Symptoms of tobacco dependence among middle and high school tobacco users - Data from the 2019-2020 National Youth Tobacco Survey.

INTRODUCTION: Previous studies have indicated that youth who use tobacco products, including cigarettes, cigars, and smokeless tobacco, demonstrate dependence symptoms. However, the tobacco marketplace has expanded dramatically in recent years, and few studies have examined dependence symptoms among youth who use novel products. This study combined 2019-2020 National Youth Tobacco Survey data to report the prevalence and determinants of tobacco dependence symptoms among U.S. middle and high school current (past 30-day) tobacco users. METHODS: Prevalence estimates were calculated to examine dependence outcomes and other covariates by user groups (single product users and multiple product users). Multivariable logistic regression analyses were used to identify independent predictors of tobacco dependence among current users of cigarettes, cigars (regular cigars, cigarillos, and little cigars), e-cigarettes, heated tobacco products, hookah, pipe tobacco, bidis, and smokeless tobacco products (chew, snuff, dip, snus, and dissolvables). RESULTS: Among current tobacco users, 15.7 % (95 % CI: 14.2-17.3) reported wanting to use tobacco within 30 min of waking and 28.3 % (95 % CI: 26.3-30.5) reported strong cravings for tobacco in the past 30 days. Nearly-two-thirds of current users were single product users, of which 80.5 % reported using e-cigarettes. Reporting of dependence symptoms was generally associated with multiple product use, higher frequency of use, earlier initiation age, and use of flavored products. CONCLUSIONS: Among U.S. adolescents, a considerable amount of current tobacco product users, even infrequent users, reported symptoms of dependence. These findings highlight the continued importance of prevention strategies for youth tobacco experimentation and progression to regular use.

Discriminative stimulus effects of mecamylamine and nicotine in rhesus monkeys: Central and peripheral mechanisms.

Mecamylamine is a non-competitive nicotinic acetylcholine receptor (nAChR) antagonist that has been prescribed for hypertension and as an off-label smoking cessation aid. Here, we examined pharmacological mechanisms underlying the interoceptive effects (i.e., discriminative stimulus effects) of mecamylamine (5.6 mg/kg s.c.) and compared the effects of nAChR antagonists in this discrimination assay to their capacity to block a nicotine discriminative stimulus (1.78 mg/kg s.c.) in rhesus monkeys. Central (pempidine) and peripherally restricted nAChR antagonists (pentolinium and chlorisondamine) dose-dependently substituted for the mecamylamine discriminative stimulus in the following rank order potency (pentolinium > pempidine > chlorisondamine > mecamylamine). In contrast, at equi-effective doses based on substitution for mecamylamine, only mecamylamine antagonized the discriminative stimulus effects of nicotine, i.e., pentolinium, chlorisondamine, and pempidine did not. NMDA receptor antagonists produced dose-dependent substitution for mecamylamine with the following rank order potency (MK-801 > phencyclidine > ketamine). In contrast, behaviorally active doses of smoking cessation aids including nAChR agonists (nicotine, varenicline, and cytisine), the smoking cessation aid and antidepressant bupropion, and the benzodiazepine midazolam did not substitute for the discriminative stimulus effects of mecamylamine. These data suggest that peripheral nAChRs and NMDA receptors may contribute to the interoceptive stimulus effects produced by mecamylamine. Based on the current results, the therapeutic use of mecamylamine (i.e., for smoking or to alleviate green tobacco sickness) should be weighed against the potential for mecamylamine to produce interoceptive effects that overlap with another class of abused drugs (i.e., NMDA receptor agonists).

Attenuated nicotine-like effects of varenicline but not other nicotinic ACh receptor agonists in monkeys receiving nicotine daily.

BACKGROUND AND PURPOSE: Chronic treatment can differentially impact the effects of pharmacologically related drugs that differ in receptor selectivity and efficacy. EXPERIMENTAL APPROACH: The impact of daily nicotine treatment on the effects of nicotinic ACh receptor (nAChR) agonists was examined in two groups of rhesus monkeys discriminating nicotine (1.78 mg·kg-1 base weight) from saline. One group received additional nicotine treatment post-session (1.78 mg·kg-1 administered five times daily, each dose 2 h apart; i.e. Daily group), and the second group did not (Intermittent group). KEY RESULTS: Daily repeated nicotine treatment produced a time-related increase in saliva cotinine. There was no significant difference in the ED50 values of the nicotine discriminative stimulus between the Daily and Intermittent group. Mecamylamine antagonized the effects of nicotine, whereas dihydro-ß-erythroidine did not. Midazolam produced 0% nicotine-lever responding. The nAChR agonists epibatidine, RTI-36, cytisine and varenicline produced >96% nicotine-lever responding in the Intermittent group. The respective maximum effects in the Daily group were 100, 72, 59 and 28%, which shows that the ability of varenicline to produce nicotine-like responding was selectively decreased in the Daily as compared with the Intermittent group. When combined with nicotine, both varenicline and cytisine increased the potency of nicotine to produce discriminative stimulus effects. CONCLUSION AND IMPLICATIONS: Nicotine treatment has a greater impact on the sensitivity to the effects of varenicline as compared with some other nAChR agonists. Collectively, these results strongly suggest that varenicline differs from nicotine in its selectivity for multiple nAChR subtypes.

