ECS-induced Retrograde Amnesia Research Articles

The effect of erythropoietin on electroconvulsive stimulation induced cognitive impairment in rats

Electroconvulsive therapy (ECT) is the most effective and fast-acting treatment for severe depression but associated with troublesome cognitive side-effects. Systemically administered erythropoietin (EPO) crosses the blood-brain-barrier and is a promising treatment for cognitive dysfunction in a wide array of neuropsychiatric and neurological disorders. In this study we trained rats to locate a submerged platform in a water maze and then subjected them to electroconvulsive stimulations (ECS, the rodent equivalent to ECT) and EPO treatment. We then analysed their ability to remember and relearn the location of the platform. In addition, we examined “wall-clinging” (thigmotaxis), a behavioural indicator of stress. ECS caused significant deficit in a probe trial administered after three weeks (nine stimulations) as well as one week (six stimulations) of treatment, indicative of induction of retrograde amnesia. ECS had no effect on relearning of the water maze task or performance in a subsequent probe trial. EPO treatment did not ameliorate the ECS-induced retrograde amnesia, but after nine ECS stimulations the animals that had received EPO relearned the position of the hidden platform faster than the animals that had not. We also found EPO to decrease “wall-clinging” behaviour, suggesting an effect of EPO on the stress response in rats. Thus, we establish the Morris Water Maze as a suitable model for ECS-induced memory loss in rats and provide some evidence for potential beneficial effects of EPO.

Investigation of the possible role of Shankapushpi in the attenuation of ECT induced amnestic deficits

Introduction:Shankapushpi (Evolvulus alsinoides and others) has received mention in traditional Indian writings as a potential enhancer of cognitive functioning. This study used an animal model to examine whether Shankapushpi improves learning and memory and attenuates anterograde and retrograde amnesia associated with electroconvulsive shocks (ECS).Materials and Methods:Adult, male, Sprague Dawley rats (n=64) were treated with an aqueous extract of Shankapushpi or vehicle all through the 13-day study. From Days 1 to 8, the animals received Shankapushpi or vehicle alone. On Days 8–10, the animals were trained in a T-maze. On Day 11, they received two true or sham 30 mC ECS 5 h apart. On Day 12, recall of pre-ECS training was examined, and on Day 13, new learning was assessed.Results:Shankapushpi-treated rats did not show better learning during the pre-ECS phase (Days 8–10). Seizure duration was not influenced by Shankapushpi treatment (Day 11). Shankapushpi did not attenuate ECS-induced retrograde amnesia (Day 12). ECS did not impair new learning, and the effect of Shankapushpi herein, therefore, could not be ascertained (Day 13).Conclusions:In this animal model of learning and memory, and of ECS-induced retrograde amnesia, Shankapushpi was found to have no favorable or unfavorable effects on either cognitive or seizure duration parameters. These findings diminish expectations of cognitive and anticonvulsant benefits of simple Shankapushpi decoctions in clinical settings, but do not preclude benefits with extracts obtained and concentrated by using other methods.

Administration of a selective glucocorticoid antagonist attenuates electroconvulsive shock-induced retrograde amnesia

Mifepristone, a glucocorticoid and progesterone receptor antagonist, has been shown to attenuate retrograde amnesia induced by repeated electroconvulsive shocks (ECS). We examined the efficacy of CORT 108297, a selective glucocorticoid antagonist, in this regard. Adult, male, Wistar rats (n=69) received either vehicle or CORT 108297 (1mg/kg) 2h before each of 5 once-daily true or sham 30mC ECS. Recall of previous exposure to a noxious stimulus in a passive avoidance (step-through) paradigm was tested 1day after the 5-ECS course. Analyses were conducted using recall operationalized in different ways: using the absolute final latency scores; defining adequate recall as a final latency of 30s or greater; defining perfect recall as a final latency of 180s; and using visual, subjective assessments of animal behavior. ECS was associated with significant impairment of recall, and this impairment was significantly attenuated by CORT 108297 on all outcome measures (with the exception of the perfect recall analyses, where outcomes narrowly missed statistical significance). In conclusion, these findings strengthen previous data from our laboratory implicating glucocorticoid mechanisms in ECS-induced retrograde amnesia. We suggest that the administration of a selective glucocorticoid receptor antagonist shortly before electroconvulsive therapy (ECT) treatments may attenuate the deleterious effect of ECT-induced acute hypercortisolemia on neural mechanisms involved in learning and memory.

