Lawrence S. Sklar

Effect of inescapable shock on subsequent escape performance: catecholaminergic and cholinergic mediation of response initiation and maintenance.

Following exposure to inescapable shock, subsequent escape performance is disrupted if the task is one in which animals receive forced exposure to shock for several seconds before escape is possible. The extent of the deficit is directly related to the severity of the initial stress and the duration of escape delay used during test. Treatment with a tyrosine hydroxylase inhibitor, α-methyl-p-tyrosine (α-MpT), a dopamine-β-hydroxylase inhibitor, FLA-63, or dopamine antagonists, haloperidol, and pimozide, mimicked the effects of inescapable shock in the different escape paradigms. The effects of haloperidol were antagonized by treatment with scopolamine. As observed in the case of inescapable shock, prior escape training abated the disruptive effects of the drug treatments. Finally, decreasing or blocking catecholamine activity or increasing cholinergic activity exacerbated the effect of a moderate amount of inescapable shock on subsequent escape performance. These treatments also induced reductions in shock-elicited activity. Conversely, treatment with a catecholamine stimulant, l-dopa, or a cholinergic blocker, scopolamine, anatagonized the reduction in shock-elicited activity and the escape deficits engendered by prior inescapable shock. It was hypothesized that both DA and NE, as well as ACh, are involved in the escape deficit observed after inescapable shock, and that these transmitters mediate the interference by their influence on response initiation and maintenance, rather than on associative or cognitive processes.

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.

Escape deficits induced by uncontrollable stress: Antagonism by dopamine and norepinephrine agonists

Exposure to inescapable shock was found to retard escape performance of Swiss-Webster mice tested 24 hr later in a modified shuttle task. In accordance with the view that depletion of norepinephrine and dopamine contribute to this effect, the dopamine receptor agonist, apomorphine, and the norepinephrine receptor agonist, clonidine, antagonized the performance disruption. This was the case regardless of whether the drugs were administered prior to inescapable shock or prior to test. These drug effects could neither be attributed to state-dependent effects nor to residual drug action. The data support the contention that the disruption of escape behavior after inescapable shock is due to deficits of response maintenance mediated by dopamine and norepinephrine depletion, rather than to learned helplessness.

Noradrenergic and dopaminergic interactions in escape behavior: Analysis of uncontrollable stress effects

The effects of norepinephrine receptor blockade on the deficits of escape behavior induced by haloperidol and by inescapable shock were evaluated. Phenoxybenzamine, the α-norepinephrine receptor blocker, was found to enhance escape behavior and to eliminate the disruptive effects of both inescapable shock and haloperidol. In contrast, the β-norepinephrine receptor antagonist, propranolol, was without effect on behavior under any of these conditions, while the dopamine-β-hydroxylase inhibitor, FLA-63, disrupted performance. Like phenoxybenzamine, the norepinephrine receptor stimulant, clonidine, was found to eliminate the behavioral disruption produced by haloperidol. These somewhat paradoxical findings were discussed in terms of the contribution of DA-NE interactions in determining behavioral change in aversive paradigms.

Cholinergic influences on escape deficits produced by uncontrollable stress

A series of experiments assessed the potential role of acetylcholine (ACh) in the escape interference produced by inescapable shock. Treatment with the anticholinesterase, physostigmine, succesfully mimicked the effects of inescapable shock. That is, the drug disrupted performance when escape was prevented for 6 s on any given trial, thereby necessitating sustained active responding. When escape was possible upon shock onset, the drug treatment did not influence performance. The centrally acting anticholinergic scopolamine hydrobromide antagonized the effects of physostigmine, and when administered prior to escape testing antagonized the disruptive effects of previously administered inescapable shock. In contrast, the peripherally acting agent scopolamine methylbromide did not influence the effects of these treatments, suggesting that the effects of physostigmine and inescapable shock involved central ACh changes. Scopolamine hydrobromide administered prior to inescapable shock did not prevent the escape interference from subsequently appearing, but this effect could not be attributed to state dependence. It was argued that the interference of escape following uncontrollable stress was due to nonassociative motor deficits. Alterations of the escape deficits by scopolamine were due to elimination of the motor disruption.

Social housing conditions influence escape deficits produced by uncontrollable stress: Assessment of the contribution of norepinephrine

A series of experiments assessed the effects of uncontrollable stress on escape behavior and on levels of brain dopamine (DA) and norepinephrine (NE) among mice housed in social isolation or in groups. Exposure to 60 inescapable foot-shocks markedly disrupted escape performance. The magnitude of the deficits was more pronounced among mice housed individually than in mice that had been group-housed. Moreover, the progressively greater escape deficits seen over the 168-hr period following the initial stress appeared to be due to the interaction between shock treatment and isolation. Exposure to 60 inescapable shocks resulted in hypothalamic and hippocampal NE depletion, regardless of housing condition. Exposure to 30 shocks resulted in NE depletion in isolated but not group-housed mice. Although the NE depletion produced by 60 shocks was transient, reexposure to 10 shocks 24 hr later reinduced the depletion. Such an effect was independent of housing condition but absolute levels of NE were lower in isolated than group-housed mice. The behavioral deficits induced by uncontrollable stress were discussed in terms of the contribution of catecholamine changes induced by stress.

Adaptation to the tumor-enhancing effects of stress

&NA; Growth of P815 mastocytoma in syngeneic DBA/2J male mice was evaluated following several stress regimens. Although escapable shock did not enhance tumor growth, an equivalent amount of inescapable shock applied in a yoked paradigm markedly augmented tumor development. If mice received repeated stress sessions on 5‐10 consecutive following tumor cell transplantation, the tumor‐enhancing effects of an acute session were abrogated. This effect was not due to an antitumor effect exerted by a shock session applied several days after cell transplantation. It seems that the tumorigenic effects of stress are subject to adaptation since stress exposure prior to cell transplantation also inhibited the effects of an acute stress session. The data were discussed in relation to stress‐induced neurochemical alterations.

The Influence of Stressors on the Progression of Neoplastic Change

It has long been considered that life stressors may have a considerable impact on an individual’s physical well being. To a great extent, this supposition has been based on anecdotal reports that traumatic events or affective changes are frequently associated with illness. Despite its intuitive appeal, experimental data consistent with this position have only recently become available. However, at present, limited information is available concerning the mechanisms subserving the relationship between stressful events and pathology. Evidence from both human and infrahuman research suggests that stressful events may have a profound impact on central neurochemical processes, immune functioning, and the progress of tumor development. The present report will provide a brief review of this literature, with particular emphasis devoted to some of the limiting conditions which influence vulnerability to central neurochemical alterations, immunocompetence and tumor development.