Comparison of the Relative Abuse Liability of Electronic Cigarette Aerosol Extracts and Nicotine Alone in Adolescent Rats: A Behavioral Economic Analysis.

Background: Characterizing the determinants of the abuse liability of electronic cigarettes (ECs) in adolescents is needed to inform product regulation by the United States Food and Drug Administration (FDA). We recently reported that Vuse Menthol EC aerosol extract containing nicotine and a range of non-nicotine constituents (e.g., menthol, propylene glycol) had reduced aversive effects compared to nicotine alone in adolescent rats, whereas Aroma E-Juice EC aerosol extract did not. The current study used a behavioral economic approach to compare the relative abuse liability of these EC extracts and nicotine alone in an i.v. self-administration (SA) model in adolescents. Methods: Adolescents were tested for the SA of EC extracts prepared using an ethanol (ETOH) solvent or nicotine and saline, with and without 4% ETOH (i.e., the same concentration in the EC extracts) in 23 h/day sessions. Results. Although acquisition of SA was faster for nicotine + ETOH compared to all other formulations, the elasticity of demand for all nicotine-containing formulations was similar. Conclusions: EC aerosol extracts did not have greater abuse liability than nicotine alone in adolescents. These data suggest that nicotine may be the primary determinant of the abuse liability of these ECs in youth, at least in terms of the primary reinforcing effects of ECs mediated within the central nervous system.

Delivery of nicotine in an extract of a smokeless tobacco product reduces its reinforcement-attenuating and discriminative stimulus effects in rats.

RATIONALE: Animal models of tobacco addiction rely on administration of nicotine alone or nicotine combined with isolated constituents. Models using tobacco extracts derived from tobacco products and containing a range of tobacco constituents might more accurately simulate tobacco exposure in humans. OBJECTIVE: To compare the effects of nicotine alone and an aqueous smokeless tobacco extract in several addiction-related animal behavioral models. METHODS: Nicotine alone and nicotine dose-equivalent concentrations of extract were compared in terms of their acute effects on intracranial self-stimulation (ICSS) thresholds, discriminative stimulus effects, and effects on locomotor activity. RESULTS: Similar levels of nicotine and minor alkaloids were achieved using either artificial saliva or saline for extraction, supporting the clinical relevance of the saline extracts used in these studies. Extract produced reinforcement-enhancing (ICSS threshold-decreasing) effects similar to those of nicotine alone at low to moderate nicotine doses, but reduced reinforcement-attenuating (ICSS threshold-increasing) effects at a high nicotine dose. In rats trained to discriminate nicotine alone from saline, intermediate extract doses did not substitute for the training dose as well as nicotine alone. Locomotor stimulant effects and nicotine distribution to brain were similar following administration of extract or nicotine alone. CONCLUSIONS: The reinforcement-attenuating and discriminative stimulus effects of nicotine delivered in an extract of a commercial smokeless tobacco product differed from those of nicotine alone. Extracts of tobacco products may be useful for evaluating the abuse liability of those products and understanding the role of non-nicotine constituents in tobacco addiction.

Nicotine self-administration in the rat: effects of hypocretin antagonists and changes in hypocretin mRNA.

