacology of lorcaserin, including its pharmacokinetic and safety profiles. Preclinical studies with lorcaserin initially focused on simple measures of food intake and body weight gain, but have now expanded to include studies on its effects on appetitive aspects of feeding behaviour and models of binge-eating. A significant number of studies have also shown that lorcaserin alters behaviours related to drug use and addiction, in rodents and non-human primates. Potential clinically-relevant effects of lorcaserin have also been reported in models of pain and seizure-like activity. Not surprisingly, the majority of clinical work with lorcaserin has focused on its effects on weight gain, and on physiological processes related to energy intake. However, results of clinical trials and experimental laboratory studies involving lorcaserin are now appearing which describe effects on a range of other behaviours and physiological functions. These include smoking cessation, cocaine self-administration, and behavioural and brain responses to food cues. All of this work suggests that lorcaserin may have therapeutic potential for a variety of disorders and conditions beyond obesity. Based on clinical experience, including the outcomes from several, large, well-powered clinical obesity trials at the approved 10mg BID dose both pre and post approval, a priori concerns about cardiac valvulopathy have largely been allayed. However, as with any recently approved first-in-class pharmacotherapy, there may be yet-unknown risks, as well as benefits, associated with use of lorcaserin. Nonetheless, the current safety profile and an expanding post approval safety data base should encourage further experimental laboratory-based and clinical trial-based research with lorcaserin in targeted populations to investigate its full therapeutic potential.

Effects of Intranasal Oxytocin on Stress-Induced Cigarette Craving in Daily Smokers.

BACKGROUND: Cigarette smoking is a well-known public health concern, and there is an urgent need to develop new treatments to reduce smoking or facilitate abstinence. One factor that is known to contribute to relapse is stress, making the stress response an important target for treatment. The neuropeptide oxytocin (OT) is believed to have stress-reducing effects, and in addition there is evidence that it reduces drug craving. The purpose of the present study was to examine the effects of intranasal OT on stress-induced cigarette craving in regular smokers after 12 h of abstinence. METHOD: Daily smokers (n = 48) completed a stress induction task and a nonstressful control task at two different sessions, receiving intranasal OT (40 IU) or placebo (PBO) before or after the task. Subjects were randomly assigned to one of three groups: Group PP (n = 16) received PBO before and after the stress/control tasks, Group OP (n = 16) received OT before the tasks and PBO after, and Group PO (n = 16) received PBO before the tasks and OT shortly after completing the tasks. Cigarette craving as well as subjective and physiological responses to stress was assessed. RESULTS: OT did not alter responses to stress, whether it was administered before or after the stressful task, on measures of cigarette craving, anxiety, heart rate, blood pressure, and cortisol levels. CONCLUSIONS: The current study findings do not support several previous reports that OT reduced either stress or drug craving. IMPLICATIONS: This study finds a null result of the neuropeptide oxytocin on stress-induced cigarette craving. Reporting null findings is part of the process of identifying potential treatments for addictive disorders.

A randomized clinical trial on the effects of bupropion and buprenorphine on the reduction of methamphetamine craving.

BACKGROUND: The purpose of this study was to compare the effect of 300 mg of bupropion and 8 mg of buprenorphine per day on the treatment of methamphetamine withdrawal cravings over a 2-week treatment interval. METHOD: Sixty-five methamphetamine-dependent men who met the DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision) criteria for methamphetamine dependence and withdrawal were randomly divided into two groups. Subjects randomly received 300 mg of bupropion or 8 mg of buprenorphine per day in a psychiatric ward. Of the 65 subjects, 35 (53.8%) received buprenorphine and 30 (46.2%) received bupropion. The subjects were assessed by using methamphetamine craving score, interview, and negative urine drug test. FINDINGS: There were no statistically significant differences between the two groups in regard to age, education, duration of methamphetamine dependency, marital status, employment, and income. The mean ages were 32.8 years (standard deviation (SD) = 7.26, range = 22 to 59) for the buprenorphine group and 32.21 years (SD = 8.45, range = 17 to 51) for the bupropion group. All 65 patients completed the 2-week study. Both medications were effective in the reduction of methamphetamine cravings. Reduction of craving in the buprenorphine group was significantly more than the bupropion group (P = 0.011). Overall, a significant main effect of day (P <0.001) and group (P = 0.011) and a non-significant group-by-day interaction (P >0.05) were detected. CONCLUSIONS: The results support the safety and effectiveness of buprenorphine and bupropion in the treatment of methamphetamine withdrawal craving. Administration of 8 mg of buprenorphine per day can be recommended for the treatment of methamphetamine withdrawal cravings. We should note that it is to be expected that craving decreases over time without any medication. So the conclusion may not be that bupropion and buprenorphine both lower the craving. As the buprenorphine is superior to bupropion, only buprenorphine does so for sure. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT) registration number: IRCT2015010320540N1 . Date registered: April 10, 2015.