Celecoxib as an in vivo probe of cyclooxygenase-2 mechanisms underlying retrograde amnesia in an animal model of ECT

Cyclooxygenase-2 (COX-2) mechanisms are involved in glutamate-mediated learning and memory as well as in glutamatergic excitotoxicity. Electroconvulsive therapy (ECT)-induced amnesia may arise from glutamatergic excitotoxicity; if so, COX-2 inhibition may attenuate retrograde amnesia with ECT. Wistar rats which received celecoxib (15 mg/kg per day) or vehicle for 18 days were trained for 3 days on a passive avoidance task. On each of the next 3 days, rats which showed perfect learning (n=51) received true or sham suprathreshold electroconvulsive shocks (ECS; 60 mC) in a factorial design; daily dosing with drug or vehicle was continued. One day after the last ECS, recall of pre-ECS learning was tested. ECS-treated rats showed impaired recall in the vehicle but not celecoxib group. Celecoxib significantly protected against ECS-induced retrograde amnesia; this benefit was independent of the drug-induced attenuation of ECS seizure duration. Celecoxib may protect against ECS-induced retrograde amnesia by attenuating ECS-induced, COX-2-mediated glutamatergic excitotoxicity.

Possible glutamatergic and lipid signalling mechanisms in ECT-induced retrograde amnesia: Experimental evidence for involvement of COX-2, and review of literature

We sought to explore nonselective vs. selective COX mechanisms in ECS-induced retrograde amnesia using indomethacin and celecoxib as in vivo probes. Adult Wistar rats ( n = 72) which showed adequate learning on a passive avoidance task received 5 once-daily 30 mC true or sham ECS. During the learning and ECS periods, indomethacin (4 mg/kg/day), celecoxib (15 mg/kg/day), or vehicle were orally administered. One day after the fifth ECS, recall of pre-ECS learning was tested. There were no baseline or pre-ECS differences in learning between groups. ECS seizure duration did not differ across groups. ECS-treated rats showed impaired recall in the vehicle but not indomethacin and celecoxib groups. Celecoxib but not indomethacin significantly protected against ECS-induced retrograde amnesia. We interpret these results as follows: ECS may impair cognition by pathologically upregulating glutmatergic signalling, thereby causing cation and water influx, oxidative stress, and saturation of hippocampal LTP. These may result from glutamatergic disinhibition through COX-2-mediated removal of endogenous cannabinoids, and by ECS-activated, NMDA-mediated upregulation of platelet activating factor and COX-2 signalling pathways. Thus, indomethacin and celecoxib, by inhibiting COX-2, may protect against ECS-induced amnesia. Furthermore, COX-2 mediated increase in hippocampal kynurenic acid may impair glutamate-dependent learning and memory processes at ionotropic glutamatergic receptor sites; the inhibition of kynurenic acid synthesis by celecoxib and its induction by indomethacin may explain the greater benefits with celecoxib. These findings suggest new avenues for the study of the neurobiology of ECT-induced amnesia and the attenuation thereof.

Anti-amnestic properties of Brahmi and Mandookaparni in a rat model

Background:We had previously demonstrated that a complex herbal formulation (Mentat; Himalaya Drug Company, Bangalore) attenuated anterograde and retrograde amnesia induced by electroconvulsive shocks (ECS) in rats. We later showed that a simplified formulation (Memorin; Phyto Pharma, Kolhapur) had similar effects.Aims:In an attempt to identify the ingredients (of the complex formulation), which purveyed the cognitive benefits, we studied two of the constituent herbs, Brahmi and Mandookaparni, separately and together. The experiments included both active (piracetam) and inactive (vehicle) controls.Methods:Adult, male, Sprague–Dawley rats (n=8 per group) were randomized to receive Brahmi, Mandookaparni, a combination of these two herbs (A300), piracetam, or vehicle from days 1 to 15. On days 11 and 12, the rats were trained in a T-maze using a food-driven paradigm. On days 13 and 14, half the rats in each group received 2 ECS (60 mC charge) per day, 5 hours apart. On day 15, recall of pre-ECS learning was assessed. On day 16, transfer of learning was assessed.Results:None of the active treatments facilitated pre-ECS learning or influenced ECS seizure duration; however, all showed varying but generally favourable profiles in the attenuation of ECS-induced retrograde and anterograde amnesia. The combination of Brahmi and Mandookaparni showed no especial advantage over the individual herbs.Conclusion:Brahmi and Mandookparni do not in themselves improve learning; however, each attenuates the amnestic effects of ECS without showing synergism in this beneficial action. Exercises in research and development are indicated to further investigate the anti-amnestic properties of these herbs, and to identify the specific chemical constituents which have procognitive effects.

