Current status of immunotherapies for addiction.

The treatment of substance use disorders has always been challenging because multiple neurotransmitters mediate addiction. However, with smoking being the leading cause of preventable death and the recent opioid epidemic in the United States, the search for novel solutions becomes more imperative. In this review, we discuss the use of antibodies to treat addictions and highlight areas of success and areas that require improvement, using examples from cocaine, nicotine, and opioid vaccines. Through each example, we examine creative problem-solving strategies for developing future vaccines, such as using an adenovirus vector as a carrier, designing bivalent vaccines, stimulating Toll-like receptors for adjuvant effects, and altering the route of administration. Our review also covers passive immunization alone to override or prevent drug toxicity as well as in combination with vaccines for more rapid and potentially greater efficacy.

Intravenous self-administration of delta-9-THC in adolescent rats produces long-lasting alterations in behavior and receptor protein expression.

RATIONALE: Initial exposure to cannabinoids, including Δ-9-tetrahydrocannabinol (THC), often occurs during adolescence. Considerable neurodevelopmental alterations occur throughout adolescence, and the environmental insult posed by exogenous cannabinoid exposure may alter natural developmental trajectories. Multiple studies suggest that long-lasting deficits in cognitive function occur as a result of adolescent cannabis use, but considerable variability exists in the magnitude of these effects. OBJECTIVES: We sought to establish a novel procedure for achieving intravenous THC self-administration in adolescent rats in order to determine if volitional THC intake in adolescence produced indices of addiction-related behavior, altered working memory performance in adulthood, or altered the expression of proteins associated with these behaviors across several brain regions. METHODS: Male and female adolescent rats learned to operantly self-administer escalating doses of THC intravenously from PD 32-51. Upon reaching adulthood they were tested in abstinence for cued reinstatement of THC-seeking and working memory performance on a delayed-match-to-sample task. In a separate cohort, glutamatergic, GABAergic, and cannabinoid receptor protein expression was measured in multiple brain regions. RESULTS: Both male and female adolescents self-administered THC and exhibited cue-induced lever pressing throughout abstinence. THC-exposed males exhibited slightly enhanced working memory performance in adulthood, and better performance positively correlated with total THC self-administered during adolescence. Adolescent THC-exposed rats exhibited reductions in CB1, GABA, and glutamate receptor protein, primarily in the prefrontal cortex, dorsal hippocampus, and ventral tegmental area. CONCLUSIONS: These results suggest that THC exposure at self-administered doses can produce moderate behavioral and molecular alterations, including sex-dependent effects on working memory performance in adulthood.

Adolescent nicotine and tobacco smoke exposure enhances nicotine self-administration in female rats.

Most people start experimenting with tobacco products or e-cigarettes in early adolescence and become habitual smokers in late adolescence or adulthood. These studies investigated if exposure to tobacco smoke or nicotine during early and mid-adolescence affects nicotine intake in late adolescence and early adulthood. Male and female rats were exposed to tobacco smoke from low- and high-nicotine SPECTRUM cigarettes or nicotine (0.3 mg/kg, twice a day) from postnatal day (P) 24-42. The self-administration sessions started at P55. The rats self-administered nicotine for 14-15 days under a fixed-ratio 1 schedule, and on the first day, the maximum number of infusions was twenty. Exposure to smoke from high, but not low, nicotine cigarettes during adolescence increased nicotine self-administration in female but not male rats. Adolescent treatment with nicotine facilitated nicotine self-administration. On the first day of nicotine self-administration, nicotine-treated rats reached the maximum number of infusions before the saline-treated control rats. Nicotine intake was also higher in the nicotine-treated female rats than in the saline-treated females. There was no sex difference in nicotine intake in controls when the data from the studies were combined. Smoke exposure led to a dose-dependent increase in plasma nicotine and cotinine levels in adolescent rats. Exposure to smoke from high-nicotine cigarettes and 0.3 mg/kg of nicotine led to plasma nicotine and cotinine levels that are similar to those in tobacco users. These findings indicate that in females, but not males, exposure to nicotine during adolescence may facilitate smoking and e-cigarette use later in life.

Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine.

