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.

Potentiated startle and hyperalgesia during withdrawal from acute morphine: effects of multiple opiate exposures.

RATIONALE: Administration of an opiate antagonist following acute morphine exposure elevates the startle response in rodents, a phenomenon that may reflect the anxiogenic effects of withdrawal. Previous acute dependence studies have demonstrated escalated withdrawal severity following multiple withdrawal episodes. OBJECTIVES: To examine the effects of prior opiate exposure on the magnitude of withdrawal-potentiated startle and an additional measure of acute dependence, withdrawal-induced hyperalgesia. METHODS: The effects of repeated naloxone-precipitated morphine withdrawals on acoustic startle responding were evaluated in experiments that varied either the dose of the opiate antagonist (8-day, repeated measures procedure) or agonist (3-day procedure). Additional experiments examined withdrawal-induced hyperalgesia utilizing either a single-day dependence paradigm or the same 3-day procedure as in the startle experiment. RESULTS: Repeated naloxone-precipitated withdrawals from acute morphine exacerbated withdrawal severity in both startle procedures, although this effect varied biphasically (inverted-U function) with morphine dose in the 3-day dependence paradigm. Withdrawal from a single morphine exposure also induced hyperalgesia, and this effect was intensified by prior withdrawal episodes. CONCLUSIONS: These data demonstrate that repeated withdrawals from acute morphine exacerbate the severity of potentiated startle and hyperalgesia. These paradigms may be useful in examining the neural plasticity underlying the development of opiate dependence.

Elevated startle during withdrawal from acute morphine: a model of opiate withdrawal and anxiety.

RATIONALE: An elevated startle response has been observed in humans and animals during withdrawal from multiple substances of abuse, a phenomenon thought to reflect the anxiogenic effects of withdrawal. Although anxiety is a common symptom of opiate withdrawal, few studies have examined the effects of morphine withdrawal on acoustic startle. OBJECTIVE: To develop a procedure for assessing opiate dependence through measurement of the startle reflex in rats. METHODS: The effects of opiate withdrawal on startle were evaluated using both spontaneous and naloxone-precipitated withdrawal from an acute dose of morphine. The ability of the treatment drugs clonidine and chlordiazepoxide to block withdrawal-induced increases in startle was also tested. RESULTS: Spontaneous withdrawal from an injection of morphine sulfate produced a significant increase in acoustic startle 2 h (3.2 mg/kg) or 4 h (10 mg/kg) after drug administration. Morphine withdrawal (10 mg/kg morphine sulfate) precipitated by the opiate antagonist naloxone (2.5 mg/kg) also produced a significant increase in startle magnitude. This elevation of startle was blocked by both clonidine (35 microg/kg) and chlordiazepoxide (10 mg/kg). CONCLUSIONS: These data demonstrate that both spontaneous and precipitated withdrawal from an acutely administered opiate produce anxiety-like effects on acoustic startle. This paradigm may be useful in the study of anxiety and the early mechanisms of drug dependence.