EtOH self-administration in anticipation of noise stress in C57BL/6J mice.

C57BL/6J mice were studied for self-administration of ethanol (EtOH) during a signal period that preceded delivery of an environmental stressor (noise) in the home cage. Animals were given 5 weeks of conditioning in which a 5-min period of 75-dB pulsed noise (SIGNAL) preceded a 20-min period of more intense, 90-dB pulsed noise (NOISE) five times daily. EtOH (10% w/v) was then provided in a choice procedure, and drink tube contacts were monitored by computer. Mice that had received the 5 weeks of SIGNAL and NOISE pairings showed an increase in EtOH-seeking behavior, as reflected in EtOH tube contacts during the SIGNAL period. The increase was significant as compared to contacts during baseline or QUIET periods and also as compared to contacts during the same period for control (Ctrl) mice that had received only the 75-dB SIGNAL during conditioning. A subsequent test for passive avoidance confirmed that the 75-dB SIGNAL was aversive for mice that had received noise conditioning but not for Ctrl mice. In sum, the results were in accord with a priori predictions that mice would not show increased EtOH tube contacts during occurrence of intense noise itself but would show increased contacts during the signal that preceded noise. These results were interpreted as preliminary evidence that C57BL/6J mice show self-administration of EtOH in anticipation of an environmental stressor.

Effects of exercise on ethanol-induced hypothermia and loss of righting response in C57BL/6J mice.

C57BL/6J mice were given 5 weeks of voluntary wheel running and then studied for ethanol (EtOH) sensitivity as indicated by EtOH-induced hypothermia and loss of righting response (LORR) after 3.8 g/kg EtOH (20% w/v). Mice were assigned to wheel (free access to a running wheel in the home cage) or no wheel conditions, and wheel counts were monitored by a computer at 5-min intervals around the clock. In Experiment 1, duration of EtOH-induced LORR was assessed as amount of time required for the animal to right itself three times in a 30-s period, and body temperature was assessed by rectal probe. Wheel animals showed significantly shorter LORR and significantly less hypothermia at regaining the righting response than no wheel controls. In Experiment 2, temperature was assessed at 45 and 90 min after EtOH challenge. Baseline temperatures for wheel and no wheel animals did not differ, but wheel animals showed dramatic resistance to EtOH-induced hypothermia at both time points. Together with our earlier work, these results provide evidence that prior exercise can offset the effects of EtOH intoxication in several domains of EtOH sensitivity.

Voluntary wheel running reduced the effects of acute ethanol on activity and avoidance in C57BL/6J mice.

C57BL/6J mice were given five weeks of voluntary wheel running and then studied for behavioral impairment after an intoxicating dose of ethanol. Forty-four mice, 22 males and 22 females, were assigned to Wheel (free access to a running wheel in the home cage) or No Wheel conditions. At the end of the training period, animals were removed from the exercise cages and tested for noise avoidance after 2.4 g/kg ethanol (EtOH) or physiological saline (Sal). Mice could avoid 87.5-dB noise by entering and remaining in a randomly designated "safe corner." In unexercised animals, EtOH caused a strong suppression of locomotor activity and avoidance behavior: No Wheel EtOH mice differed significantly from No Wheel Sal mice on both measures. In exercised animals, EtOH failed to cause significant suppression: Wheel EtOH animals did not differ significantly from Wheel Sal animals on either measure. The present results suggest that prior exercise training may be effective in offsetting the effects of acute ethanol intoxication.

Amphetamine: differential effects on defensive flight and motor behavior in the rat.

As in previous research, hooded rats treated with an acute high dose of d-amphetamine sulfate (5 mg/kg free base) showed a dramatic defensive flight reaction to a novel stimulus (mechanical robot) that did not elicit flight from saline controls. Both the defense response and stereotypy behavior (repetitive movements and oral, licking chewing) were assessed at eight time periods after injection: 1, 15, 30, 45, 75, 105, 135, and 165 min. The defense response peaked early (15-30 min) after injection and showed a significant decline by 75 min, with no reemergence as stereotypy subsided. Stereotypy peaked later (45 min) and did not decline until 105 min. Tests in the absence of the robot provided a control for motor effects of the drug. Whereas stereotypy occurred in both Robot and No Robot conditions, the defense response occurred only in the Robot condition. These results were thought to provide further evidence that the effects of amphetamine on defensive flight could not be attributed to purely motor reactions. Thus, amphetamine-induced defensive flight may be an appropriate pharmacological model of affective psychosis. As such, it may be helpful in establishing differential pharmacological profiles for affective versus motor potencies of potential antipsychotic compounds.

Chronic amphetamine: effects on defensive flight in the rat.