The initial response to an addictive substance can facilitate repeated use: That is, individuals experiencing more positive effects are more likely to use that drug again. Increasing evidence suggests that psychoactive cannabinoid use in adolescence enhances the behavioral effects of cocaine. However, despite the behavioral data, there is no neurobiological evidence demonstrating that cannabinoids can also alter the brain's initial molecular and epigenetic response to cocaine. Here, we utilized a multiomics approach (epigenomics, transcriptomics, proteomics, and phosphoproteomics) to characterize how the rat brain responds to its first encounter with cocaine, with or without preexposure to the synthetic cannabinoid WIN 55,212-2 (WIN). We find that in adolescent (but not in adult) rats, preexposure to WIN results in cross-sensitization to cocaine, which correlates with histone hyperacetylation and decreased levels of HDAC6 in the prefrontal cortex (PFC). In the PFC, we also find that WIN preexposure blunts the typical mRNA response to cocaine and instead results in alternative splicing and chromatin accessibility events, involving genes such as Npas2 Moreover, preexposure to WIN enhances the effects of cocaine on protein phosphorylation, including ERK/MAPK-targets like gephyrin, and modulates the synaptic AMPAR/GluR composition both in the PFC and the nucleus accumbens (NAcc). PFC-NAcc gene network topological analyses, following cocaine exposure, reveal distinct top nodes in the WIN preexposed group, which include PACAP/ADCYAP1. These preclinical data demonstrate that adolescent cannabinoid exposure reprograms the initial behavioral, molecular, and epigenetic response to cocaine.

Differential effects of nicotine delivery rate on subjective drug effects, urges to smoke, heart rate and blood pressure in tobacco smokers.

RATIONALE: The nicotine delivery rate is a key feature of tobacco product design, yet there have been limited human studies examining the effects of nicotine as a function of delivery rate. OBJECTIVE: We developed an intravenous nicotine infusion protocol to evaluate differential effects of nicotine delivery rate on subjective drug effects, smoking urges, abstinence symptoms, heart rate, and blood pressure. METHODS: Eighteen non-treatment seeking, overnight abstinent male and female smokers (18 to 30 years old), who smoked ≥ 5 cigarettes per day for the past year completed four sessions, in which they were randomly assigned to a saline infusion, or a 1 mg per 70-kg body weight dose of nicotine delivered over 1, 5, or 10 min at rates of 0.24, 0.048, or 0.024 µg/kg/s, respectively. RESULTS: Smoking urges, as assessed by the Brief Questionnaire of Smoking Urges, were reduced relative to placebo for the 1- and 5-min infusion, but not the 10-min infusion. Although the 1- and 5-min infusions reduced smoking urges to a similar extent, the 1-min infusion induced a greater heart rate and blood pressure increase. Changes to subjective drug effects, heart rate, and blood pressure delineate the differential effects of nicotine delivery rate for these outcomes. CONCLUSIONS: We have characterized the delivery rate-response curve for a nicotine dose that is roughly the amount of nicotine (~ 1 mg) delivered by smoking a standard tobacco cigarette. Our findings reinforce the importance of nicotine delivery rate when evaluating the potential effects of nicotine from tobacco products.

Ifenprodil Attenuates Methamphetamine-Induced Behavioral Sensitization Through the GluN2B-PP2A-AKT Cascade in the Dorsal Striatum of Mice.

Drug addiction can be described as a chronic and relapsing brain disease. Behavioral sensitization is believed to share similar mechanisms with relapse. Our previous studies have demonstrated that ifenprodil could attenuate methamphetamine (METH)-induced behavioral sensitization. However, the mechanism underlying this process has not been fully investigated. Protein phosphatase 2A (PP2A) is a conserved serine/threonine protein phosphatase that has been linked to many neurological diseases; however, there are few reports about PP2A in the context of drug addiction. In this study, we measured the level of phosphorylated (p-) GluN2B (Serine; Ser 1303), PP2A/B (a regulatory subunit of PP2A), and PP2A/C (a catalytic subunit of PP2A) in different brain regions such as the prefrontal cortex (PFc), nucleus accumbens (NAc), dorsal striatum (DS), and hippocampus (Hip). We also used ifenprodil, a selective antagonist of GluN2B to clarify the relationship between GluN2B and PP2A. The results showed that METH increased the level of p-GluN2B (Ser 1303) and PP2A/B in the DS and ifenprodil blocked this increase. We further examined the interaction between PP2A/B and PP2A/C in the DS and found that METH treatment increased the interaction between PP2A/B and PP2A/C, which was also blocked by ifenprodil. Then, we explored the pathway downstream of PP2A in the DS and found that p-AKT (Threonine; Thr 308) but not p-AKT (Ser 473) was dephosphorylated by PP2A. Taken together, these results indicated that the GluN2B-PP2A-AKT cascade was involved in METH-induced behavioral sensitization.

