J. Suresh Chandra

Effect of innate direction bias on T-maze learning in rats: implications for research.

Adult, male Wistar rats showed substantial left (22.2%) or right (52.8%) bias in spontaneous arm preference in the T-maze; this bias was consistent over 2 days of testing separated by a 30 day interval. Left and right biased rats learnt very rapidly when trained to enter the arm ipsilateral to the bias; learning was significantly poorer or did not occur in the contralateral arm. This contralateral learning difficulty was particularly evident when transfer of learning was assessed. Right-biased rats were more impaired in contralateral learning than left-biased rats. Unbiased rats (25%) also showed learning difficulties. This study has important implications for spatial tasks of learning and memory; with specific reference to the T maze, it is concluded that animals should be preselected for capacity to learn in both arms, randomization into experimental and control groups should be stratified for spontaneous arm bias, and original learning should be directed towards the contralateral arm while transfer of learning, if required, can be directed into the ipsilateral arm.

Effects of pulse amplitude, pulse frequency, and stimulus duration on seizure threshold: a laboratory investigation.

Background Stimulus intensity during electroconvulsive therapy (ECT) is reckoned in units of charge (mC). The values of pulse amplitude, pulse width, pulse frequency, and stimulus duration can be varied to yield different composite stimuli, all of which have the same charge. There is little information on the extent to which variations in these stimulus parameters influence the seizure threshold at constant charge in the context of ECT. Methods We administered once daily electroconvulsive shocks (ECS) to two groups of rats, starting with a stimulus intensity of 1 mC and increasing in 1 mC steps until the thresholds of each of three different types of seizure were identified. In one group (n = 10), the charge was raised first by increasing pulse amplitude and later by increasing pulse frequency. In the other group (n = 10), the charge was raised by increasing the stimulus duration only. Results The mean seizure threshold ranged from 8.4 to 11.4 mC, depending on the type of seizure described, in the group in which pulse amplitude and frequency were manipulated; this range was 2.5 to 5.5 mC in the group in which the stimulus duration was manipulated (p < 0.001 for each of three types of seizures). Rats (n = 7) that did not convulse with an 8-mC stimulus in the amplitude and frequency group all convulsed with a 5-mC stimulus from the stimulus duration schedule. The first manifestation of seizure activity was significantly less likely to be generalized with amplitude and frequency titration than with stimulus duration titration (20% vs. 90%, respectively). The mean motor seizure durations (at different thresholds) were comparable with the two methods of stimulus titration. Conclusions Seizure thresholds are lower when stimulus duration is the parameter that is increased during dose titration. The many clinical implications of this finding require study.

Effect of stimulus intensity and number of treatments on ECS-related seizure duration and retrograde amnesia in rats.

Background Animal models are frequently used to generate and test hypotheses about amnesia resulting from electroconvulsive therapy (ECT). Although many predictors of ECT-induced amnesia are known, their relative effects have been inadequately researched in the context of the animal models. Objective We sought to determine the relative retrograde amnestic effects of electroconvulsive shock (ECS) stimulus intensity (dose) and number on strong memories in rats. We also sought to identify dose-dependent ceiling amnestic effects, if any. Methods Adult rats (n = 144) were overtrained in a passive avoidance task using a step down apparatus. The rats were then randomized in a factorial design to receive one, two, or three once-daily bilateral ECS at 0-mC (sham ECS), 30-mC, 60-mC, 120-mC, or 180-mC doses. Recall of the pre-ECS training was assessed 1 day after the last ECS. Results Retrograde amnesia was observed only in rats that received 3 ECS; dose-dependent amnestic effects did not emerge. Higher stimulus intensity was associated with a small (13%) but significant increase in motor seizure duration, but only at the first ECS; stimulus intensity did not influence the attenuation of seizure duration across repeated occasions of ECS. Conclusion With bilateral ECS, the number of ECSs administered is a more important variable than the ECS dose in weakening a strong, recently acquired, noxious memory; this finding may have important clinical implications. Higher stimulus intensity marginally increases motor seizure duration at the first ECS but does not influence the decrease in seizure duration across repeated ECSs.

Attenuation of ECS-induced retrograde amnesia by using an herbal formulation.

Earlier research indicated the efficacy of a complex herbal formulation in the attenuation of electroconvulsive shock (ECS)-induced amnestic deficits in rats; this study sought to ascertain whether a simplified herbal formulation (Memorin; Phyto-Pharma, India) also was effective. Rats pretreated for a fortnight with Memorin (200 mg/kg/day) or vehicle were exposed to a passive-avoidance learning paradigm in a shuttle box. The next day, the rats were administered two true or sham ECSs, 5 h apart; recall of the pre-ECS learning was reassessed on the following day. ECS was found to produce significant retrograde amnesia (p < 0.002). Memorin attenuated the ECS-induced amnesia (p=0.00003) without influencing the ECS seizure duration. The clinical implications of these findings are discussed.

