John P. J. Pinel

Conditioned defensive burying: A new paradigm for the study of anxiolytic agents

Behavioral paradigms that have been designed to mimic forms of learning that are important for the survival of animals in the wild, rather than to minimize the contributions of adaptive predispositions, may prove to be particularly useful for studying the behavioral effects of drugs. In the present experiments, the propensity of rats to bury sources of aversive stimulation was disrupted in a dose-dependent fashion by a single injection of the anxiolytic drug, diazepam. This suggested that the conditioned defensive burying paradigm could prove to be a valuable addition to the paradigms available for studying anxiolytic effects. Supporting this view were two additional observations. First, the relative potencies of diazepam, chlordiazepoxide, and pentobarbital in the burying paradigm compared favorably with their relative potencies in clinical settings. Second, the effects of anxiolytics on conditioned burying appeared to be dissociable from the effects of other drugs that disrupt this behavior.

Experimental epileptogenesis: Kindling-induced epilepsy in rats

Abstract When electrical stimulation is periodically applied to any one of a number of forebrain sites, there is a progressive development and intensification of elicited motor seizures which can culminate in the development of an epileptic syndrome characterized by spontaneously recurring motor seizures; however, spontaneous motor seizures have been observed in relatively few kindled animals. In the present experiment rats received amygdaloid stimulation about 300 times during a 134-day period. The initial development and intensification of elicited clonic motor seizures progressed as others have described it; however, with continued stimulation running fits were eventually elicited in most of the subjects, and seizures with a tonic component were elicited in a few. Spontaneous motor seizures similar to those elicited by stimulation were observed in 16 of the 18 kindled subjects. Thus, rather than being an idiosyncratic response of a few kindled rats, spontaneous motor seizures appear to be a reliable manifestation of long-term amygdaloid kindling.

Postseizure inhibition of kindled seizures

Abstract Rats were kindled until each periodic, bipolar, amygdaloid stimulation reliably elicited and afterdischarge and a generalized motor seizure. The inhibitory effects of one amygdaloid stimulation (antecedent stimulation) on the afterdischarges and motor seizures typically produced by the next (test stimulation) were studied in a series of experiments. Levels of antecedent stimulation which themselves elicited afterdischarges and motor seizures produced marked inhibitory effects which dissipated in approximately 90 min, whereas levels of antecedent stimulation which elicited local afterdischarges but no motor seizures had only mild inhibitory consequences. Regardless of their intensity, stimulations which evoked no epileptic responses themselves did not inhibit the responses to subsequent test stimulations. The inhibitory effect of a series of antecedent stimulations was more complex than that produced by a single stimulation. A series of 19 kindled motor seizures was elicited by amygdaloid stimulations applied at 1.5-h intervals without any indication of inhibitory effects; however, the next day the response to a single amygdaloid stimulation was almost completely suppressed. This marked inhibitory effect dissipated gradually during the next 5 days.

Impaired object recognition memory in rats following ischemia-induced damage to the hippocampus

Transient cerebral ischemia can produce irreversible neuronal damage and permanent learning and memory impairments in humans. This study examined whether ischemia-induced brain damage in rats results in impairments on the delayed nonmatching-to-sample (DNMS) task, a nonspatial recognition task analogous to tests on which amnesic patients display impairments. Male Wistar rats received either sham surgery or 20-min forebrain ischemia induced by bilateral carotid occlusion and hypotension. Four weeks after surgery, ischemic rats were significantly impaired in both learning and performing the DNMS task at retention intervals up to 5 min. Extensive presurgical training did not reduce this impairment. Observable cell loss in ischemic rats was limited to CA1 pyramidal neurons and a subset of cells in the dentate gyrus. The results indicate that ischemic damage to the hippocampus in rats results in recognition memory deficits similar to those produced by ischemic damage in humans.

Backward Conditioning: A Reevaluation of the Empirical Evidence

There is an apparent discrepancy between the widespread view that backward conditioning does not occur and the experimental evidence which suggests that it does. Backward pairing of conditioned and unconditioned stimuli frequently has resulted in effects similar to those produced by forward pairing, and the results of several recent experiments have established that such effects cannot be attributed to factors other than stimulus pairing per se. Surprisingly, even some of the earlier experiments that provided the basis for the current skepticism concerning backward conditioning provide evidence of its existence. The failure to recognize backward conditioning as a legitimate phenomenon seems to reflect theoretical biases rather than a paucity of empirical evidence. Thus backward conditioning and its properties merit renewed interest and rcexamination.