The Biological Impact of Menthol on Tobacco Dependence.

In the 1920s, tobacco companies created a marketing campaign for what would one day be their most profitable series of products: mentholated tobacco cigarettes. Menthol provides the smoker with a pleasant mint flavor in addition to a cooling sensation of the mouth, throat, and lungs, giving relief from the painful irritation caused by tobacco smoke. Promising a healthier cigarette using pictures of doctors in white coats and even cartoon penguins, tobacco companies promoted these cigarettes to young, beginner smokers and those with respiratory health concerns. Today, smoking tobacco cigarettes causes one in five US Americans to die prematurely, crowning it as the leading cause of preventable death. In contrast to the dubious health claims by tobacco companies, mentholated cigarettes are in fact more addictive. Smokers of mentholated cigarettes have lower successful quit rates and in some cases are resistant to both behavioral and pharmacological treatment strategies. There is now considerable evidence, especially in the last 5 years, that suggest menthol might influence the addictive potential of nicotine-containing tobacco products via biological mechanisms. First, menthol alters the expression, stoichiometry, and function of nicotinic receptors. Second, menthol's chemosensory properties operate to mask aversive properties of using tobacco products. Third, menthol's chemosensory properties aid in serving as a conditioned cue that can both enhance nicotine intake and drive relapse. Fourth, menthol alters nicotine metabolism, increasing its bioavailability. This review discusses emerging evidence for these mechanisms, with an emphasis on preclinical findings that may shed light on why menthol smokers exhibit greater dependence. IMPLICATIONS: Mentholated cigarettes have been shown to have greater addictive potential than their nonmentholated counterparts. Evidence is pointing toward multiple mechanisms of action by which menthol may alter tobacco dependence. Understanding menthol's biological functions as it pertains to nicotine dependence will be helpful in crafting novel pharmacotherapies that might better serve menthol smokers. In addition, a better understanding of menthol's pharmacology as it relates to tobacco dependence will be valuable for informing policy decisions on the regulation of mentholated cigarettes.

JUUL electronic cigarettes: Nicotine exposure and the user experience.

BACKGROUND: As of March 2019, JUUL electronic cigarettes are the most popular e-cigarette on the U.S. market, but little is known of nicotine exposure and dependence on JUUL and user experience. METHODS: JUUL users participated in a community-based study involving questionnaires, saliva collection and a qualitative interview. RESULTS: Fifteen participants were enrolled (80% male, 53% White) and had an average age of 29.8 (standard deviation = 10) years. Daily exposure to nicotine assessed via salivary cotinine was similar to those reported for other e-cigarette and tobacco cigarette users in general. The majority reported low to moderate nicotine dependence. Qualitative interview themes included: the importance of social networks in adoption and use of the product; device features such as small size and vapor cloud reinforced product use; the product provided satisfaction compared to a tobacco cigarette; and a perceived sense of addiction to the product. CONCLUSIONS: JUUL e-cigarettes expose users to levels of nicotine similar to other e-cigarettes but may be more satisfying due to unique device features. JUUL may be quite acceptable to tobacco cigarette smokers who are seeking to quit. However, it holds addictive potential and can reinforce long-term nicotine use.

Overexpression of miR-9 in the Nucleus Accumbens Increases Oxycodone Self-Administration.