Oxytocin treatment in the prelimbic cortex reduces relapse to methamphetamine-seeking and is associated with reduced activity in the rostral nucleus accumbens core.

Addiction to the psychostimulant Methamphetamine (METH) is characterised by high rates of relapse. Currently there are no approved effective pharmacotherapies for METH dependence. The neuropeptide oxytocin (OXY) potently reduces METH-seeking behaviours in rodent models of relapse and is now being used in clinical trials to treat drug-dependent individuals. However, OXY administration in humans may be impeded by its poor penetration of the brain. Therefore, identification of the neural mechanisms by which OXY reduces METH relapse may guide the development of improved OXY-based therapies for METH addiction. Systemic OXY administration is associated with attenuated METH-induced activity in the prelimbic cortex (PrL); a key brain region which exerts control over much of the reward and addiction circuitry. However, it is not known whether OXY acts directly in the PrL to cause reductions in drug-seeking and downstream brain activity. Therefore, the present study sought to determine whether OXY infused into the PrL reduces cue-induced and METH-primed reinstatement and METH-induced neuronal activity in the downstream nucleus accumbens core (NAcc). Male Sprague Dawley rats underwent intravenous METH self-administration, extinction, and subsequent reinstatement tests. OXY was infused bilaterally into the PrL prior to cue-induced (0, 1 µg/side) and METH-primed reinstatement (0, 0.33, 1.0, 3.0 µg/side). Finally, we quantified cFos immunofluorescence in the NAcc as a proxy for downstream neuronal activity following a PrL infusion of OXY (0, 1 µg/side) prior to METH-primed reinstatement. OXY in the PrL significantly reduced both cue-induced and METH-primed reinstatement. Additionally, intra-PrL OXY reduced METH-induced cFos expression in the rostral but not caudal pole of the NAcc. These findings demonstrate OXY action in the PrL in reducing METH-seeking behaviours and METH-induced activity in the reward circuit. Furthermore, these results suggest that the therapeutic effects of systemically administered OXY on reducing METH-seeking behaviours may involve the PrL-NAc pathway.

Oxytocin Reduces Cigarette Consumption in Daily Smokers.

INTRODUCTION: Despite widespread knowledge of the dangers of cigarette consumption, smoking continues to be a public health concern. One compound that has shown potential for treatment in preclinical models is the neuropeptide oxytocin (OT). The purpose of the present study was to examine the effects of intranasal oxytocin on cigarette craving, behavioral economic demand for cigarettes, and cigarette consumption, in regular smokers after 18 hours of abstinence. METHOD: Otherwise healthy daily smokers (n = 35) completed two sessions where they received OT (40 IU intranasal) or placebo (PBO) and completed measures of craving and cigarette demand, and they were given six opportunities to smoke partial cigarettes in exchange for money. RESULTS: On average participants smoked few cigarettes after receiving OT than after receiving PBO, and they reported less desire for additional cigarettes during the smoking period. OT did not affect cigarette demand or standardized measures of cigarette craving. CONCLUSIONS: This study suggests that OT decreases some indices of smoking desire and consumption, providing modest support for the idea that OT might be effective for reducing cigarette smoking. IMPLICATIONS: This study provides new evidence that oxytocin might have clinical value in the treatment of addictive disorders, in this case tobacco addiction. The study adds to a growing literature suggesting that this neuropeptide, which is mainly known for its role in social bonding and attachment, may also affect mood and motivational states relevant to addiction.

Topiramate Pharmacotherapy for Alcohol Use Disorder and Other Addictions: A Narrative Review.

: Topiramate is a non-benzodiazepine anticonvulsant medication with multi-faceted pharmacologic action. It has emerged as an efficacious pharmacotherapeutic option for the treatment of addiction, especially alcohol use disorder (AUD). We present a broad narrative review of the putative mechanism of action and clinical utility of topiramate with regard to AUD and other substance use disorders. Collective evidence suggests topiramate is an effective treatment option in AUD, with notable efficacy in reducing harmful drinking patterns in AUD. Though not currently approved by the United States Food and Drug Administration for the indication of AUD, topiramate should be considered as a pharmacological treatment option with high utility among AUD patients. Early pharmacogenetic studies raise the intriguing possibility of identifying patients likely to respond to topiramate using genetic testing, and initial studies show that topiramate may also be useful in treating cocaine use disorder, smoking cessation and behavioral addictions. However, further research is needed in all these areas.

