chimp would select a different key which provided access to food inside a different box. Spragg wrote
" .. .since morphine addiction seems to depend essentially upon forming an association between the administration of the drug and the alleviation of withdrawal symptoms, and since this sequence involves a time lag of 10-15 min or more, the value of using subjects high enough in the phyletic scale to be able to make a delayed association of this nature is obvious. By this token, animals such as the rat, for example, could probably never become addicted to morphine, simply because they are not capable of forming associations of this order... (p 126)
The quote illustrates two important presumptions of the early literature. The first is the notion that drug taking is phylogenetically biased toward primates and the second is that ► physical dependence is a necessary precondition of drug self-administration in animals. These assumptions went unchallenged for two decades.
Weeks (1962) of the Upjohn Company published a seminal paper which marked the beginning of modern self-administration studies. By combining operant conditioning techniques, a pump mechanism that delivered precise amount of drug and a chronically indwelling jugular catheter that allowed animals to move freely within a cage, Weeks demonstrated that rats learned to respond on a lever which resulted in the delivery of an intravenous injection of morphine. Clearly rats were capable of making the correct associations and were able to self-administer morphine. Weeks' initial demonstration used animals that were first made physically dependent. Later, however, it was shown that physical dependence was not a necessary precondition for drug self-administration. Readers are referred to the 1978 NIDA Monograph No. 20, Self-Administration of Abused Substances: Methods for Study (http://www. drugabuse.gov/pdf/monographs/20.pdf) for a collection of reviews which summarize the foundational work in the field.
The pattern of drug self-administration depends on the pharmacological class of the drug as well as experimental factors such as dose, price, and availability. Figure 1 shows the pattern of ► cocaine self-administration in a rat using the most basic schedule, a ► Fixed Ratio 1 (FR1). Note the brief burst of responding in the first few minutes of the session; for the remainder of the session the interval between each injection is relatively consistent. As the unit dose is reduced, the number of self-administered injections increase within the 2-h session until, at some
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Self-Administration of Drugs. Fig. 1. Examples of a rat self-administering various doses of cocaine on an FR1 schedule. Each line is an event record of a daily 2 h session with each injection indicated by an upward tick. The unit dose for each daily session is indicated to the left. The figure illustrates that (above some threshold) lower doses are self-administered more frequently.
point, the dose no longer supports sustained responding (bottom two event records). This dose-response relationship for a group of animals is shown in Fig. 2 (left). The gradual ascending limb apparent to the left of the apex is an artifact of averaging across a group of animals and does not reflect the fact that the behavior of an individual animal shows an abrupt change from a non-reinforcing to a threshold reinforcing dose (see Fig. 1). To the right of the apex is a descending limb with a very small variance surrounding the mean rate at each dose. Figure 2 (right) shows the same data plotted according to total drug intake during the session. This graph illustrates that above some threshold dose animals tend to self-administer similar amounts or show a slight increase in intake at each supra-threshold doses.
It is important to distinguish between two related concepts in drug self-administration: appetitive versus consum-matory responses. A consummatory response is determined by the route of administration. For example, the consummatory response for ► alcohol might involve opening a bottle and drinking from it. For smoking tobacco or ► crack cocaine, it is the act of preparing and lighting a cigarette or pipe and inhaling the smoke. For intravenous drug use, it is filling the syringe and injecting the drug into a vein. Such consummatory behaviors can become extremely ritualistic and powerful habits.
Self-Administration of Drugs. Fig. 2. The effect of manipulating dose on rate of responding (left) and total intake (right) for a group of rats. Each rat in the group was implanted with an IV catheter and trained to self-administer cocaine. Each animal was then tested using a descending series of doses as illustrated in Fig. 1. The graph on the left illustrates that above a mean threshold dose (apex) the rate of self-administration deceases as the unit injection dose is increased. The graph on the right illustrates that in spite of the decrease in the number of injections self-administered, the amount consumed within a session increased gradually with dose (Oleson and Roberts 2009).
By contrast, appetitive responses serve to make the drug available. In humans, appetitive responses might involve working for money to buy the alcohol, tobacco product, or drug; in a laboratory situation it could be pressing on a lever and completing a response requirement. The difference between appetitive and consum-matory responses is relatively straightforward in humans; however, the distinction becomes blurred in animals receiving drug via intravenous catheters. The appetitive response is obvious - animals can be shown to work quite hard to receive an injection. But since the drug is infused automatically via a catheter the consummatory act is harder to define. It might be argued the consummatory act is the last response on the lever prior to the injection. With that being the case, the single operant response on an FR1 schedule is both appetitive and consummatory.
Schedules will be reviewed below which attempt to address separately the appetitive and motivational factors which influence drug seeking. For the moment it is assumed that responding on an FR1 is largely consummatory and that the rate and pattern of responding reflects the preferred level of consumption.
The pattern shown in Fig. 1 has been taken as evidence that animals regulate (or titrate) their intake around some preferred blood or brain level. The early burst is a ''loading phase,'' during which blood levels of cocaine increase presumably to a preferred plateau. The subsequent regular pattern reflects a maintenance phase with each postinfusion pause determined by the ► half-life of the unit injection dose. Longer acting drugs, such as ► amphetamine, produce longer post-infusion pauses.
Independent variables such as session length and timeout periods can dramatically affect the daily pattern and rates of consumption. An examination of these factors illustrates the qualitative differences between stimulant and opiate drug use. Subjects given 24 h/day access to cocaine or other stimulant drugs on an FR1 schedule tend to ''► binge'' for many hours or days. It is unclear what actually terminates a binge; however, animals generally do not eat or sleep during this period so that a deterioration of their physical health probably contributes. A drug binge inevitably resumes after some recuperative drug-abstinence period. Unlimited access to stimulant drugs, therefore, results in a series of binge-abstinence cycles. Toxic effects can accumulate with repeated cycles resulting in an increased likelihood of convulsions. The probability of lethal overdose is extremely high virtually for all psychostimulants tested including cocaine, amphetamine, and ► methamphetamine. This is true for every species tested. By contrast, unlimited access to ► opiates results in a very different outcome. Heroin and morphine intake is relatively circadian rather than binge-like. Drug intake increases gradually over days as ► tolerance and physical dependence develops. The danger of lethal overdose is far less for opiates than for stimulants. Instead, a severe withdrawal reaction during experimenter-imposed opiate deprivation becomes a concern.
Any examination of extended access to stimulant drugs must necessarily limit intake in some fashion to avoid toxicity. The majority of cocaine and amphetamine studies constrain intake by restricting the daily session to 1 or 2 h a day. This produces a very consistent pattern of intake from day to day. Longer sessions (6 h) have been shown to produce an escalation of intake across days
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