Intravenous self-administration of abused solvents and anesthetics in mice

Abstract

Volatile organic solvents, fuels and anesthetics are subject to abuse. The aim of the present study was to evaluate i.v. self-administration of several of these chemicals in drug- and experiment-naive mice using a commercially available vehicle, intralipid. Two strains of mice (DBA/2 and Swiss) were allowed to self-administer toluene (0.0017–0.17 μmol/infusion), 1,1,1-trichloroethane (0.006–0.19 μmol/infusion), ethanol (0.32–1.6 μmol/infusion), cyclohexane (0.0017–0.052 μmol/infusion), propofol (0.01–0.53 μmol/infusion) and flurothyl (0.00042–0.072 μmol/infusion) or their vehicles during 30-min tests. During the test, each nose-poke of the master mouse resulted in a 1.88-μl i.v. infusion to the master mouse and a yoked control mouse. When the delivery line was loaded with a reinforcing drug solution, the number of nose-pokes of the master mice significantly exceeded that for yoked control mice. In the present experiments, significant differences in rates of nose-poking were observed between mice receiving response-contingent and response-noncontingent deliveries of ethanol and toluene in both strains of mice and of 1,1,1-trichloroethane in Swiss mice. These data suggest that the reinforcing effects of abused inhalants can be studied using i.v. self-administration procedures.

Introduction

Human exposure to volatile solvents is common due to their widespread industrial, commercial, and medical uses, as well as through voluntary self-administration to produce intoxication. Although inhalant abuse is a significant public health problem throughout the world (Kozel et al., 1995), much less is known about the properties of the chemicals that lead to their abuse than for most other classes of drugs of abuse. In particular, there have been very few studies of the reinforcing effects of abused solvents despite the well-established importance of animal drug self-administration studies with other classes of abused drugs Schuster and Johanson, 1981, Brady, 1991. Such investigations can help establish the behavioral and neurobiological bases for drug-taking behavior. Also, because drugs abused by humans are typically self-administered by laboratory animals Griffiths et al., 1980, Johanson, 1990, Balster, 1991, these methods can be used to assess the abuse potential of drugs Johanson, 1990, Woolverton and Nader, 1990, Balster, 1991. Clearly, reliable animal methods for studying abused solvent self-administration are needed.

Solvents are usually abused by inhalation, and this is perhaps one of the reasons why animal models for assessing their reinforcing effects have been difficult to establish. There have been a few studies of self-administration via inhalation in animals. Yanagita et al. (1970) used rhesus monkeys implanted with nasal catheters. Lever-press responses resulted in 2- to 5-min deliveries of air or test vapors. In another study on self-administration of inhaled nitrous oxide (Wood et al., 1977), squirrel monkeys were seated in a chair with a helmet placed over their head. Lever presses resulted in 1-min exposures to various concentrations of nitrous oxide during 1-h daily sessions. Despite these earlier successes with monkeys, there have been no other reports of solvent vapor self-administration in these species and none that we are aware of using rodents, an important species for drug abuse research. In addition to the specific pharmacological effects these vapors may have, they also have very strong odors, which may deter voluntary exposure. Since inhaled vapors are carried to the brain by blood, where their abuse-related effects are presumably produced (Balster, 1998), it may be possible to circumvent the problems arising from inhalation studies by administering the test materials intravenously.

The present study sought to test whether several organic solvents and general anesthetics, toluene, 1,1,1-trichloroethane, cyclohexane, ethanol, propofol, and flurothyl are self-administered by mice. Self-administration behavior was assessed using a protocol that was specifically designed for studies in drug- and experiment-naive mice. Using this procedure, there were successful demonstrations of significant self-administration of all major abused drug classes such as cocaine, amphetamine, morphine, nicotine, ethanol, caffeine and others (e.g., Martellotta et al., 1995, Martellotta et al., 1998, Semenova et al., 1995, Zvartau et al., 1995, Kuzmin et al., 1997, Rasmussen and Swedberg, 1998). Our study was conducted with two strains of mice—DBA/2 and Swiss. The DBA/2 strain was selected because this strain readily acquires intravenous self-administration of various drugs such as morphine Semenova et al., 1995, Kuzmin et al., 1997, cocaine (Kuzmin et al., 1997), ethanol (Zvartau et al., 1995) and nicotine (Paterson et al., 2003). Swiss mice (Charles River Swiss) have been extensively used for characterizing the behavioral effects of abused solvents (e.g., Bowen et al., 1996a, Bowen et al., 1996b, Balster et al., 1997). For the present studies, toluene and 1,1,1-trichloroethane were chosen because they are among the most commonly abused inhalants and their behavioral effects were previously shown to resemble those of major abused drugs such as barbiturates, benzodiazepines, phencyclidine and ethanol Rees et al., 1987a, Rees et al., 1987b, Knisely et al., 1990, Balster, 1998, Bowen et al., 1999. Cyclohexane is a solvent used for many industrial and household formulations (e.g., adhesives). Ethanol was selected to serve as a positive control since intravenous self-administration of ethanol is well documented both in humans and laboratory animals, including mice (e.g., Grahame and Cunningham, 1997). Propofol is an injectable anesthetic that acts at least in part through the GABA–benzodiazepine–barbiturate receptor complex and may therefore possess an abuse potential similar to that of other sedative-hypnotics with similar receptor interaction profiles Concas et al., 1990, Sanna et al., 1995, Orser et al., 1998. For instance, a recent study in baboons revealed that propofol maintained high levels of self-injection behavior (Weerts et al., 1999). Finally, flurothyl, a proconvulsant agent (Adler, 1975), was added to the solvent test list as a potential negative control. Previous studies have suggested that flurothyl does not produce behavioral effects similar to those seen after exposure to toluene and 1,1,1-trichloroethane Rees et al., 1987a, Bowen et al., 1996a. Fat emulsion, intralipid, was used as a vehicle in this study because of earlier reports demonstrating its utility for intravenous delivery of propofol and abused solvents (LeSage et al., 2000).