BACKGROUND: There is an urgent need to identify factors that increase vulnerability to opioid addiction to help stem the opioid epidemic and develop more efficient pharmacotherapeutics. MicroRNAs are small non-coding RNAs that regulate gene expression at a posttranscriptional level and have been implicated in chronic drug-taking in humans and in rodent models. Recent evidence has shown that chronic opioid treatment regulates the microRNA miR-9. The present study was designed to test the hypothesis that miR-9 in the nucleus accumbens potentiates oxycodone addictive-like behavior. METHODS: We utilized adeno-associated virus (AAV) to overexpress miR-9 in the nucleus accumbens of male rats and tested the effects on intravenous self-administration of the highly abused prescription opioid, oxycodone, in 1-hour short-access followed by 6-h long-access sessions, the latter of which leads to escalation of drug intake. In separate rats, we assessed the effects of nucleus accumbens miR-9 overexpression on mRNA targets including RE1-silencing transcription factor (REST) and dopamine D2 receptor (DRD2), which have been shown to be regulated by drugs of abuse. RESULTS: Overexpression of miR-9 in the nucleus accumbens significantly increased oxycodone self-administration compared with rats expressing a control, scrambled microRNA. Analysis of the pattern of oxycodone intake revealed that miR-9 overexpression increased "burst" episodes of intake and decreased the inter-infusion interval. Furthermore, miR-9 overexpression decreased the expression of REST and increased DRD2 in the nucleus accumbens at time points that coincided with behavioral effects. CONCLUSIONS: These results suggest that nucleus accumbens miR-9 regulates oxycodone addictive-like behavior as well as the expression of genes that are involved in drug addiction.

Effect of menthol on nicotine intake and relapse vulnerability in a rat model of concurrent intravenous menthol/nicotine self-administration.

RATIONALE: Epidemiological data suggest that menthol may increase vulnerability to cigarette/nicotine use and relapse. While menthol's sensory properties are often attributed as the underlying cause of the enhanced vulnerability, an alternative possibility is that they are mediated via pharmacological interactions with nicotine. OBJECTIVE: This study addressed the possibility that menthol enhances nicotine intake and relapse vulnerability via pharmacological interactions with nicotine using a concurrent intravenous menthol/nicotine self-administration procedure. METHODS: Following acquisition, adolescent rats were given 23-h/day access to nicotine (0.01 mg/kg/infusion), nicotine plus menthol (0.16, 0.32, or 0.64 mg/kg/infusion), or menthol alone (0.16, 0.32, 0.64 mg/kg/infusion) for a total of 10 days. Nicotine-seeking was assessed using an extinction/cue-induced reinstatement procedure following 10 days of forced abstinence. We also assessed the effect of menthol (0.32 mg/kg/infusion) on progressive ratio responding for nicotine (0.01 mg/kg/infusion). RESULTS: Menthol decreased PR responding for nicotine but did not affect self-administration under extended access conditions. The low dose of menthol tended to decrease subsequent extinction responding, and was not different from menthol alone, whereas the high dose decreased reinstatement responding. Although not significant, the highest levels of extinction responding were observed in a minority of rats in the moderate and high menthol-nicotine groups; rats in these groups also took longer to extinguish. CONCLUSIONS: Taken together, these results demonstrate that pharmacological interactions of menthol with nicotine reduce, rather than increase, nicotine's reinforcing effects and some measures of relapse vulnerability. Importantly, however, moderate and high menthol doses may increase some aspects of relapse vulnerability in a minority of individuals.

Sexual addiction in drug addicts: The impact of drug of choice and poly-addiction / Dependência sexual em dependentes químicos: o impacto de diferentes drogas de escolha e de polidependência

Summary Objective: To compare the risk of comorbid sexual addiction in a sample of individuals with a diagnosis of substance dependence, stratifying the sample by drug of choice as well as by mono versus polysubstance addiction. Method: All data were collected at Santa Casa de São Paulo, Brazil. The study sample comprised all alcohol or drug dependents admitted to the Addiction Treatment Unit between November 2013 and August 2014. A generalized linear model with a binomial distribution was performed to compare the odds of having a Sexual Addiction Screening Test (SAST) score greater than 6 points in the subgroups analyzed. Results: A total of 133 participants were included in our analysis, all reporting cocaine/crack and/or alcohol as drug of choice. Polysubstance addicts had a significant higher risk of a positive screening for sexual addiction compared to monosubstance addicts, age-sex adjusted odds ratios of sexual addiction being respectively 2.72 (95CI 1.1-6.71) and 0.37 (95CI 0.15-0.91). The odds of a SAST score greater than 6 was not statistically different between the cocaine/crack and alcohol groups, respectively 0.38 (95CI 0.14-1.02) and 2.67 (95CI 0.98-7.25). We found a significant relation between stronger drug addiction and greater levels of sexual addiction in the cocaine/crack group (p=0.0012), but not in the alcohol group. Conclusion: Our study reinforces the importance of assessing sexual behavior of drug addicts in clinical practice, especially considering users of multiple substances or with severe dependence.