BR-16A restricts development of electroconvulsive shock-induced retrograde amnesia

Forty nine adult male Sprague Dawley rats were selected for rapid learning in a T-maze to study the effects of BR-16A, a herbal preparation on ECS-induced retrograde amnesia. Half the rats received 200 mg/kg BR-16A and the other half received vehicle alone. The rats were trained to run into the enclosed chamber of either the left or the right arm on a T-maze; a food pellet served as a reward in the correct arm. Satisfactory learning was defined as 9 correct arm entries over 10 consecutive trials on the maze. On the 5 th day, the rats in both the groups were randomised to receive true or sham ECS. The post-ECS data revealed that the number of trials to satisfactory learning and the number of trials with wrong arm entries were large in the ECS-vehicle group, which suggests that BR-16A prevented the development of amnesia. Cholinergic facilitation may be involved, as evidenced by the reversal of scopolamine-induced amnesia and it may also influence opioid neurotransmission. Since ECT-induced retrograde amnesia is a particularly distressing adverse consequence of the treatment, it is hoped that BR-16A will offer a viable solution to the problem of memory deficits following ECT.

Spectral EEG effects of electroconvulsive shock stimulus parameters: the development of a rationale for the optimization of the ECT stimulus.

Background Electroconvulsive therapy (ECT) stimulus parameters, such as pulse amplitude, pulse width, pulse frequency, and stimulus duration, differently influence seizure threshold and, possibly, other neurobiological effects of ECT. We examined the influence of these parameters on the EEG power spectrum in an animal model. Methods Adult, male, Wistar rats (n = 54) were randomized to receive one of five differently constituted (approximately) 30-mC electroconvulsive shock (ECS) stimuli administered once on alternate days for a total of three ECS. A single-lead, unipolar EEG recording was obtained before, during, and immediately after each ECS seizure. EEG power was computed in eight frequency bands from 2 to 40 Hz. Greater ictal EEG power, greater postictal EEG suppression, and greater interictal EEG power, especially in lower frequency bands, were a priori defined as proxies of seizure efficacy. Results Motor and EEG seizure duration and a proxy for seizure generalization did not differ significantly across the five stimulus groups. Despite equivalent charge, the five stimuli varied widely in their effects on the EEG proxies of seizure efficacy. The narrow (0.6 milliseconds) pulse width, high (100 Hz) pulse frequency combination was best associated with EEG proxies of seizure efficacy; with this combination, a longer stimulus train duration appeared superior to a greater pulse amplitude. The wide (2 milliseconds) pulse and low (30 Hz) frequency combination was least associated with EEG proxies of efficacy. Stimulus “on” time, number of pulses delivered, and the rate of delivery of charge were not associated with the EEG proxies; the former finding questions the validity of dosing ECT in units of charge. Conclusions These findings suggest a rationale for optimizing stimulus parameter choices during ECT and provide a framework for the evaluation of electrical aspects of the ECT stimulus.

High but not low ECS stimulus intensity augments apomorphine-stimulated dopamine postsynaptic receptor functioning in rats

Background Clinical research shows that the antidepressant and cognitive adverse effects of electroconvulsive therapy are both dependent on the administered electrical stimulus intensity (dose); however, dose-dependent neurotransmitter system changes in the brain, which might underlie the therapeutic or adverse effects, remain to be demonstrated. Objective We used a behavioral model to examine dose-related effects of electroconvulsive shock (ECS) on dopamine postsynaptic receptor functioning in the rat brain. Methods In a factorially designed study, rats (n = 100) were treated with five once-daily ECSs at three levels (sham ECS, 30 mC ECS, and 120 mC ECS), and with drug at two levels (saline, and 1 mg/kg s.c. apomorphine). Motility was assessed in the small open field. Results Apomorphine-elicited, dopamine postsynaptic receptor-mediated hypermotility was significantly increased by 120 mC ECS but not by 30 mC ECS. An additional but unrelated finding was that, while the ECS seizure duration expectedly decreased across time, no dose-dependent effects were observed. Conclusion ECS-induced dopamine postsynaptic receptor up-regulation may depend on the intensity of the administered electrical stimulus.

Confirmation of whole-brain kindling with repeated subthreshold electroconvulsive shocks: a controlled study.

Background Repeated, subconvulsive electroconvulsive shock (ECS) stimuli, administered a day apart, lower the ECS seizure threshold in rats. It is not known, however, whether this kindling results from the repeated subconvulsive stimulation or from the stress induced by the experimental procedures. Materials and Methods Adult, male Wistar rats were randomized to receive a 3-mC ECS stimulus (n = 20), a 30-V (0.3-s) footpad shock (n = 20), or sham ECS and sham footpad shock (n = 20). All procedures were conducted once daily for 3 consecutive days. On the fourth day, all rats received a 3-mC ECS stimulus. Results At the end of the experiment, 85% of the rats in the ECS group but only 35% of the rats in each of the other two groups had experienced a seizure with the 3-mC stimulus (p < 0.001). Conclusion The lowering of the ECS seizure threshold by repeated, once-daily subconvulsive stimuli is caused by the subconvulsive stimulation itself, not by experimental stress.