Effects of stimulus parameters on seizure duration and ECS-induced retrograde amnesia.

A selected electroconvulsive therapy stimulus dose can result from different combinations of pulse amplitude, pulse width, pulse frequency, and stimulus duration; however, the roles of these stimulus variables in the effects of the overall stimulus dose are not clearly understood. A series of studies on Wistar rats was therefore conducted to assess the effects of different stimulus compositions at constant stimulus charge. In the first two studies, two differently composed 60 mC charge unidirectional electroconvulsive shock (ECS) stimuli were administered once daily for 3 days, while in the third study three differently composed 120 mC charge unidirectional ECS stimuli were administered on a single occasion. At constant charge, a markedly longer stimulus duration was associated with ear burns and an approximately 12.5% longer seizure duration. At constant charge, however, different stimulus compositions were not associated with different degrees of impairment in two passive avoidance models of ECS-induced retrograde amnesia. These preliminary findings have implications for the choice of stimulus settings during dose titration and dose selection procedures. While the findings encourage further investigation, it appears that variations in stimulus duration are biologically significant, but minor variations in other stimulus elements may not influence the effects of electrically induced seizures very much.

Phenylephrine and ECS-induced retrograde amnesia.

Phenylephrine is a nonselective alpha-receptor agonist. This study examined whether the administration of phenylephrine immediately before electroconvulsive shocks (ECS) attenuated ECS-induced retrograde amnesia. Adult male Wistar rats received phenylephrine (0.25 mg/kg i.p.) or saline 3 min before each of three once-daily true or sham ECS. Retention of pre-ECS learning was studied 1 day after the ECS course using a passive avoidance task. Phenylephrine increased seizure duration in ECS-treated rats, and also enhanced recall in both true and sham ECS groups. The latter finding suggests that phenylephrine nonspecifically improves cognitive functions, perhaps through adrenergic mechanisms that improve memory consolidation and storage. Since phenylephrine increases blood pressure, its cognitive effects also weaken the hypothesis that ECT-induced cognitive impairment results from the seizure-related hypertensive surge.

Nitroprusside and ECS-Induced Retrograde Amnesia

Previous research found that the administration of verapamil and felodipine immediately before electroconvulsive shocks (ECS) attenuated ECS-induced retrograde amnesia. This study examined whether sodium nitroprusside, an antihypertensive drug that does not affect calcium channels, has a similar action. Adult male Sprague-Dawley rats received nitroprusside (0.5 mg/kg ip) or saline 3 minutes before each of three once-daily true or sham ECS. Retention of pre-ECS learning was studied 1 day after ECS using a passive avoidance task. Nitroprusside was associated with increased seizure duration in ECS-treated rats, and with enhanced recall in both true and sham ECS groups. The latter finding suggests that nitroprusside nonspecifically improves cognitive functions, and does not support the hypothesis that ECS-induced cognitive impairment is a result of blood-brain barrier breach. Nitric oxide mechanisms may underlie the benefits purveyed by nitroprusside.

Naloxone in the Prevention of the Adverse Cognitive Effects of ECT: A Within-Subject, Placebo Controlled Study

Electroconvulsive therapy (ECT) is a highly effective treatment for major depression, but is also associated with characteristic cognitive side effects. Several reports document that endogenous opioids and their receptors are activated by electroconvulsive shock (ECS) and that naloxone in doses sufficient to block endogenous opioid receptors may reverse ECS-induced retrograde amnesia. This placebo-controlled, randomized, within-patient study was conducted to examine the potential of naloxone, given in doses sufficient to block opioid receptors (high dose), to ameliorate acute anterograde and retrograde memory impairments following ECT. Compared to placebo and low dose naloxone, high dose naloxone administered immediately before ECT resulted in significant reductions in anterograde amnesia, and better performance on an attention task. Both low and high dose naloxone improved verbal fluency. There were no beneficial effects of high dose naloxone on retrograde amnesia, and an indication that high dose naloxone may have worsened retrograde amnesia for shape stimuli. There were no effects of high dose naloxone on seizure duration, vital signs, and subjective side effects. The study is consistent with prior research in which change in behavioral and physiological measures was produced principally by naloxone doses sufficient to block endogenous opioid receptors and offers evidence of the potential for ameliorating some adverse cognitive effects associated with ECT.

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.

