Behavioral Mechanism of Action
High doses of amphetamines and cocaine or prolonged use/abuse can lead to significant behavioral pathology (Box 4.9). Amphetamine abusers persist in repetitive thoughts or actions for hours. These behaviors can include repetitively cleaning the house or car, bathing in a tub all day, elaborately sorting small objects, or endlessly dismantling and putting back together items such as clocks or radios. Termed “punding” by Rylander (1971), this behavior was described as “organized, goal-directed, but meaningless activity.” Such repetitive behavior under the influence of amphetamines and cocaine is called “stereotyped behavior” and can be defined as “integrated behavioral sequences that acquire a stereotyped character, being performed at an increasing rate in a repetitive manner.” (Randrup A, Munkvad I. Biochemical, anatomical and psychological investigations of stereotyped behavior induced by amphetamines. In: Costa E, Garattini S (eds.) International Symposium on Amphetamines and Related Compounds. Raven Press, New York, 1970, pp. 695–713). Stereotyped behavior is observed in many animal species. Monkeys will pick at their skin, exhibit mouth and tongue movements, and stare. Rats will sniff intensely in one location. Pigeons will repetitively peck at one location on a stimulus display.
Figure 4.9 Schematic drawing depicting the relative distribution of varying behavioral activities within a given time sample relative to increasing doses of D-amphetamine. Notice that as the dose increases, the number of activities decreases, but the rate of behavior within a given behavioral activity increases. [From: Lyon M, Robbins TW. The action of central nervous system stimulant drugs: a general theory concerning amphetamine effects. In: Essman WB, Valzelli L (eds.) Current Developments in Psychopharmacology, vol. 2. Spectrum Publications, New York, 1975, pp. 79–163.]
Insights into the nature and behavioral mechanism of action of amphetamine-like drugs derived from further experimental and theoretical analysis of stereotyped behavior (Figure 4.9). Lyon and Robbins (1975) hypothesized that as the dose of amphetamine increases, the repetition rate of all motor activity increases, with the result that the organism will exhibit “increases in response rates within a decreasing number of response categories.” This type of analysis makes a number of predictions. Complex behavioral ensembles are the first to be eliminated as the response categories decrease. Behaviors capable of repetition without long pauses then dominate, and shorter and shorter response sequences result. As a result, high rates of responding in operant situations decrease and locomotor activity decreases. Thus, the classic inverted U-shaped (i.e., ∩-shaped) dose-response function that relates amphetamines to locomotor activity (or any other high rate behavior) – in which the dose is plotted on the X-axis and the behavior is plotted on the Y-axis – may reflect the competitive nature of that activity and stereotyped behavior. The inverted U-shaped function that relates the psychostimulant dose to performance is also reflected in the famous behavioral pharmacological principle of “rate dependency.” One of the strong propositions associated with rate dependency is that general differences in the rates of responding will determine differences in the effects of a drug. High rates of responding are decreased and low rates of responding are increased with administration of psychostimulants, and this effect generalizes to a broad range of behaviors. Some aspects of the behavioral principle for stimulants outlined above, in which the increasing rates of behavior combine with a decreasing number of response categories, can be considered a form of rate dependency. In rodents, as the psychostimulant dose increases, high rates of behavior in operant situations decrease, locomotor activity decreases, and rearing, head bobbing, and other forms of stereotyped behavior that have an initially low frequency increase. Such stereotyped behavior may actually contribute to the cycle of abuse associated with the compulsive use of these drugs by narrowing an individual’s behavioral repertoire toward the singular act of drug use.