Jill Irwin

Deficits of escape performance following catecholamine depletion: Implications for behavioral deficits induced by uncontrollable stress

Following exposure to inescapable shock, mice exhibit deficits of escape performance, which are progressively more pronounced as training continues. Comparable effects were produced by DA and NE depletion by α-MpT and reserpine, NE depletion by FLA-63, and DA receptor blockade through haloperidol. Treatment with PCPA or 5-HTP did not influence performance. The disruptive effects of reserpine and α-MpT, as well as haloperidol and FLA-63, were additive. Unexpectedly, mice that received both reserpine and FLA-63 exhibited escape latencies that were significantly lower than those of mice that received either treatment alone. Consistent with the view that increased DA synthesis in the reserpine plus FLA-63 condition prevented the escape interference, L-DOPA antagonized the effects of both α-MpT and FLA-63. The results suggest that DA and NE act in a serial fashion to produce the escape deficits. Moreover, although both newly synthesized and previously stored amines contribute to the interference, the short latency responses seen during initial test trials could not be ascribed to previously stored amines.

Sensitization of norepinephrine activity following acute and chronic footshock

Acute inescapable shock provokes an increase of norepinephrine (NE) utilization, leading to transient reductions of amine concentrations. In contrast, increased amine levels are evident after chronic shock, apparently because of a compensatory increase in synthesis. In acutely shocked animals subsequent re-exposure to even a limited amount of shock reinduced the NE reduction, whereas in chronically shocked mice a comparable re-exposure stressor increased amine levels and utilization. It is suggested that the mechanisms responsible for the amine release in acutely stressed animals, as well as those mechanisms subserving the increased amine levels evident after chronic stressor application, may be subject to conditioning or sensitization processes.

Central norepinephrine and plasma corticosterone following acute and chronic stressors: influence of social isolation and handling

Exposure to acute inescapable shock resulted in a decline of hypothalamic norepinephrine (NE), and an increase of plasma corticosterone concentrations. With repeated application of the stressor over 15 successive days the reduction of NE was eliminated and concentrations of the amine actually exceeded those of control animals. In contrast to the NE variations, plasma corticosterone concentrations were elevated irrespective of whether mice received a single or repeated sessions of inescapable footshock. Moreover, unlike NE concentrations, handling mice on successive days in the absence of the shock treatment was sufficient to provoke a modest, but reliable increase of corticosterone concentrations. It is suggested that the hypothalamic NE and plasma corticosterone changes may be reflective of different attributes of the stressor or are subserved by different mechanisms. It is suggested that variations in both these systems represent adaptive changes to meet environmental demands.

Differential effects of inescapable shock on escape performance and discrimination learning in a water escape task.

The effects of inescapable shock on subsequent T-maze water escape and position discrimination performance were evaluated in seven experiments. Escapable shock did not disrupt water escape performance; however, escape performance was retarded 24 hr after inescapable shock. These deficits were not apparent if escape was possible upon stress inception; however, pronounced deficits were noted if sustained active responding was necessitated by briefly (3-5 sec) preventing escape. When water escape testing was conducted in relatively warm water (20 degrees C), the disruptive effects of preshock were not apparent. In colder water (15 degrees C), which increases the motor difficulty of the task, the disruptive effects of preshock were noted. When the motor difficulty of the task was increased further, by testing mice in 10 degrees C water, or when the associative difficulty was increased by using a vigorous reversal learning task, the differences between the preshocked and nonpreshocked groups were obviated. Exposure to inescapable shock did not disrupt position discrimination performance regardless of the motor difficulties of the task. Similarly, deficits of discrimination performance were not apparant in mice exposed to inescapable shock even when the associative difficulty of the task was increased by removing intramaze cues or by testing animals in a position discrimination reversal task. It is concluded that inescapable shock results in deficits of response maintenance but probably has a minor, if any, influence on cognitive/associative processes.

Variations of norepinephrine concentrations following chronic stressor application

Exposure to acute uncontrollable footshock increased utilization of central norepinephrine (NE), and in some brain regions, most notably the hypothalamus, a decline in amine concentrations was induced. Utilization of NE was likewise increased in mice exposed to footshock on 14 consecutive days, but the NE reduction was not evident, suggesting that the chronic stressor provoked a compensatory increase of amine synthesis. In mice that were decapitated 24 hr after the chronic shock regimen, NE concentrations exceeded those of nonshocked animals or mice decapitated immediately after the last shock session, possibly reflecting a sustained increase of amine synthesis. The altered NE utilization and concentrations associated with chronic footshock were evident irrespective of whether the stressor was applied on a predictable schedule or on an intermittent basis, although the former treatment was somewhat more effective in increasing concentrations and utilization.

Cross-stressor immunization against the behavioral deficits introduced by uncontrollable shock.