The discriminative stimulus effects of mecamylamine in nicotine-treated and untreated rhesus monkeys.

The extent to which chronic nicotine treatment can alter the effects of the nicotinic acetylcholine receptor antagonist mecamylamine, and whether those effects can be attenuated by nicotine have not been clearly established in the literature. Here, the discriminative stimulus effects of mecamylamine were compared between one group of rhesus monkeys receiving a continuous infusion of nicotine base (5.6 mg/kg/day subcutaneously) and another group of monkeys not receiving nicotine treatment. Both groups responded under a fixed ratio 5 schedule of stimulus-shock termination. Stimulus control was obtained at doses of 1.78 mg/kg mecamylamine in monkeys receiving continuous nicotine and 5.6 mg/kg mecamylamine in monkeys not receiving continuous nicotine treatment. Nicotine did not attenuate the discriminative stimulus effects of mecamylamine in either group. Discontinuation of continuous nicotine produced responding on the mecamylamine lever within 24 h in some but not all monkeys. This may indicate a qualitative difference in the discriminative stimulus effects of mecamylamine between groups, perhaps reflecting antagonism of nicotine and nicotine withdrawal in monkeys receiving continuous nicotine. The failure of nicotine to reverse the effects of mecamylamine is consistent with a noncompetitive interaction at nicotinic acetylcholine receptors and indicates that mecamylamine-induced withdrawal cannot be readily modified by nicotine.

Discriminative stimulus and hypothermic effects of some derivatives of the nAChR agonist epibatidine in mice.

RATIONALE: Receptor mechanisms underlying the in vivo effects of nicotinic acetylcholine receptor (nAChR) drugs need to be determined to better understand possible differences in therapeutic potential. OBJECTIVE: This study compared the effects of agonists that are reported either to differ in intrinsic activity (i.e., efficacy) at α4ß2 nAChR in vitro or to have in vivo effects consistent with differences in efficacy. The drugs included nicotine, varenicline, cytisine, epibatidine, and three novel epibatidine derivatives: 2'-fluoro-3'-(4-nitrophenyl)deschloroepibatidine (RTI-7527-102), 2'-fluorodeschloroepibatidine (RTI-7527-36), and 3'-(3″-dimethylaminophenyl)-epibatidine (RTI-7527-76). METHODS: Mice discriminated nicotine base (1 mg/kg base) from saline; other mice were used to measure rectal temperature. RESULTS: In the nicotine discrimination assay, the maximum percentage of nicotine-appropriate responding varied: 92 % for nicotine, 84 % for epibatidine, 77 % for RTI-7527-36, and 71 % for varenicline and significantly less for RTI-7527-76 (58 %), RTI-7527-102 (46 %), and cytisine (33 %). Each drug markedly decreased rectal temperature by as much as 12 ºC. The rank-order potency in the discrimination and hypothermia assays was epibatidine > RTI-7527-36 > nicotine > RTI-7527-102 > varenicline = cytisine = RTI-7527-76. The nAChR antagonist mecamylamine (3.2 mg/kg) antagonized the discriminative stimulus effects of epibatidine and RTI-7527-102, as well as the hypothermic effects of every drug except cytisine. The ß2-subunit selective nAChR antagonist dihydro-ß-erythroidine (DHßE; up to 10 mg/kg) antagonized hypothermic effects but less effectively so than mecamylamine. CONCLUSIONS: The marked hypothermic effects of all drugs except cytisine are due in part to agonism at nAChR containing ß2-subunits. Differential substitution for the nicotine discriminative stimulus is consistent with differences in α4ß2 nAChR efficacy; however, collectively the current results suggest that multiple nAChR receptor subtypes mediate the effects of the agonists.

Multiple nicotine training doses in mice as a basis for differentiating the effects of smoking cessation aids.