Hooded rats were injected with physiological saline or d-amphetamine sulfate for 13 days on a schedule designed to mimic patterns of abuse: one injection on days 1-11, two injections on day 12, and three injections on day 13; amphetamine dosage for the first three injections was 3.5 mg/kg and for all subsequent injections was 5.0 mg/kg. Amphetamine-treated rats (Amphet) showed a dramatic flight reaction in response to a novel stimulus (mechanical robot) that did not elicit flight from saline control animals. Tested on a slow-moving treadmill that carried them toward the stimulus, Amphet rats accumulated only 15% of the trial time at the front of the apparatus nearest the stimulus and accumulated approximately 75% of the trial time at the extreme rear of the apparatus, farthest from the stimulus. Control tests of Amphet rats in the absence of the stimulus ruled out interpretations in terms of motor behavior. In fact, a major advantage of the present procedure is that animals are able to execute the relatively simple defense response despite the occurrence of motor stereotypy. These results suggest that the defense-response paradigm is suitable for the study of chronic amphetamine and may provide a useful adjunctive to existing models of amphetamine psychosis.

Amphetamine: effects on defensive flight or avoidance in the rat.

Treatment with a moderately high dose of amphetamine caused rats to retreat from a stimulus they would normally approach and explore (mechanical robot or live white rabbit). While saline-treated rats spent approximately equal amounts of time in the area of the apparatus near the stimulus, amphetamine-treated rats spent a high percentage of trial time in the area of the apparatus farthest from the stimulus. The drug effects were dose related (range: 1.75, 3.5 and 7.0 mg/kg) with higher avoidance time at higher doses, and significant linear trends accounting for much of the variance. The highest dose of amphetamine elicited response stereotypy. However, control conditions ruled out the possibility that the present results could be explained by competing motor responses of stereotypy or increased activity. Thus, apart from its actions on motor behavior, amphetamine treatment resulted in rats avoiding or retreating from an otherwise neutral stimulus.

Physostigmine: effects on fear or defense responses in the rat.

Previous research had shown that the anticholinergic drug, scopolamine, decreased innate defensive responses of rats to a live cat or mechanical robot, and that the effects of scopolamine were attributable to actions of the drug on the central nervous system. In the present research, the anticholinesterase, physostigmine, which increases central cholinergic activity, caused an increase in the defense responses of male hooded rats. Physostigmine caused significantly more freezing and significantly more suppression of feeding and suppression of time near the aversive stimulus (ROBOT). Dose-response curves showed a positive, linear relationship between dose (0.025, 0.05, 0.1 and 0.2 mg/kg) of physostigmine and defense responses. The present results could not be attributed to general response suppression since the effects of physostigmine were situation-specific, i.e., the drug had no significant effect on behavior in the non-aversive or NO ROBOT condition. The present results were taken as further evidence of the involvement of cholinergic activity in the mediation of defense responses. The effects of cholinergic and anticholinergic drugs on the observable defense response of freezing were thought to have important implications for the large literature relating these drugs and avoidance responding.

Scopolamine: effects on fear or defense responses in the rat.

In previous research scopolamine reduced fear or defense responses of rats to a cat, and removal of the rats' olfactory bulbs had the same effect. This suggested that scopolamine might have affected defense responses by blocking olfactory perception of the stimulus cat. The present experiments studied this possibility and explored further the effects of scopolamine on defense responses of the hooded rat. In Experiment 1 rats treated with scopolamine were found to be responsive to olfactory cues from a cat. When cat smell, but not a cat, was present in the apparatus, scopolamine-treated rats showed a large and significant suppression of food consumption. In Experiment 2 the effects of scopolamine on defense responses were shown to be generalizable to an inanimate stimulus, mechanical robot. Scopolamine caused significantly less freezing and avoidance and significantly shorter latencies to drink in the presence of the robot. One of the primary findings of the present research is that scopolamine has now been shown to reduce the defensive response of freezing in a variety of stimulus situations. This finding was thought to have important implications for the literature relating anticholinergic drugs and avoidance behavior.

Comparing the effects of scopolamine on operant and aggressive responses in squirrel monkeys.

The anticholinergic drug, scopolamine, causes disinhibition or an increase in responses that an animal normally suppresses. Experiment 1 confirmed this effect in squirrel monkeys. Experiment 2 explored the implications of drug-produced disinhibition on aggressive interactions. In Experiment 1, scopolamine produced increased unreinforced responding on a DRL schedule and increased responding during unreinforced (Time Out) periods. In contrast, the peripheral control drug, methyl scopolamine, caused decreased responding in both situations. In Experiment 2, social rank and drug treatment interacted. When space was restricted so that the opportunity for social interactions was maximized, scopolamine consistently increased aggressiveness in the dominant monkey and decreased aggressiveness in a submissive monkey. When space was increased so that the opportunity for social interactions was minimized, scopolamine caused decreased aggressive responses in all monkeys. Neither the effective dosage nor the drug's effect on the operant task could be easily generalized to aggressive responses.