Cracking the Betel Nut: Cholinergic Activity of Areca Alkaloids and Related Compounds.

INTRODUCTION: The use of betel quid is the most understudied major addiction in the world. The neuropsychological activity of betel quid has been attributed to alkaloids of Areca catechu. With the goal of developing novel addiction treatments, we evaluate the muscarinic and nicotinic activity of the four major Areca alkaloids: arecoline, arecaidine, guvacoline, and guvacine and four structurally related compounds. METHODS: Acetylcholine receptors were expressed in Xenopus oocytes and studied with two-electrode voltage clamp. RESULTS: Both arecoline- and guvacoline-activated muscarinic acetylcholine receptors (mAChR), while only arecoline produced significant activation of nicotinic AChR (nAChR). We characterized four additional arecoline-related compounds, seeking an analog that would retain selective activity for a α4* nAChR, with diminished effects on mAChR and not be a desensitizer of α7 nAChR. We show that this profile is largely met by isoarecolone. Three additional arecoline analogs were characterized. While the quaternary dimethyl analog had a broad range of activities, including activation of mAChR and muscle-type nAChR, the methyl analog only activated a range of α4* nAChR, albeit with low potency. The ethyl analog had no detectable cholinergic activity. CONCLUSIONS: Evidence indicates that α4* nAChR are at the root of nicotine addiction, and this may also be the case for betel addiction. Our characterization of isoarecolone and 1-(4-methylpiperazin-1-yl) ethanone as truly selective α4*nAChR selective partial agonists with low muscarinic activity may point toward a promising new direction for the development of drugs to treat both nicotine and betel addiction. IMPLICATIONS: Nearly 600 million people use Areca nut, often with tobacco. Two of the Areca alkaloids are muscarinic acetylcholine receptor agonists, and one, arecoline, is a partial agonist for the α4* nicotinic acetylcholine receptors (nAChR) associated with tobacco addiction. The profile of arecoline activity suggested its potential to be used as a scaffold for developing new tobacco cessation drugs if analogs can be identified that retain the same nicotinic receptor selectivity without muscarinic activity. We report that isoarecolone is a selective partial agonist for α4* nAChR with minimal muscarinic activity and 1-(4-methylpiperazin-1-yl) ethanone has similar nAChR selectivity and no detectable muscarinic action.

NAChR α4ß2 Subtype and their Relation with Nicotine Addiction, Cognition, Depression and Hyperactivity Disorder.

BACKGROUND: Neuronal α4ß2 nAChRs are receptors involved in the role of neurotransmitters regulation and release, and this ionic channel participates in biological process of memory, learning and attention. This work aims to review the structure and functioning of the α4ß2 nAChR emphasizing its role in the treatment of associated diseases like nicotine addiction and underlying pathologies such as cognition, depression and attention-deficit hyperactivity disorder. METHODS: The authors realized extensive bibliographic research using the descriptors "Nicotine Receptor α4ß2" and "cognition", "depression", "attention-deficit hyperactivity disorder", besides cross-references of the selected articles and after analysis of references in the specific literature. RESULTS: As results, it was that found 179 relevant articles presenting the main molecules with affinity to nAChR α4ß2 related to the cited diseases. The α4ß2 nAChR subtype is a remarkable therapeutic target since this is the most abundant receptor in the central nervous system. CONCLUSION: In summary, this review presents perspectives on the pharmacology and therapeutic targeting of α4ß2 nAChRs for the treatment of cognition and diseases like nicotine dependence, depression and attention-deficit hyperactivity disorder.

The effect of nicotine and nicotine+monoamine oxidase inhibitor on the value of alcohol.

Alcohol is the most commonly abused drug in the USA and many people suffer from alcohol use disorder. Many factors are associated with alcohol use disorder, but the causal role of comorbid nicotine use has not been extensively considered. Nicotine has reward-enhancing properties and may increase the value of alcohol. Monoamine oxidase inhibition increases nicotine self-administration and may increase the reward-enhancing effects of nicotine. We assessed the effect of nicotine and nicotine in combination with a commonly used monoamine oxidase inhibitor (tranylcypromine) on the value of alcohol using a progressive ratio schedule of reinforcement in rats. Nicotine administration increased the breakpoint for alcohol, but nicotine in combination with tranylcypromine decreased the breakpoint for alcohol. The current study adds to previous research showing that nicotine increases the value of alcohol. This finding has important implications for the etiology of addiction because of the comorbidity of smoking with many drugs of abuse. The finding that nicotine in combination with tranylcypromine reduces the value of alcohol warrants further investigation.