RATIONALE: Receptor mechanisms underlying the behavioral effects of clinically used nicotinic acetylcholine receptor agonists have not been fully established. OBJECTIVE: Drug discrimination was used to compare receptor mechanisms underlying the effects of smoking cessation aids. METHODS: Separate groups of male C57BL/6J mice discriminated 0.56, 1, or 1.78 mg/kg of nicotine base. Nicotine, varenicline, and cytisine were administered alone, in combination with each other, and in combination with mecamylamine and dihydro-ß-erythroidine (DHßE). Midazolam and morphine were tested to examine sensitivity to non-nicotinics. RESULTS: The ED50 value of nicotine to produce discriminative stimulus effects systematically increased as training dose increased. Varenicline and cytisine did not fully substitute for nicotine and, as compared with nicotine, their ED50 values varied less systematically as a function of nicotine training dose. Morphine did not substitute for nicotine, whereas midazolam substituted for the low and not the higher training doses of nicotine. As training dose increased, the dose of mecamylamine needed to produce a significant rightward shift in the nicotine dose-effect function also increased. DHßE antagonized nicotine in animals discriminating the smallest dose of nicotine. Varenicline did not antagonize the effects of nicotine, whereas cytisine produced a modest though significant antagonism of nicotine. CONCLUSIONS: These results suggest that differences in pharmacologic mechanism between nicotine, varenicline, and cytisine include not only differences in efficacy at a common subtype of nicotinic acetylcholine receptor, but also differential affinity and/or efficacy at multiple receptor subtypes.

Pharmacologic characterization of a nicotine-discriminative stimulus in rhesus monkeys.

This study examined mechanisms by which nicotine (1.78 mg/kg base s.c.) produces discriminative stimulus effects in rhesus monkeys. In addition to nicotine, various test compounds were studied including other nicotinic acetylcholine receptor agonists (varenicline and cytisine), antagonists [mecamylamine and the α4ß2 receptor-selective antagonist dihydro-ß-erythroidine (DHßE)], a nicotinic acetylcholine receptor antagonist/indirect-acting catecholamine agonist (bupropion), and non-nicotinics (cocaine and midazolam). Nicotine, varenicline, and cytisine dose-dependently increased drug-lever responding; the ED(50) values were 0.47, 0.53, and 39 mg/kg, respectively. Bupropion and cocaine produced 100% nicotine-lever responding in a subset of monkeys, whereas mecamylamine, DHßE, and midazolam produced predominantly vehicle-lever responding. The training dose of nicotine resulted in 1128 ng/ml cotinine in saliva. Mecamylamine antagonized the discriminative stimulus effects of nicotine and varenicline, whereas DHßE was much less effective. Nicotine and varenicline had synergistic discriminative stimulus effects. In monkeys responding predominantly on the vehicle lever after a test compound (bupropion, cocaine, and midazolam), that test compound blocked the nicotine-discriminative stimulus, perhaps reflecting a perceptual-masking phenomenon. These results show that nicotine, varenicline, and cytisine produce discriminative stimulus effects through mecamylamine-sensitive receptors (i.e., nicotinic acetylcholine) in primates, whereas the involvement of DHßE-sensitive receptors (i.e., α4ß2) is unclear. The current nicotine-discrimination assay did not detect a difference in agonist efficacy between nicotine, varenicline, and cytisine, but did show evidence of involvement of dopamine. The control that nicotine has over choice behavior can be disrupted by non-nicotinic compounds, suggesting that non-nicotinics could be exploited to decrease the control that tobacco has over behavior.

The effects of nicotine, varenicline, and cytisine on schedule-controlled responding in mice: differences in α4ß2 nicotinic receptor activation.

Nicotine, varenicline, and cytisine are pharmacotherapies for tobacco dependence; the extent to which their in vivo effects vary as a function of differences in nicotinic acetylcholine receptor agonism is not clear. Male C57BL/6J mice responding under a fixed ratio 30 schedule of food delivery were used to establish the potency and time course of nicotine, varenicline, and cytisine; antagonism was examined with the non-competitive, non-selective antagonist mecamylamine and the competitive, α4ß2 nicotinic receptor antagonist dihydro-ß-erythroidine (DHßE). Intraperitoneal nicotine, varenicline, and cytisine dose-dependently decreased responding; nicotine was more potent (ED(50) value=0.83 mg/kg) than varenicline (ED(50) value=2.51 mg/kg) and cytisine (ED(50) value=2.97 mg/kg). The agonists had a similar time course including a rapid onset (5 min or less) and relatively short duration of action (30 min). Mecamylamine dose-dependently attenuated the rate-decreasing effects of a fixed dose of nicotine (1.78 mg/kg), varenicline (5.6 mg/kg), and cytisine (5.6 mg/kg). Mecamylamine (1mg/kg) produced parallel rightward shifts in the dose-response curves for nicotine (3.3-fold), varenicline (3.1-fold), and cytisine (2.3-fold). In contrast, DHßE (3.2mg/kg) produced 2-fold antagonism of nicotine and did not antagonize varenicline or cytisine. The data strongly suggest that nicotinic acetylcholine receptors mediate the effects of the agonists to decrease operant responding in mice. However, α4ß2 receptor agonism appears to contribute partially to the rate-decreasing effects of nicotine but not to the rate-decreasing effects of varenicline and cytisine. Differential activation of α4ß2 receptors in vivo might contribute to differences in the effectiveness of these smoking cessation aids.