RATIONALE: The hypocretin (hcrt) system has been implicated in addiction-relevant effects of several drugs, but its role in nicotine dependence has been little studied. OBJECTIVES: These experiments examined the role of the hcrt system in nicotine reinforcement. METHODS: Rats were trained for nicotine self-administration (NSA) on fixed-ratio schedules. The effects of acute, presession treatments with the hcrtR1 antagonist SB334867 and the hcrtR1/2 antagonist almorexant were examined on NSA maintained on a fixed-ratio (FR) 5 schedule. Gene expression for the hcrt system (mRNA for hcrt, hcrtR1, and hcrtR2) was measured in animals following NSA on a FR 1 schedule for a 19-day period. RESULTS: The hcrtR1 antagonist SB334867 and the hcrtR1/2 antagonist almorexant both reduced NSA dose-dependently (significantly at doses of 30 and 300 mg/kg, respectively); SB334867 did not affect food-maintained responding whereas almorexant (at the 300 mg/kg) did. Tissue from animals collected 5 h after self-administration showed an increase in hcrtR1 mRNA in the arcuate nucleus compared to control subjects. In tissue collected immediately after a similar 19-day self-administration period, mRNA for hcrtR1 was decreased in the rostral lateral hypothalamus compared to controls. CONCLUSIONS: These data confirm a previous report (Hollander et al., Proc Natl Acad Sci U S A 105:19480-19485, 2008) that the hypocretin receptor hcrtR1 is activated in nicotine reinforcement and in addition show that both the arcuate nucleus and lateral hypothalamus are sites at which hcrt receptor mechanisms may influence reinforcement. Different patterns of mRNA expression at different times after NSA suggest that changes in the hcrt system may be labile with time.

Effects of the selective dopamine D3 receptor antagonist SB-277011A on the reinforcing effects of nicotine as measured by a progressive-ratio schedule in rats.

The dopamine D3 receptor is primarily localized within the mesocorticolimbic system, and may therefore have potential as a pharmacotherapeutic target for the treatment of drug dependence. Studies have shown that the selective dopamine D3 receptor antagonist SB-277011A reduces a variety of dependence-related behavioral effects of cocaine, alcohol and heroin. A previous study examining SB-277011A on nicotine self-administration using relatively low doses of the antagonist and a low response requirement for nicotine found no effect on drug-taking behavior per se, whereas reinstatement of nicotine-seeking was reduced. The purpose of the present study was to further examine the effects of higher doses of SB-277011A on nicotine self-administration in rats under a progressive-ratio (PR) schedule, which imposes relatively high response requirements for nicotine. Rats were trained to respond under a PR schedule of either nicotine or food reinforcement. Once responding was stable, SB-277011A (3-56 mg/kg) or vehicle was administered i.p. 1 h prior to the operant session. The highest dose tested significantly decreased the mean number of reinforcers and mean response rates in the nicotine self-administration group, but had no effect on either the mean number of reinforcers or response rate in the food group. In a separate set of experiments, the effects of SB-277011A on locomotor activity were measured. At the dose that significantly decreased nicotine self-administration, total distance traveled was also significantly decreased, suggesting that the effect on operant responding at the high dose of SB-277011A is at a threshold for motor effects and may not be directly mediated by an action at dopamine D3 receptors.

Tobacco extract but not nicotine impairs the mechanical strength of fracture healing in rats.

The influence of nicotine and tobacco extract (without nicotine) alone and in combination on and mechanical strength of closed femoral fractures in rats was investigated. One hundred four male Sprague-Dawley rats were divided into four groups receiving: nicotine, tobacco extract, tobacco extract plus nicotine, and saline. One week prior to fracture, osmotic pumps were implanted subcutaneously in all animals to administer nicotine equivalent to the serum level of nicotine observed in a smoker consuming one to two packs of cigarettes daily. An equivalent volume of saline was administered to the control animals. Tobacco extract was administered orally. A closed transverse femoral diaphysial fracture was performed, and stabilized with an intramedullary pin. The fractures were mechanically tested after 21 days of healing. Tobacco extract alone decreased the mechanical strength. Ultimate torque and torque at yield point of the tobacco extract group were decreased by 21% (p=0.010) and 23% (p=0.056), respectively, compared with the vehicle (saline) group, and by 20% (p=0.023) and 26% (p=0.004), respectively, compared with the nicotine group. No difference was found between the tobacco extract and tobacco extract plus nicotine groups. An 18% (p=0.013) reduction in torque at yield point was observed in the tobacco extract plus nicotine group compared with the nicotine group. No differences in ultimate stiffness, energy absorption, and callus bone mineral content at the fracture line were found between any of the groups. Serum levels of nicotine were between 40-50 ng/mL in the group given nicotine alone and the group given tobacco extract plus nicotine (equivalent to serum levels observed in persons smoking one to two packs of cigarettes per day).