The Association between the Level of Plasma Oxytocin and Craving among Former Heroin Users.

BACKGROUND: Animal studies have demonstrated that oxytocin can influence addiction behaviors and might interact with the dopaminergic system, which is a key component of addiction behaviors. However, related evidence from clinical studies is scarce. The aim of our study was to explore the relationship between plasma oxytocin level and heroin craving among patients receiving methadone maintenance treatment, and to ascertain whether this relationship is moderated by novelty-seeking. METHODS: The study was conducted in a methadone maintenance therapy clinic of a medical center in Taiwan. Seventy-seven patients with heroin addiction were enrolled. Plasma oxytocin was measured using an ELISA kit. Craving was assessed using an established instrument, the Chinese Craving Scale. RESULTS: A significant negative association was found between the plasma oxytocin level and craving score, which remained robust after controlling the effects of social support and low-density lipoprotein cholesterol. An interaction between oxytocin and novelty-seeking indicated that this relationship was stronger among patients with a lower level of novelty-seeking. CONCLUSION: This finding may be taken into account in future studies and may provide a basis for the development of potential treatment for addiction. The effect of oxytocin for the treatment of opioid dependence might be modulated by some psychological factors.

[Temporary approval for intranasal naloxone: Setting up in a French addiction center]. / Pratique de l'ATU de cohorte de la naloxone intranasale (Nalscue®) : mise en place dans un CSAPA parisien.

Intranasal naloxone aims at preventing opioid overdose related deaths in active drug users. In France, it has been available since July 2016 through a temporary approval which requires a hospital-based pharmacy and a nominative registration of each patient. We present the characteristics of the first patients who could receive this prescription in our hospital-based addiction center and how they used naloxone during follow-up. Results favor a larger dispensing of naloxone. Patients' as well as peers' and families' education is needed.

Animal Models of Addiction and Neuropsychiatric Disorders and Their Role in Drug Discovery: Honoring the Legacy of Athina Markou.

Each of the co-authors worked with Athina Markou, at different stages of our careers and in different capacities, to develop, optimize, and use animal models of drug addiction and, more generally, mental health disorders such as anxiety, depression, and schizophrenia. Here, we briefly summarize some of our work with Athina, primarily involving the use of the intracranial self-stimulation and intravenous drug self-administration procedures. This work established that excessive consumption of addictive drugs can induce profound dysfunction in brain reward circuits. Such drug-induced reward deficits are likely to play a key role in precipitating the emergence of compulsive drug-seeking behaviors. We also summarize findings suggesting that perturbations in glutamatergic transmission contribute to brain reward deficits in drug-dependent animals and that metabotropic glutamate receptors are potential targets for the development of novel medications to facilitate long-term drug abstinence and prevention of relapse.

The relationships between depression, neuroticism, and attitudes (NDA model) in heroin abusers in Taiwan.

BACKGROUND AND OBJECTIVES: Heroin use is a severe problem worldwide. To develop more effective treatments for heroin abusers, a comprehensive psychosocial model of heroin use should be established and examined. We created and assessed a neuroticism, depression, attitudes, and heroin addiction (NDA) model. METHODS: In this cross-sectional study, 234 patients undergoing methadone replacement treatment were recruited from psychiatric clinics. We used Structural Equation Modeling (SEM) to assess all for neuroticism, depression, and a positive outcome expectancy (POE) (attitudes). RESULTS: The full model had acceptable goodness-of-fit indices, but neuroticism was not significantly associated with a POE or heroin use. A reduced model that deleted insignificant paths had better goodness-of-fit indices, and neuroticism had indirect effects on heroin use via depression and a POE CONCLUSIONS: Our findings provide evidence that depression, neuroticism, and POE affect heroin use. We also found that POE mediates between depression and heroin use. Despite the emotional regulation strategies recommended to help heroin abusers with depression to reduce the likelihood of their heroin use, teaching them with negative attitudes using heroin should also be considered when developing treatments for heroin abusers with depression. SCIENTIFIC SIGNIFICANCE: Our findings provide a comprehensive mechanism of addiction that is integrated with emotion, cognition, and personality. Drug-related beliefs and emotional regulation can be targeted to reduce the likelihood of relapse in abusers with higher levels of neuroticism. (Am J Addict 2018;27:139-143).