Exposure to inescapable shock disrupted performance in both shock- and water-escape tasks. These deficits were prevented in mice that were previously trained in the same task. However, an asymmetrical immunization effect was seen in a cross-stressor paradigm. Whereas deficits of water-escape performance engendered by inescapable shock were prevented by prior shock-escape training, the deficits of shock-escape performance were not eliminated by prior water-escape training. Evidently, the immunization effect occurs when initial training and subsequent testing are conducted in the same task, or when the initial training and uncontrollable stress session involve the same aversive stimulus. Norepinephrine determinations revealed that reductions of the amine introduced by inescapable shock were unaffected by prior shock-escape training and were enhanced by prior exposure to the stress of water immersion. Thus, although the performance deficit introduced by inescapable shock may be related to variations of norepinephrine, the immunization effect probably was unrelated to alterations of this transmitter. Rather, the data provisionally suggested that the immunization stems from two independent factors: Namely, initially training animals in an active escape task may (a) disrupt subsequent learning that the inescapable stress actually is uncontrollable and (b) limit the influence of the motor deficits introduced by uncontrollable shock on subsequent escape performance.

Alteration of exploration and the response to food associated cues after treatment with pimozide

A series of experiments assessed the effects of pimozide on spontaneous alternation in a Y- and 8-arm radial maze, and on approach to food or cues that had previously been associated with food. Mice treated with pimozide (0.2, 0.4 and 0.8 mg/kg) displayed a dose dependent reduction of alternation performance, without engendering a perseverative tendency and apparently without affecting the course of habituation. When food deprived mice entered an arm of the maze that was baited with a food pellet they consumed the food and remained in the vicinity of the food cup. Moreover, upon retesting in the non-drug state mice still exhibited a preference for cues that had been associated with food. It seems that although pimozide at the doses tested produced a haphazard pattern of exploration, the drug did not alter the rewarding value of secondary reinforcers. Contrary to an anhedonic hypothesis, it is suggested that higher doses of pimozide may actually increase, rather than decrease, the saliency of biologically significant stimuli.

Effects of dopamine receptor blockade on avoidance performance: assessment of effects on cue-shock and response-outcome associations.

Treatment with pimozide, a neuroleptic drug which blocks postsynaptic dopamine receptors, retarded active avoidance performance among naive mice. The performance deficit was eliminated among mice that were previously trained in the avoidance task. Like avoidance training, prior CS-shock pairings enhanced avoidance performance, but this treatment did not reduce the effects of pimozide on later avoidance performance. Likewise, treatment with pimozide prior to CS-shock pairings did not influence the performance enhancements evident in a later nondrug test of avoidance performance. Moreover, the drug did not influence the extinction of avoidance induced by response prevention (flooding). Together, these data suggest that pimozide does not influence S-S associations, but affects avoidance performance by disrupting response initiation processes.

Shock-induced locomotor excitation following acute and chronic amphetamine treatment.

Foot-shock, which ordinarily reduced locomotor activity in mice, enhanced the locomotor excitation produced by d-amphetamine. Moreover, the extent of the foot-shock excitation became progressively more pronounced with successive shock presentations. Although a competitive relationship was demonstrated between the temporal changes in amphetamine-induced locomotor activity and stereotypy. the occurrence of the post-shock excitation was independent of these behaviors. Reduction of norepinephrine and dopamine by pretreatment with α-MpT antagonized the amphetamine effects on all three behaviors. In contrast, reduction of norepinephrine by FLA-63 had no effect on locomotor activity, increased stereotypy to a limited extent, and produced a small but significant decline in the post-shock excitation. Finally, the effects of chronic amphetamine administration on the post-shock excitation paralleled the effects produced by FLA-63, and appeared to be independent of changes in general locomotor activity and stereotypy following chronic exposure to the drug. Results were discussed in terms of the role of norepinephrine and dopamine in mediating these behaviors.

Ontogenetic variations in amphetamine-induced stimulus perseveration.

Ontogenetic variation in amphetamine-induced stimulus perseveration was evaluated in a spontaneous alternation task. Swiss—Webster mice 15–20 days of age exhibited chance-level alternation, whereas 25–30-day-old mice exhibited alternation which exceeded chance. While scopolamine reduced alternation to chance levels, treatment with d-amphetamine produced marked perseverative behavior (i.e., below chance-level alternation). Among 15-day-old animals a lower dose of amphetamine was sufficient to elicit the perseveration. Apparatus preexposure enhanced perseveration among 25- to 30-day-old animals and produced minimal effects among 15- to 20-day-old mice. These results were discussed in terms of the involvement of cholinergic mechanisms in modifying the amphetamine-induced perseveration, as well as developmental factors which determine the perseverative response.