Zebrafish Behavior in Novel Environments: Effects of Acute Exposure to Anxiolytic Compounds and Choice of Danio rerio Line.

Zebrafish (Danio rerio) associative responses are useful for pharmaceutical and toxicology screening, behavioral genetics, and discovering neural mechanisms involved in behavioral modulation. In novel environments, zebrafish swim to tank bottoms and dark backgrounds, behaviors attributed to anxiety associated with threat of predation. To examine possible genetic effects of inbreeding and segregation on this behavior, we compared Zebrafish International Resource Center (ZIRC) AB and WIK lines to zebrafish and GloFish® from a pet store (PETCO) in two qualitatively different novel environments: the dive tank and aquatic light/dark plus maze. Behavior was observed in the dive tank for 5 min, immediately followed by 5 min in the light/dark plus maze. Among strains, WIK spent more time in the dive tank top than AB (76 ± 30 vs. 17 ± 11 sec), and AB froze in the plus maze center for longer than PETCO or GloFish® (162 ± 61 vs. 72 ± 29 or 27 ± 27 sec). Further, behavior of zebrafish exposed for 3 min to 25 mg/L nicotine, desipramine, chlordiazepoxide, yohimbine, 100 mg/L citalopram, 0.05% DMSO, or 0.5% ethanol was compared to controls. Approximately 0.1% of drug is available in brain after such exposures. Desipramine or citalopram-exposed fish spent more time in the dive tank top, and both reuptake inhibitors bound to serotonin transporters in zebrafish brain with high affinity (K(i) = 7 ± 5 and 9 ± 5 nM). In the plus maze, chlordiazepoxide, ethanol and DMSO-exposed fish crossed more lines and spent more time in white arms. Neither 25 mg/L nicotine nor yohimbine altered zebrafish behavior in novel environments, but nicotine was anxiolytic at higher doses. Overall, the light/dark plus maze and dive tank are distinct behavioral measures that are sensitive to treatment with anxiolytic compounds, but zebrafish line selection and solvents can influence baseline behavior in these tests.

Lobeline augments and inhibits cocaine-induced hyperactivity in rats.

Lobeline has high affinity for nicotinic receptors and alters presynaptic dopamine storage and release in brain. Moreover, lobeline decreases the reinforcing and locomotor-activating properties of methamphetamine, suggesting that lobeline may be a pharmacotherapy for psychostimulant abuse. This study determined if lobeline alters cocaine-induced hyperactivity and if lobeline alters the induction and/or expression of sensitization to cocaine. On Days 1-12, male rats were administered lobeline (0.3 or 1.0 mg/kg) or saline, placed in an automated activity monitor for 20 min, administered cocaine (10, 20 or 30 mg/kg) or saline and returned to the monitor for 60 min. On Day 13, the effect of lobeline on the induction and expression of sensitization to cocaine was determined. Lobeline did not alter the effect of cocaine after acute injection. However, 1.0 mg/kg lobeline attenuated cocaine (10 and 20 mg/kg)-induced hyperactivity after repeated administration and prevented the development of sensitization to these cocaine doses. Interestingly, 0.3 mg/kg lobeline augmented cocaine (10 mg/kg)-induced hyperactivity after repeated administration. Lobeline did not alter the effect of 30 mg/kg cocaine. The present results indicate a complex interaction of lobeline with cocaine and support other research indicating a role for nicotinic receptors in the development of sensitization to psychostimulants.

Interaction of lobeline and nicotinic receptor ligands with the discriminative stimulus properties of cocaine and amphetamine.

Lobeline has high affinity for nicotinic acetylcholine receptors and inhibits the function of vesicular and plasmalemmal monoamine transporters. Moreover, lobeline has been shown to alter the neurochemical and behavioral effects of psychostimulants. The present study determined the effect of lobeline and drugs selective for nicotinic receptors on the discriminative stimulus properties of low doses of cocaine (1.6 or 5.0 mg/kg) or d-amphetamine (0.3 mg/kg) in rats, using a standard two-lever drug discrimination procedure with food reinforcement. Nicotine substituted for both amphetamine and cocaine. The nicotinic receptor antagonists mecamylamine and hexamethonium did not substitute for or block the cocaine or amphetamine stimulus. In contrast, lobeline substituted for cocaine, but did not substitute for amphetamine. In antagonism tests, lobeline doses that did not substitute for cocaine decreased responding on the cocaine-paired levers. Surprisingly, lobeline did not alter the discriminative stimulus properties of amphetamine. This research further supports the supposition that nicotine, cocaine and amphetamine produce similar, but distinct subjective states. Furthermore, the present findings suggest that lobeline has a complex mechanism of action to disrupt the behavioral effects of drugs of abuse.