Object-recognition memory is only mildly impaired in rats with lesions of the hippocampus and amygdala

Rats were trained on the nonspatial delayed nonmatching-to-sample task that we recently developed to mimic the task that is commonly used to study amnesia in monkeys. The rats were tested at retention delays of 4, 15, 60, 120, and 600 sec, both before and after surgery. Each experimental rat received bilateral lesions of the hippocampus, amygdala, or both. In comparison to no-surgery control rats, the rats in each of the three experimental groups were significantly and equally impaired only at the 600-sec delay. These findings indicate that neither separate nor combined lesions of the amygdala and hippocampus cause severe object-recognition impairments in pretrained rats.

Electrode placement and kindling-induced experiemental epilepsy

Abstract Electrical stimulation of the amygdala, caudate, hippocampus, or entorhinal cortex two or three times per day led to the development and progressive intensification of elicited motor seizures in rats. After a few hundred stimulations ( X = 348 ) the subjects in all four experimental groups displayed spontaneous motor seizures which continued to recur even after the regimen of stimulation had been curtailed. Although the development of spontaneous interictal discharges at the stimulation site preceded the initial manifestation of spontaneous motor seizures in all rats kindled by amygdaloid or hippocampal stimulation and in a few of the animals kindled through entorhinal electrodes, such discharges were not recorded in the caudate subjects.

Nonrecurring-items delayed nonmatching-to-sample in rats: A new paradigm for testing nonspatial working memory

Rats were trained on a nonrecurring-items delayed nonmatching-to-sample task, using a newly designed apparatus and a training protocol similar to that used in experiments on nonspatial working memory in humans and monkeys. On each trial, the rats were briefly presented with a sample object, which was presented again along with another object after a delay; the rats were rewarded with food if they chose the novel object. New stimuli were used on each trial. With delays of 4 sec between the sample and choice runs, the rats learned the task to 90% accuracy in less than 250 trials. When the delay was subsequently increased to 15, 60, 120, and 600 sec, the rats scored approximately 91%, 81%, 77%, and 57%, respectively. These results establish that rats are capable of excellent performance on a nonspatial working-memory task that is comparable to those commonly used in monkey models of amnesia, and they suggest that the nonrecurring-items delayed nonmatching-to-sample paradigm may prove valuable in modeling brain-damage-produced amnesia in rats.

Changes in emotional behavior produced by long-term amygdala kindling in rats

The effects of long-term amygdala kindling on emotional behavior were investigated. In Experiment 1, rats received 99 basolateral amygdala, central amygdala, or sham stimulations. The rats in both kindled groups displayed more resistance to capture from an open field and more open-arm activity on an elevated plus maze than did the sham control rats. In Experiment 2, rats received either 20, 60, or 100 amygdala stimulations or sham stimulations. Compared to the sham controls, the kindled rats explored less during the first 30s in a novel open field, avoided the central area of the open field, resisted being captured from the open field, and engaged in more open-arm activity on the elevated plus maze. The magnitude of these effects was greatest in the 100-stim rats and least in the 20-stim rats. Together, these results suggest that long-term amygdala kindling in rats is a useful model for studying the emotionality associated with temporal lobe epilepsy.

Disruption of Spatial but Not Object-Recognition Memory by Neurotoxic Lesions of the Dorsal Hippocampus in Rats

Ischemia-induced cell loss in the CA1 region of the dorsal hippocampus results in severe deficits on delayed non-matching-to-sample (DNMS), whereas hippocampectomy produces little or no impairment, suggesting that partial hippocampal damage is more detrimental to DNMS performance than total ablation. To test this hypothesis, rats with or without preoperative DNMS training were given partial cytotoxic lesions of the dorsal hippocampus. When tested, neither group displayed any DNMS deficits despite widespread cell loss in the CA1 and other regions of the dorsal hippocampus. In the final experiments, rats tested previously on DNMS were found to be impaired on the Morris water maze. The finding that partial hippocampal lesions disrupt spatial memory while leaving object-recognition memory intact indicates a specialized role for the hippocampus in mnemonic processes.