The roles of information reactivation and nonassociative arousal in recovery from ECS-induced retrograde amnesia

Restoration of memory by pretest reminder treatments following ECS-induced amnesia in principle could be mediated by nonassociative arousal and/or reactivation of information by the reminder stimuli. In the present research, arousal value of the reminder treatment was largely a function of the novelty of the context in which the reminder cues occurred. After producing ECS-induced amnesia in rats for a signaled passive avoidance task, presentation of the signal outside of the training and test context proved to be an effective reminder cue. However, prereminder familiarization with the reminder location, which was sufficient to reduce exploratory behavior suggestive of a decrease in the arousal value of the context, did not influence recovery from amnesia. These data indicate that reminder treatments are capable of reversing experimental amnesia by initiating further processing of previously acquired information even when the treatment does not produce appreciable arousal.

ECS-induced retrograde amnesia is not due to increased sensitivity to sources of ordinary forgetting

A series of experiments was conducted with rats to determine if the amount of potentially interfering information presented to a rat immediately following training and electroconvulsive shock (ECS) influenced the magnitude of ECS-induced amnesia. Using one-trial passive avoidance, multitrial active avoidance, one-trial active approach, and appetitive delayed alternation tasks, ECS intensity thresholds were established for each task (Experiments 1, 3, 5, and 7, respectively). Then some subjects were exposed to task-irrelevant high environmental stimulation (of low affective value) immediately following ECS of an intensity that was normally just below the amnestic threshold. Simultaneously, other subjects were exposed to sensory isolation immediately following ECS of an intensity that was normally just above the amnestic threshold (Experiments 2, 4, 6, and 7, respectively). The posttraining environment in the absence of ECS had no effect on passive avoidance, a nonsignificant tendency towards an effect on active avoidance and active approach, and a strong effect on delayed alternation. When the posttraining environment did have an effect, high stimulation impaired retention and sensory isolation enhanced retention. In no case was there evidence that retroactive stimulus interference was more than algebraically additive with respect to ECS-induced amnesia.

The effect of somatostatin, its fragments and an analog on electroconvulsive shock-induced amnesia in rats

In the present study the effects of intracerebroventricularly /icv/ administered somatostatin /linear and cyclic/, soma ostatin3–6, somatostatin7–10 and des AA1,2,4,5,12,13 /D-Trp 8/ somatostatin /ODT8-SS/ were investigated on electroconvulsive shock /ECS/-induced retrograde amnesia in rats. The ECS significantly decreased the foot shock-induced avoidance latency, and thus caused retrograde amnesia. Somatostatin /linear and cyclic/ in a dose of 0.6 nM had no action on the ECS-induced retrograde amnesia, while in doses of 3 nM and /cyclic only/ 6 nM it significantly prevented it. Somatostatin3–6, somatostatin7–10 and ODT8-SS in doses of 0.6, 3 and 6 nM had no effect on the ECS-induced amnesia. These results indicate that the whole sequence of the original somatostatin molecule is needed to block the ECS-caused retrograde amnesia.

Intracerebroventricular somatostatin attenuates electroconvulsive shock-induced amnesia in rats

In the present study the effect of intracerebroventricularly (ICV) administered somatostatin on electroconvulsive shock- (ECS) induced retrograde amnesia was investigated in rats. The ECS significantly decreased foot shock-induced avoidance latency. Somatostatin in a dose of 1 μg 4 μl (ICV) had no action on the ECS-induced retrograde amnesia, while in a dose of 4 μg 4 μl it significantly increased the avoidance latency if the treatment was performed immediately, 4 hr, 20 hr or 23 hr after the ECS. The results suggest that ICV administered somatostatin has an antiamnesic effect.

Reduction of ECS-induced retrograde amnesia of passive avoidance conditioning after 5,7-dihydroxytryptamine median raphe nucleus lesion in the rat.

5,7-Dihydroxytryptamine (5,7-DHT), median raphe nucleus (MRN)-lesioned and sham-lesioned rats were submitted to one-trial passive avoidance conditioning followed by electroconvulsive shock (ECS) or sham-ECS. On test session (24 h later) MRN-lesioned rats presented a longer conditioned response and, chiefly, a remarkable reduction of ECS-induced retrograde amnesia in comparison to sham-lesioned animals. This effect appeared unrelated to major changes in spontaneous behavior: on training session MRN-lesioned rats exhibited a faster stepping-down from the platform; their exploratory activity into a novel cage was characterized by a slightly higher initial response; moreover MRN lesion did not significantly effect pain threshold. A reduced brain 5-HT functional activity following MRN lesion was suggested by the study of the hyperactivity syndrome induced by tranylcypromine plus L-tryptophan. Lastly, MRN-lesioned rats showed a significantly lower brain 5-HT steady level without differing from the sham-lesioned ones with respect to turnover rate. The reduction of ECS-induced retrograde amnesia observed in 5,7-DHT, MRN-lesioned rats was considered as due to a lower synaptic availability of 5-HT at the time of ECS administration.