Resumo Objetivo: Comparar o risco de dependência sexual em uma amostra de indivíduos com diagnóstico de dependência química, estratificados por droga de escolha e por dependência única ou de múltiplas substâncias. Método: Todos os dados foram coletados na Santa Casa de São Paulo, Brasil. A amostra estudada correspondeu a todos os indivíduos dependentes de álcool ou outras substâncias admitidos no Ambulatório de Dependência Química entre novembro de 2013 e agosto de 2014. Modelos lineares generalizados com distribuição binomial foram utilizados para comparar o risco de escores maiores que seis na Escala de Rastreamento para Dependência de Sexo (SAST) nos subgrupos analisados. Resultados: Foram analisados os dados de 133 pacientes usuários de cocaína/crack e/ou álcool. Usuários de múltiplas substâncias apresentaram risco significativamente maior de um screening positivo para dependência sexual comparados com usuários de uma única substância. Os odds ratios de dependência sexual ajustados por sexo e idade obtidos nos dois grupos foram, respectivamente, 2.72 (IC95% 1.1-6.71) e 0.37 (IC95% 0.15-0.91). O risco de dependência sexual entre usuários de cocaína/crack e álcool foi estimado, respectivamente, em 0.38 (IC95% 0.14-1.02) e 2.67 (IC95% 0.98-7.25), não indicando diferença significativa. Foi encontrada uma relação significativa entre severidade de dependência química e maiores níveis de dependência sexual entre dependentes de cocaína/crack, mas não de álcool. Conclusão: Nosso estudo reforça a importância de avaliar o comportamento sexual de dependentes químicos na prática clínica, especialmente considerando usuários de múltiplas substâncias, ou casos de maior severidade.

Preweaning iron deficiency increases non-contingent responding during cocaine self-administration in rats.

Iron deficiency (ID) is the most prevalent single-nutrient deficiency worldwide. There is evidence that ID early in development (preweaning in rat) causes irreversible neurologic, behavioral, and motor development deficits. Many of these effects have been attributed to damage to dopamine systems, including ID-induced changes in transporter and receptor numbers in the striatum and nucleus accumbens. These mesolimbic dopaminergic neurons are, in part, responsible for mediating reward and thus play a key role in addiction. However, there has been relatively little investigation into the behavioral effects of ID on drug addiction. In 2002, we found that rats made ID from weaning (postnatal day 21) and throughout the experiment acquired cocaine self-administration significantly more slowly than controls and failed to increase responding when the dose of the drug was decreased. In the present study, we assessed addiction for self-administered cocaine in rats with a history of preweaning ID only during postnatal days 4 through 21, and iron replete thereafter. The results showed that while ID did not affect the number of cocaine infusions or the overall addiction-like behavior score, ID rats scored higher on a measure of continued responding for drug than did iron replete controls. This increase in responding, however, was less goal-directed as ID rats also responded more quickly to the non-rewarded manipulandum than did control rats. Thus, while ID early in infancy did not significantly increase addiction-like behaviors for cocaine in this small study, the pattern of data suggests a possible underlying learning or performance impairment. Future studies will be needed to elucidate the exact neuro-behavioral deficits that lead to the increase in indiscriminate responding for drug in rats with a history of perinatal ID.

Estradiol impacts the endocannabinoid system in female rats to influence behavioral and structural responses to cocaine.

Compared with men, women show enhanced responses to drugs of abuse, and consequently are thought to be more vulnerable to addiction. The ovarian hormone estradiol has emerged as a key facilitator in the heightened development of addiction in females. These actions of estradiol appear mediated by estrogen receptor (ER) activation of metabotropic glutamate receptor type 5 (mGluR5). However, the downstream effectors of this ER/mGluR5 signaling pathway are unknown. Here we investigate whether cannabinoid 1 receptor (CB1R) activation is a part of the mechanism whereby estradiol influences behavioral and synaptic correlates of addiction. Following repeated cocaine administration, estradiol-treated ovariectomized rats exhibited both sensitized locomotor responses and decreases in the dendritic spine density of nucleus accumbens core medium-spiny neurons in comparison to oil-treated controls. Both effects of estradiol were blocked by AM251, a CB1R inverse agonist. These results indicate that part of the signaling mechanism through which estradiol impacts behavioral and synaptic correlates of addiction in female rats requires activation of CB1Rs.

