Intravenous self-administration of abused solvents and anesthetics in mice
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).
Section snippets
Subjects
Adult male drug- and experiment-naive Swiss (Swiss bred at Rappolovo) and DBA/2 (20–33 g) were purchased from the State Breeding Farm Rappolovo (St. Petersburg, Russia). The animals were housed in groups of 10 with food and water available ad libitum. All experiments were conducted during the light period of a 12/12-h day–night cycle (08:00–20:00 h). The experiments were approved by the Institutional Ethics Committee of Pavlov Medical University and were performed in accordance with the
Results
There were no overall significant differences between treatment groups with regard to their performance during the 10-min pre-tests. The nose-poke activity of master and yoked control mice did not differ for any treatment group.
Fig. 1 presents dose–effect curves for each of the agents tested. Toluene concentration had overall significant effects on R-values for both Swiss (F(6,63)=3.4, P<0.01) and DBA/2 (F(5,45)=2.5, P<0.05) mice. Individual comparisons showed that R-values were significantly (P
Discussion
Evidence is presented that the reinforcing properties of abused inhalant can be studied using i.v. self-administration procedures in mice. Toluene and 1,1,1-trichloroethane are well established to be abused solvents Balster, 1987, Gerasimov et al., 2003, Kozel et al., 1995 and both were self-administered. Two control procedures were used to establish that these chemicals were serving as reinforcers. One control was based on a yoked-control procedure. Ratios of nose-poking rates were obtained
Acknowledgements
This study was supported by NIDA grants DA-14169 (E.E.Z.) and DA-03112 (R.L.B.). A preliminary account of this work was presented in poster form at the 63rd CPDD Meeting, June 16–21, 2001, Scottsdale, AZ.
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First two authors contributed equally to the experiments described in this manuscript.