Administration of Amphetamines to Rodent Subjects

2015

As mentioned above, ethical concerns preclude the use of humans in many experimental situations; however, we can understand many features of the human central nervous system by understanding the brains of other animals. The animal most widely used in the area of amphetamine experimentation is the rodent, which has an analogous, rather than homologous, brain structure to humans. In the following sections, we examine the modification of aggressive behavior in rodents by amphetamines. The various aspects of aggressive behavior include the tendency for provoked attack, the influence of environment on behavior, social factors, and the neurological basis of aggression.

Behavioral Observations

When using nonhuman subjects to study aggressive behavior, the typical research methodologies most usually employed by experimenters include pain-, isolation-, and brain stimulation-induced aggression. However, when making a comparison between animals of different species the outcomes of these tests yield varying and somewhat contradictory results, which in turn hampers one’s ability to generalize to the human population. Additionally, it has been found that the most important aspects of amphetamine-stimulated aggressive and defensive responses vary with the nature of the species involved, the stimulus situation, prior experience with these certain behaviors, and the dosage and chronicity of drug exposure; the last is of primary concern ().

When observing the effects of amphetamines on the aggressive responses of rodent subjects, the behavioral categories most commonly analyzed are nonsocial exploration, social exploration, immobility, threat/attack, escape/avoidance, and defensive/submissive reactions. The nonsocial exploration category includes behavioral elements such as exploring the surroundings. It has been shown in various studies that acute doses — single or intermittent doses rather than chronic daily doses — of amphetamine increase significantly the occurrence of such exploratory behavior ().

In the mouse, social exploration involves crawling over and under other mice, grooming, sniffing, and other social interactions. Increased social activity in response to amphetamine is dose dependent. In other words, as the dose of the drug increases, the amount of behavior observed also increases. In the case of amphetamine, as the dose of the drug is increased in mice, social exploration increases as well (); however, no noticeable effect has been observed in subjects treated intermittently — two injections a week or injections on alternating days (). Thus, the chronicity of administration clearly has an effect on the behavioral consequence. This suggests that a single dose of amphetamine can have effects very different from chronic doses.

Squatting, crouching, and a general lack of movement comprise immobility and are typically used as an index of fear (). Previous literature shows that both the frequency and the mean duration of this behavior are significantly reduced after amphetamine administration (). This means that treated mice spend considerably less time motionless with shorter intervals between the periods of movement, which clearly indicates a direct relationship between the administration of d-amphetamine (dextroamphetamine) and the rate of motor activity. It also suggests that amphetamine may have the effect of reducing fear. However, the effects of amphetamine seem to be complex. Flight from a potentially dangerous conspecific can also be a sign of fear. Whereas acute and intermittent administration of amphetamine causes an increase in flight from a conspecific, chronic administration causes a reduction in flight ().

Threat/attack behaviors consist of upright, offensive stances, lunging, attacking, and chasing. Moro et al. (1996) found that the total duration of time spent in threat postures was increased by a low acute dose of amphetamine (0.25 mg/kg); however, the total duration of attacks was reduced significantly in comparison with a saline-treated control group at intermediate (1.5 mg/kg) or high (3 mg/kg) dose ranges (). Furthermore, intervals between the attacks were considerably shorter for amphetamine-treated animals, resulting in a higher rate of attack (). Taken together with the biphasic effect of amphetamine on the duration of attack, this result suggests that amphetamine changes the quality of attack in a dose-dependent manner.

Dose-Dependent Effects

Acute Administration

The administration of amphetamine causes dose-dependent changes in either the type of behavior observed or the intensity of the behavior observed. As described in the previous section, higher doses of amphetamine can result in a disruption in the patterns of aggressive behavior displayed by male mice (). This effect was evidenced by (1) repeated attacks separated by shorter time periods and (2) treated mice showing less sensitivity to their opponents’ displays of submission, which, consequently, caused continued attack (). Other studies have shown that distorted perceptions of social signals caused a decrease in the attack and threat behavior of dominant animals to subordinates, in territoriality toward intruders, and in lactating mothers defending their litters ().

There is a common belief among health-care workers and workers in the criminal justice system that amphetamine has a dose-dependent effect on aggressive behavior. Research shows, however, that d-amphetamine has quite different effects that vary in accordance with species, dose of amphetamine, and the type of stimuli used. Miczek and Tidey (1989) suggest that pain-induced aggressive or defensive reactions in rats and mice were noticeably increased after the administration of low doses of amphetamine. However, at intermediate to high dose levels these effects were reduced or disrupted, along with a decrease in isolation- and extinction-induced aggressive behavior. Moro et al. (1996) obtained similar results in an isolation-induced aggression experiment using 52 male mice. It was found that lower doses (less than 4 mg/kg) increased the occurrence of threat and attack behaviors (especially at 0.25 mg/kg) and produced other ambiguous outcomes, whereas intermediate to high doses (above 4 mg/kg) yielded clear antiaggressive effects. These findings consequently strengthened the principle of rate dependency or dose dependency, which is the idea that varying quantities of amphetamine will have diverse effects on the treated subject, otherwise known as biphasic effects. It is interesting to note that the frequency of escape and defensive responses to threat during times of social conflict was increased in a dose-dependent manner in a much less ambiguous way (). Aggressive and defensive responses are mediated by very different neurological systems. Thus, one possible explanation for the perception that amphetamine leads to aggressive behavior may be a misperception of the nature of aggressive behavior. Caseworkers may be calling “defensive” responses “aggressive” responses.

Chronic Administration

Chronic administration — repeated or regular administration over a certain time period — of a drug can have very different effects when compared with acute administration. This is because neurochemical changes occur in the brain after repeated drug administration. Thus, chronic administration of a drug can lead to behavioral changes even when the user is not actively under the influence of the drug. Acute effects of a drug that has been administered chronically (i.e., when a chronic user stops using for a period of time and then starts again) can also have effects different from acute effects of a drug that has not been administered chronically. This sequence occurs potentially because the drug can alleviate withdrawal.

Tolerance to the antiaggressive effects of amphetamine has been shown with a daily dose of 1.5 mg/kg for 7 days (). Chronic and acute administration of amphetamine led to increases in defensive and escape behaviors, and no statistically significant differences were discovered between one group of mice that had received seven daily injections of amphetamine and another that had received the same dosage of saline ().

Note: By using selective antagonists it has been shown that dopamine receptors of the D2 subtype () are most effective in reducing the increased motor activity brought on by amphetamine intoxication (). This inhibition does not, however, carry over to the disruptive effects on social and aggressive behavior. It would appear that agonism of the D2 receptor is most likely not associated with amphetamine control of aggressive behavior. Other dopamine receptor antagonists such as haloperidol and chlorpromazine have been found to reduce aggressive and social behavior, yet none has reversed the effects of amphetamine on these actions ().