Keep off the grass? Cannabis, cognition and addiction.

In an increasing number of states and countries, cannabis now stands poised to join alcohol and tobacco as a legal drug. Quantifying the relative adverse and beneficial effects of cannabis and its constituent cannabinoids should therefore be prioritized. Whereas newspaper headlines have focused on links between cannabis and psychosis, less attention has been paid to the much more common problem of cannabis addiction. Certain cognitive changes have also been attributed to cannabis use, although their causality and longevity are fiercely debated. Identifying why some individuals are more vulnerable than others to the adverse effects of cannabis is now of paramount importance to public health. Here, we review the current state of knowledge about such vulnerability factors, the variations in types of cannabis, and the relationship between these and cognition and addiction.

Effects of gender on ketamine-induced conditioned placed preference and urine metabonomics.

OBJECTIVE: The aim of this study was to examine whether or not there was a gender difference in CPP (conditioned placed preference) induced by ketamine and to further explore the effect of sex on metabolic responses to ketamine inducing in SD rats. METHODS: We measured ketamine-induced conditioned place preference and ketamine-induced metabolic changes in urine by using (1)H nuclear magnetic resonance (NMR) coupled with principal component analysis (PCA), partial least squares (PLS) and orthogonal signal correction (OSC) analysis. RESULTS: In the CPP experiment, ketamine served as a positive reinforcing agent in both male and female rats, but, in particularly, the preference score of female rats was significantly higher than that of male rats. Compared with male rats, the metabolic trajectory fluctuation of the female rats was relatively larger. At the same time, different metabolites (1, 3-dimethyluric acid, cysteine-S-sulfate, glyceraldehydes, glycine, ribitol, acetoacetic acid, creatine, 3-methyladenine, hypotaurine, taurine, dimethylglycine and theobromine) between male and female rats were found. CONCLUSIONS: Female Sprague-Dawley rats were more sensitive to the ketamine-induced CPP than male rats. The fluctuation ranges of metabolic trajectory and metabolite contents in urine were both different between female and male rats. This would provide targeted suggestions for ketamine abuser, for example, men and women should take different drug withdrawal therapeutic methods.

Nicotinic effects of tobacco smoke constituents in nonhuman primates.

RATIONALE: Recent studies in rodents suggest that non-nicotine constituents of tobacco smoke (e.g., minor tobacco alkaloids) may promote tobacco consumption-either through their own pharmacological effects or by augmenting the effects of nicotine. However, there is scant information on the behavioral pharmacology of minor tobacco alkaloids in primate species. OBJECTIVE: The present studies were conducted to determine whether the minor tobacco alkaloids nornicotine, anabasine, anatabine, myosmine, and cotinine exhibit nicotine-like behavioral effects in squirrel monkeys. METHODS: Initial experiments were conducted to determine the effects of nicotine (0.032-1.0 mg/kg) and the minor tobacco alkaloids nornicotine (1-1.8 mg/kg), anabasine (0.1-1.0 mg/kg), anatabine (10-32 mg/kg), myosmine (0.32-1.8 mg/kg), and cotinine (10-180 mg/kg) on food-maintained performance (n = 4). Next, the ability of tobacco alkaloids to substitute for the α4ß2-selective nicotinic agonist (+)-epibatidine in drug discrimination experiments was evaluated in a separate group of monkeys (n = 4). RESULTS: Results show that nicotine and each minor tobacco alkaloid except cotinine (a) produced dose-related decreases in food-maintained responding; (b) substituted for (+)-epibatidine and, in additional experiments, produced additive effects when combined with nicotine; (c) induced emesis or tremor at doses that reduced food-maintained responding and had (+)-epibatidine-like discriminative-stimulus effects; and (d) based on correlation with reported receptor binding affinities, likely produced their behavioral effects through α4ß2 receptor mechanisms. CONCLUSION: Selected minor tobacco alkaloids have nicotinic-like effects that may contribute to tobacco consumption and addiction.

How Menthol Alters Tobacco-Smoking Behavior: A Biological Perspective.

