Animal Models of the Binge/Intoxication Stage of the Addiction Cycle

Intravenous Drug Self-Administration

Both animals and humans will readily self-administer drugs in the nondependent state. Drugs of abuse have powerful positive reinforcing properties. Animals will perform many different tasks to obtain drugs, even when not dependent. Drugs that have positive reinforcing effects, measured by direct self-administration, lowering of brain stimulation reward thresholds, and conditioned place preference in rodents and primates, correspond very well with the drugs that have high abuse potential in humans, including alcohol, cocaine, and heroin, among many others (Table 3.2).

The animal model of intravenous drug self-administration is a powerful tool for exploring the neurobiology of positive reinforcement. Intravenous cocaine and heroin self-administration in rodents produces a characteristic and predictable pattern of behavior that lends itself to pharmacological and neuropharmacological study. Rats on a simple schedule of continuous reinforcement, such as a fixed-ratio 1 schedule (in which one press of a lever or one nosepoke in a hole results in one drug delivery), will develop a highly stable pattern of drug self-administration in a limited-access situation (Caine et al., 1993; Figure 3.1). If the dose is decreased, then the animals increase their rate of self-administration. Conversely, if the dose is increased, then the animals decrease their rate of self-administration. Thus, experimental manipulations that increase the self-administration rate on this fixed-ratio schedule, such as administering a drug that counteracts the effects the drug of abuse, mimic a decrease in the unit dose and may be interpreted as decreasing the reinforcing potency of the drug under study.

TABLE 3.2

Animal Models of the Binge/Intoxication Stage of the Addiction Cycle

  • Intravenous and oral drug self-administration
  • Brain stimulation reward
  • Conditioned place preference
  • Drug discrimination
  • Genetic animal models of high drinking
  • Drug taking in the presence of aversive consequences

As predicted by this dose-response model, low to moderate doses of dopamine receptor antagonists increase cocaine self-administration maintained on a fixed-ratio schedule in a manner that is similar to decreasing the dose of cocaine, suggesting that dopamine receptor antagonism by a dopamine receptor antagonist reduces the reinforcing potency of cocaine. Conversely, dopamine receptor agonists decrease cocaine self-administration in a manner similar to increasing the dose of cocaine, suggesting that the combined effects of dopamine receptor agonists and cocaine on self-administration can be additive, perhaps because of their common activation of the same neural substrates.

The use of different schedules of reinforcement (differential delivery of the reinforcer based on time or effort, in which the reinforcer is the discrete delivery of a drug) in intravenous self-administration models can provide an important control for nonspecific effects (that is, effects that are different from the primary endpoints under study, such as increases in exploratory activity and locomotion) and motivational effects, such as a loss of reinforcement efficacy. Such schedules can include progressive-ratio, second-order, and multiple schedules of reinforcement.

To model a measure of reinforcer efficacy for a self-administered drug, researchers can use a progressive-ratio schedule of reinforcement, in which the response requirement (like the number of times the animal has to press a lever) to receive a reinforcer (drug infusion) increases. This type of schedule will determine the breakpoint at which an animal will no longer respond to receive the drug. This schedule effectively determines the relative reinforcing strength of different reinforcers, including drugs. The dose-response model discussed above has shown that increasing the unit dose of a self-administered drug will increase an animal’s breakpoint on a progressive-ratio schedule. Dopamine receptor antagonists have been shown to decrease the breakpoint for cocaine self-administration (Figure 3.2). To bring such an animal model back to the perspective of the human condition, performance on a progressive-ratio schedule can be linked to the following DSM-5 criterion for addiction: “a great deal of time spent in activities necessary to obtain the substance.”

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