Attenuation of response deficits by electroconvulsive shock

Rats previously exposed to inescapable footshock were inferior to nonshocked rats in acquiring a shock-escape response. In three separate experiments, these response deficits were improved by electroconvulsive shock (ECS) given 1 h prior to testing. Subsequent experiments suggested that this effect cannot be attributed to ECS-induced (1) retrograde amnesia, (2) decreased shock thresholds, or (3) increased general activity.

Biphasic effects of nicotine upon ECS-induced retrograde amnesia in mice.

The effects of nicotine in (a) attenuating the amnesic effect of a post-conditioning electroconvulsive shock (ECS; G), (b) facilitating avoidance-response acquisition by isolation-housed mice (5), and (c) antagonizing the effects of stress effects upon memory (3) have suggested several biochemical substrates for those systems to which these actions relate. One hypothesis that has emerged from these studies is that the increased content of brain 5-hydroxytryptamine (5-HT), decrease in its turnover rate, and increase in its turnover time -as result from ECS (1, 2) can be maximally blocked by nicotine (6) given 45 min. before ECS and augmented when nicotine is administered I5 min. prior to ECS (2). O n the basis of previous behavioral findings I[ was further hypothesized that ECS-induced retrograde amnesia (which has been suggcstcd as being 5-HT-dependent) can be antagonized or potentiated depending upon [he time between nicotine treatment and a postconditioning ECS. Four groups of 30 CF-Is strain mice were given nicotine sulfate (1.0 mg.kg. i.p.) or 0.9% saline in an equivalent volume at either 15 or 45 min. prior to a single passive avoidance conditioning trial (4) followed within 10 sec. by a single transcorneal ECS (20 mA, 400 V, 200 msec.). Previous scudies (1, 2) have established that mice given no training reinforcement did not show acquisition or retention of the avoidance response and that in the absence of post-training ECS there was a high (-90%) incidence of response retention. All mice were tested for retention of the passive avoidance response 24 hr. after the training-ECS sequence. Saline-treated mice did not differ in the incidence of retrograde amnesia as a function of pre-ECS treatment time (x' = 0.11, p > 50); however, 80% of those mice treated with nicotine 45 min. before the training-ECS sequence showed criterion retention of the passive avoidance response, as compared with only 209% of the controls (x2 = 19.28, p < ,001). For the mice given nicotine 15 min. prior to [he training-ECS sequence, the incidence of conditioned response retention (10%) was less than that observed for controls (25%). Thus, the time between the administration of nicotine and ECS treatment after single-trial avoidance conditioning in mice is critical for determining whether the same dose of this drug antagonizes or potentiates the amnesic properties of such treatment. These findings are consistent with previous findings which indicate that the occurrence of rerrograde amnesia by post-training ECS depends upon alterations in cerebral 5-HT content and metabolism (2). The time course of the cerebral aminergic effens of nicotine (3) is consistent with the biphilsic requirements for temporally dependent interanion with the amnesic effect of ECS. REFERENCES 1. ESSMAN, W. B. Electroshock-induced retrograde amnesia and brain serotonin effects of several antidepressant compounds. Psychopharmacologia (Bedin), 1968, 13, 258-266.

Reduction of ECS produced retrograde amnesia by post-trial introduction of strychnine

Strychnine sulfate was used to reduce the amount of retrograde amnesia induced by electroconvulsive shock (ECS). Male Swiss-Webster mice were trained on the step-down passive avoidance task, given ECS and then injected intraperitoneally with either 0.1 mg/kg strychnine or saline. The animals were tested in the apparatus one to twenty-four hours later. Mice given ECS alone displayed partial memory for the training (by responding with longer latencies) if tested within two hours after training, but did not display retention twenty-four hours later. Animals given strychnine following ECS had significantly longer step-down latencies at twenty-four hours than did the saline or no injection controls. Further experiments replicated the basic results, and also showed that strychnine injections delayed two hours after the training trial attenuated ECS-induced retrograde amnesia, but that a three hour injection delay was ineffective. The results were interpreted in terms of changes in short-term and long-term memory.