Animal Models of the Binge/Intoxication Stage of the Addiction Cycle
Oral Drug Self-Administration
Oral self-administration almost exclusively involves alcohol because of the obvious face validity. Such animal models include two-bottle choice responding and operant self-administration. Historically, home-cage drinking and preference have been used to characterize genetic differences in drug preference, most often with alcohol, and to explore the effects of pharmacological treatments on drug intake and preference.
Figure 3.1(Top) Drawing describing the procedure for intravenous self-administration in the rat. (Bottom) Event record and dose-response relationship relating dose of cocaine to the number of infusions. Rats implanted with intravenous catheters and trained to self-administer cocaine with limited access (3 h/day) will show stable and regular drug intake over each daily session. No obvious tolerance or dependence develops. Rats are generally maintained on a low-requirement, fixed-ratio (FR) schedule for intravenous infusion of the drug, such as an FR1 or FR5. In an FR1 schedule, one lever press is required to deliver one intravenous infusion of cocaine. In an FR5 schedule, five lever presses are required to deliver one infusion of cocaine. A special aspect of using an FR schedule is that the rats appear to regulate the amount of drug that they self-administer. Lowering the dose from the training level of 0.75 mg/kg/injection increases the number of self-administered infusions and vice versa. [Taken with permission from Caine SB, Lintz R, Koob GF. Intravenous drug self-administration techniques in animals. In: Sahgal A (ed) Behavioral Neuroscience: A Practical Approach, vol 2. IRL Press, Oxford, 1993, pp. 117–143.]
FIGURE 3.2 Effect of SCH 23390 pretreatment in rats on the number of reinforcers obtained under a progressive-ratio schedule of reinforcement. (A) Each point represents the average number of reinforcers obtained in a session with saline or SCH 23390 (10 μg/kg, s.c.) pretreatment. (B) Each point represents the average number of reinforcers obtained in a session with subcutaneous pretreatment with saline or SCH 23390. Saline or SCH 23390 was tested against the training dose of cocaine (0.90 mg/kg). [Taken with permission from Depoortere RY, Li DH, Lane JD, Emmett-Oglesby MW. Parameters of self-administration of cocaine in rats under a progressive-ratio schedule. Pharmacology Biochemistry and Behavior, 1993, (45), 539–548.]
In a two-bottle choice procedure, a choice is offered between two bottles: one that contains a drug solution and one that contains alternative solutions (often water). Researchers will then simply measure the weight of each bottle after the experimental session and determine the proportion of drug intake relative to total intake, yielding the preference ratio. For two-bottle choice testing for alcohol in mice and rats, the animals are housed one per cage. The researcher places two bottles in the cage: one that contains alcohol and one that contains water. Most commonly, the animals are allowed free choice between these bottles for successive 24 h periods, with simultaneous free access to food.
Two variations of the two-bottle choice procedure can result in binge-like drinking in rodents (see What is Addiction? for the definition of a binge). In the intermittent-access model, originally developed by Wise (1973) and revisited by Simms et al. (2008), rats are given intermittent access to alcohol in a two-bottle choice procedure for 24 h on Mondays, Wednesdays, and Fridays; on the intervening days, the rats have no access to alcohol (only water). Rats in the intermittent-access model progressively escalate their alcohol intake over the course of 2–3 weeks, reaching blood alcohol levels that are equivalent to human binge drinking (50–100 mg%).
A new variant of binge-like drinking in mice is called drinking-in-the-dark, in which mice drink intoxicating amounts of alcohol with limited 2–4 h access, beginning 3 h after lights out, a time when rodents normally initiate eating and drinking behavior (Rhodes et al., 2005). The mice are initially allowed to drink a 20% alcohol solution under this schedule for three consecutive days. On the fourth day, they are given 4 h access, also 3 h after lights out. Under such experimental conditions, the mice drink at levels of 80 mg% or above.
For operant alcohol self-administration, animals can be trained to lever press for alcohol using a variety of techniques, but first the researchers much overcome the challenge of getting the animals to drink alcohol, which typically has an aversive taste. To do this, the animals are initially given an alcohol solution that contains a specific amount of a sweetener, usually saccharin. This is called a sweetened solution fading procedure. As the animals learn to lever press for alcohol, the amount of sweetener can be gradually faded out, to the point that the animals respond for concentrations up to about 40% (80 proof). Using such a procedure, animals can be trained to perform the operant task on both fixed-ratio and progressive-ratio schedules of reinforcement, obtaining significant blood alcohol levels in a 30 min session (Figure 3.3). The operant oral self-administration of alcohol has also been validated as a measure of the reinforcing effects of alcohol in primates. The advantages of the operant approach are that the effort to obtain the substance can be separated from the consummatory response (e.g., drinking), and intake can easily be charted over time.