Sensitization to Drugs. Fig. 1. An illustration of the different ways of viewing psychomotor sensitization. The specific behavior quantified is amphetamine-induced rotational behavior in rats with a unilateral 6-OHDA lesion. The dose-effect function for this behavior is linear over a much wider range of doses than for locomotor activity (see Fig. 2). Left panel: a within-subjects measure of sensitization, in which rats were given an injection of 3 mg/kg of D-amphetamine (or saline) once every 3-4 days for a total of ten injections. Amphetamine produced more and more rotational behavior (''psychomotor activation'') with successive injections, whereas the response to saline did not change. The increase in behavioral effect is called behavioral or psychomotor sensitization. Middle panel: a between-subjects measure of sensitization, in which rats that were previously treated with saline or amphetamine both received a challenge injection of amphetamine (1.5 mg/kg). The behavioral response in rats that previously received ten injections of amphetamine (left panel) is much greater than in those that previously received saline, and the magnitude of the group difference indicates the degree of sensitization. Right panel: dose-effect analysis, in which rats previously treated as in the left panel received a challenge injection with different doses of amphetamine. In this case the degree of sensitization is indicated by the magnitude of the shift to the left in the dose-effect function. (Data are from Anagnostaras S, Robinson TE (1996) Sensitization to the psychomotor stimulant effects of amphetamine: modulation by associative learning. Behav Neurosci 110:1397-1414).
movements (licking and biting), rotational behavior, etc. Which psychomotor effect dominates behavior depends on many factors, including the drug, dose, the test environment, the time after drug administration, and many others. For example, in animals previously exposed to amphetamine a subsequent injection may initially increase locomotor activity, which then decreases and is replaced by complex patterns of stereotyped behaviors performed "in place,'' and then this followed by the re-emergence of locomotor hyperactivity ("post-stereotypy hyperactivity"). What is critical to realize is that each of these different psychomotor effects can be dissociated, and they do not all change uniformly as a function of repeated drug treatment (see Fig. 2). Repeated drug administration does not have the same effect on each of these behaviors, presumably in part because they are mediated by different neural systems that are changing in different ways, and in part because of the competitive relationship between different behaviors.
For this reason, negative findings can be very difficult to interpret in studies of sensitization. If a given manipulation is reported to not produce, or to prevent the expression of "sensitization" - one must immediately ask - by what measure? It could be that the manipulation influenced the induction or expression of locomotor sen-sitization, but had no effect on some other measure of psychomotor sensitization, or on other psychological processes that undergo sensitization (see below). Or, it could
Sensitization to Drugs. Fig. 2. Different measures of psychomotor activation in a within-subjects study of behavioral sensitization. On the first day of treatment, rats were given three injections of cocaine in ascending doses (0, 7.5, 15, and 30 mg/kg), with 45 min between each treatment. For the next 6 days, they received one injection of 15 mg/kg each day. Then, on the seventh day they again received multiple doses, as on day 1. The graph show three different behavioral measures on day 1 and day 7 of testing, obtained from video. Panel A shows a measure of locomotion (distance traveled in cm). Between day 1 and 7 the animals showed an increase in locomotor activity when given 7.5 mg/kg, no change when given 15 mg/kg, and a decrease in locomotor activity when given 30 mg/kg. This highlights the complexity of the dose-effect function when using locomotor activity as a measure of psychomotor activation (compare with Fig. 1). For example, under the conditions of this study, if only a dose of 15 mg/kg were used, one would conclude that the animals did not sensitize. However, other measures of psychomotor activation reveal robust sensitization. Panel B shows the average velocity of each bout of locomotion, and there is a large effect of repeated drug treatment on this measure (the effect at a dose of zero also reveals a conditioned effect not evident in the distance traveled). Panel C shows the average frequency of head movements, and again this measure reveals robust psychomotor sensitization, at all doses. These data illustrate the importance of using multiple measures of psychomotor activity in studies of sensitization, especially if negative findings are obtained. (Data are from Flagel and Robinson 2007).
be that the measure of locomotion was not the most appropriate measure under the conditions of the study. For example, repeated exposure to cocaine may have no influence on one measure of locomotion, such as distance traveled, while at the same time dramatically increasing the velocity of each individual bout of locomotion and the frequency of stereotyped head movements (Flagel and Robinson 2007; Fig. 2). Thus, the apparent absence of locomotor sensitization may not allow one to conclude no effect on "sensitization," but only on one behavioral measure. Unfortunately, in many studies only one measure is provided making it nearly impossible to interpret negative results.
It is also important to remember that many other behavioral effects of drugs can sensitize, besides just psychomotor effects. Other behaviors that have been reported to sensitize include acoustic ► startle, drinking behavior, lick rate, discriminative effects, and the disrupting effect of amphetamine on ► latent inhibition and ► selective attention, to name a few (Badiani and Robinson 2009; Kalivas and Barnes 1988; Robinson and Becker 1986;
Stewart and Badiani 1993). In humans the psychotomi-metic effects of psychostimulant drugs also sensitize (Featherstone et al. 2007; Robinson and Becker 1986). In addition, there is considerable evidence that repeated exposure to a variety of drugs of abuse increases some aspect of their rewarding or incentive motivational effects (Vezina and Leyton 2009). Repeated exposure to a number of potentially addictive drugs facilitates the later acquisition of ► drug self-administration behavior and a ► conditioned place preference, facilitates the learning of S-R habits, increases motivation for drug based on performance on a ► progressive ratio schedule and running in an alley, and increases the incentive salience attributed to stimuli associated with drug and nondrug rewards. This latter form of sensitization - incentive sensitization - may be especially important in the development of addiction because it may result in people being mala-daptively attracted to drugs and cues associated with drugs, thus instigating and maintaining drug-seeking behavior even when there is a desire to remain abstinent (Robinson and Berridge 2008).
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