Amphetamine, conditioned stimulus, and nondebilitating preshock effects on activity and avoidance: further evidence for interactions between associative and nonassociative changes.

A literature survey and preliminary experiments with rats on the consequences of shock preexposure on subsequent activity and escape or avoidance showed the need for further work on the interactions between nondebilitating preshock and various test and treatment factors. The two main experiments used 16 preexposure conditions, namely, presence or absence of unavoidable punishment (36 shocks of 2.5 mA and 5 sec subdivided in three daily sessions), a light CS, a central partition in the shuttle-box, and dl-amphetamine sulfate (1 mg/kg ip 15 min before each session). In both experiments the four factors studied exerted more than additive effects on activity in preexposure sessions, leading to a very high frequency of crossing in the CS-shock-no-partition-drug condition. Upon retesting for activity (Experiment 1) suppression of locomotion by prior shock was less marked in animals preexposed to CS-US pairings in the absence of partition, while proactive amphetamine effects consisted mainly of a progressive increase of activity over successive retest sessions in the groups not preshocked. Upon retesting for light-cued, two-way avoidance acquisition (Experiment 2) the groups preexposed to US only were mostly retarded, while those preexposed to paired CS and US were mostly facilitated. Other changes, including drug pretreatment consequences, were negligible or unsystematic, but in general the data showed that the effects of various preexposure conditions on activity could not account for those on avoidance. Overall, it appears that the interactions between nondebilitating preshock and other test and treatment factors can be further exploited to clarify the respective roles of various associative and nonassociative mechanisms in modulation of activity and adaptive responding in aversive situations.

Scopolamine and acquisition of go-no go avoidance: a further analysis of the perseverative antimuscarinic deficit.

Rats treated with scopolamine (0.5 mg/kg SC daily) during the acquisition of a discrimination task with symmetrical negative reinforcement (light-go, noise/light-no go) showed a learning impairment, with both active and passive avoidance deficits. In the initial stage of such training, however, fewer passive avoidance errors and more active avoidance errors were made by treated animals if active avoidance pretraining had occurred in the no-drug state. A similar experiment using the same stimulus arrangement with asymmetrical reinforcement (no punishment of intertrial, and no go signal, responses) showed a scopolamine effect consisting mainly of increased responding to extinction signals and during intertrial intervals, with little or no active avoidance deficit. Furthermore, interactions due to changes in treatment conditions in successive stages of training were minimized in the latter task, suggesting that the effects of the shift-no shift factor on distribution of errors in the early stages of active-passive avoidance learning were unlikely to have been due to a genuine drug dissociation. Overall, these results and others obtained previously in the same and related tasks tend to rule out some unidimensional explanations of antimuscarinic effects, e.g., response disinhibition (an exclusively motor deficit) or impairment of stimulus sensitivity (an exclusively sensory deficit). The data rather confirm the notion of a sensorimotor drug bias leading to a shift in response prepotencies depending jointly on stimuli, responses, and response consequences. Prior learning history and behavioural compensation for adverse treatment consequences at the reinforcement level may interact with the sensorimotor bias so as to produce "set perseveration" (perseveration of response tendencies).

Behaviorally augmented tolerance during chronic cholinesterase reduction by paraoxon.

Repeated injection of paraoxon to pretrained rats 2 hr before avoidance sessions, at a dose causing considerable intoxication symptoms and reduction of brain acetylcholinesterase (0.125 mg/kg SC daily), induced marked performance depression followed by progressive development of tolerance. Additional groups treated either after each session (i.e., 23.5 hr before each subsequent session), or treated and not tested, showed a substantial depression when shifted to treatment 2 hr before sessions after achievement of tolerance by the animals tested from the beginning of the experiment at the time of maximal paraoxon effect. This indicates that chronic paraoxon tolerance cannot be ascribed entirely to metabolic and/or physiological changes occurring as a consequence of repeated treatment per se, but must be explained at least in part by postulating a behaviorally augmented (or "learned") component. In an additional experiment chronic paraoxon animals (0.1 mg/kg SC daily) were indistinguishable from control rats with respect to acquisition of light/go, noise-light/no go discrimination, i.e., of an active-passive avoidance task known to be highly sensitive to the disrupting (response-disinhibiting) effect of antimuscarinics. Therefore, the enhanced sensitivity to antimuscarinics in organophosphate tolerant rats, which is usually ascribed to cholinergic receptor changes, does not appear to be associated with a spontaneous "antimuscarinic-like" syndrome.

Test factors affecting the time course of avoidance depression after DFP and paraoxon.

The time course of avoidance depression induced by DFP and Paraoxon in rats was measured in four experiments using sublethal doses which induced approximately equivalent changes at the time for maximal behavioral depression (3 hr after 1.1 mg/kg DPF or 0.25 mg/kg Paraoxon SC). The trends obtained with pretrained animals intoxicated for the first time, and not tested during the period between treatment and testing at any given interval (3, 8, 13, 18, and 24 hr after injection), served as baselines to assess (1) proactive consequences of one or more avoidance sessions on subsequent measurements, and (2) sensitivity changes upon repetition of treatment with the same or the other agent after a 5-week resting period. The changes in the time course of avoidance depression due to these factors were generally unimpressive. Some of the interactions observe, however, provided direct or indirect evidence (1) for an enhanced residual depression at long post-treatment intervals upon repetition of organophosphate intoxication; (2) for a proactive impairing effect sometimes appearing after behavioral testing at the time of maximal depression (3 hr), when total or near-total avoidance failure causes extensive exposure to shock; and (3) for a proactive facilitating effect sometimes appearing after testing at a time of moderate avoidance impairment (8 hr), which may be ascribed to behaviorally augmented tolerance ("learned" tolerance).