Mentholated cigarettes gained popularity in the 1950s and were often marketed as "healthy" cigarettes, attributable to their pleasurable mint flavor and cooling sensation in the mouth, lungs, and throat. While it is clear that nicotine is the primary psychoactive component in tobacco cigarettes, recent work has suggested that menthol may also play a role in exacerbating smoking behavior, despite original health claims. Recent evidence highlights four distinct biological mechanisms that can alter smoking behavior: 1) menthol acts to reduce the initially aversive experiences associated with tobacco smoking; 2) menthol can serve as a highly reinforcing sensory cue when associated with nicotine and promote smoking behavior; 3) menthol's actions on nicotinic acetylcholine receptors may change the reinforcing value of nicotine; and 4) menthol can alter nicotine metabolism, thus increasing nicotine bioavailability. The purpose of this review is to highlight and evaluate potential biological mechanisms by which menthol can alter smoking behavior.

Animal models to assess the abuse liability of tobacco products: effects of smokeless tobacco extracts on intracranial self-stimulation.

BACKGROUND: Preclinical models are needed to inform regulation of tobacco products by the Food and Drug Administration (FDA). Typically, animal models of tobacco addiction involve exposure to nicotine alone or nicotine combined with isolated tobacco constituents (e.g. minor alkaloids). The goal of this study was to develop a model using extracts derived from tobacco products that contain a range of tobacco constituents to more closely model product exposure in humans. METHODS: This study compared the addiction-related effects of nicotine alone and nicotine dose-equivalent concentrations of aqueous smokeless tobacco extracts on intracranial self-stimulation (ICSS) in rats. Extracts were prepared from Kodiak Wintergreen, a conventional product, or Camel Snus, a potential "modified risk tobacco product". Binding affinities of nicotine alone and extracts at various nicotinic acetylcholine receptor (nAChR) subtypes were also compared. RESULTS: Kodiak and Camel Snus extracts contained levels of minor alkaloids within the range of those shown to enhance nicotine's behavioral effects when studied in isolation. Nonetheless, acute injection of both extracts produced reinforcement-enhancing (ICSS threshold-decreasing) effects similar to those of nicotine alone at low to moderate nicotine doses, as well as similar reinforcement-attenuating/aversive (ICSS threshold-increasing) effects at high nicotine doses. Extracts and nicotine alone also had similar binding affinity at all nAChRs studied. CONCLUSIONS: Relative nicotine content is the primary pharmacological determinant of the abuse liability of Kodiak and Camel Snus as measured using ICSS. These models may be useful to compare the relative abuse liability of other tobacco products and to model FDA-mandated changes in product performance standards.

Electrophysiological changes in laterodorsal tegmental neurons associated with prenatal nicotine exposure: implications for heightened susceptibility to addict to drugs of abuse.

Prenatal nicotine exposure (PNE) is a risk factor for developing an addiction to nicotine at a later stage in life. Understanding the neurobiological changes in reward related circuitry induced by exposure to nicotine prenatally is vital if we are to combat the heightened addiction liability in these vulnerable individuals. The laterodorsal tegmental nucleus (LDT), which is comprised of cholinergic, GABAergic and glutamatergic neurons, is importantly involved in reward mediation via demonstrated excitatory projections to dopamine-containing ventral tegmental neurons. PNE could lead to alterations in LDT neurons that would be expected to alter responses to later-life nicotine exposure. To examine this issue, we monitored nicotine-induced responses of LDT neurons in brain slices of PNE and drug naive mice using calcium imaging and whole-cell patch clamping. Nicotine was found to induce rises in calcium in a smaller proportion of LDT cells in PNE mice aged 7-15 days and smaller rises in calcium in PNE animals from postnatal ages 11-21 days when compared with age-matched control animals. While inward currents induced by nicotine were not found to be different, nicotine did induce larger amplitude excitatory postsynaptic currents in PNE animals in the oldest age group when compared with amplitudes induced in similar-aged control animals. Immunohistochemically identified cholinergic LDT cells from PNE animals exhibited slower spike rise and decay slopes, which likely contributed to the wider action potential observed. Further, PNE was associated with a more negative action potential afterhyperpolarization in cholinergic cells. Interestingly, the changes found in these parameters in animals exposed prenatally to nicotine were age related, in that they were not apparent in animals from the oldest age group examined. Taken together, our data suggest that PNE induces changes in cholinergic LDT cells that would be expected to alter cellular excitability. As the changes are age related, these PNE-associated alterations could contribute differentially across ontogeny to nicotine-mediated reward and may contribute to the particular susceptibility of in utero nicotine exposed individuals to addict to nicotine upon nicotine exposure in the juvenile period.