The effect of para-chlorophenylalanine and scopolamine on passive avoidance in chicks

Four-day-old Vantress x Arbor Acre chicks were treated for key-peck passive avoidance (PA) learning following intraperitoneal injections of parachlorophenylalanine (PCPA) and/or scopolamine. In Experiment 1, chicks were pre-treated with either three or five injections of PCPA (150 mg/kg) or saline across th first three posthatch days and then tested for PA learning on the fourth posthatch day. In Experiment 2, chicks were first pre-treated with three injections of PCPA (150 mg/kg) or saline, and then injected with either scopolamine (0.5 mg/kg) or saline 20 min prior to PA testing on the fourth posthatch day. Major findings were: (a) Chicks pre-treated with PCPA did not significantly differ from saline control chicks in either the acquisition or maintenance of response suppression during PA testing; (b) chicks injected with scopolamine were significantly disrupted in PA learning as compared to saline control chicks; and (c) PCPA pre-treatment did not significantly affect the scopolamine-induced disruption of PA learning. These findings, therefore, suggest that cholinergic, but not serotonergic, mechanisms are involved in PA learning of the young chick.     

Impaired performance by post-trial injections of cycloheximide in a passive avoidance task

Summary Cycloheximide, injected subcutaneously after training in a passive avoidance task resulted in impaired performances on the retest given 7 days later. A gradient was observed for this effect, injections given immediately after training producing most impairment and injections given 2 h after training producing none.This research was supported by USPHS Research Grant MH 05319, 5T1 MH 6418, MH 01225, and MH 12773 and Career Development Award K3 MH 18232.     

Double dissociation between the effects of muscarinic antagonists and benzodiazepine receptor agonists on the acquisition and retention of passive avoidance

Both muscarinic antagonists, such as scopolamine, and benzodiazepine receptor (BZR) agonists, such as diazepam, produce a reliable impairment in the performance of one trial passive avoidance. Such deficits are frequently interpreted as drug-induced amnesia. However, these deficits could also result from a learning impairment. The present experiments compared the effects of two BZR agonists, lorazepam (0, 0.125, 0.25, and 0.375 mg/kg, IP) and diazepam (0, 0.78, 1.56, and 3.13 mg/kg, IP) with the effects of two muscarinic antagonists, scopolamine (0, 0.6, 0.8 and 1.0 mg/kg, SC) and atropine (0, 15, 30 and 60 mg/kg, IP) on a multiple trial passive avoidance task. In this procedure, the rats were trained with a 5-min inter-trial interval until a learning criterion was achieved. Retention was assessed 24 h later. This enabled the effects of the drugs on the acquisition and the retention of a passive avoidance response to be dissociated. Both atropine and scopolamine produced a marked impairment in the acquisition of the passive avoidance response, but did not impair retention. In contrast, diazepam and lorazepam did not alter the acquisition of a passive avoidance response, but did produce a dose-dependent impairment of retention. These results therefore demonstrate a double dissociation between the effects of muscarinic antagonists and BZR agonists on the acquisition and retention of passive avoidance.     

Effects of chlordiazepoxide on passive avoidance responses in rats

The effect of chlordiazepoxide on the retention of a passive avoidance response was determined in rats. Chlordiazepoxide or saline was given before testing in a two compartment passive avoidance response (PAR) apparatus or in an open field, and again after 48 and 72 h.The PAR was usually depressed by chlordiazepoxide (CDP) given during acquisition, and it remained present after 48 and 72 h. Treatment with chlordiazepoxide before the second and third testing abolished the depression of PAR. CDP had most effect on the acquired PAR.Shock treatment resulted in an increase in defecation and urination and a decrease in ambulation and rearing in the PAR apparatus as well as in the open field. These effects were reduced by CDP, irrespective of drug-state changes. A clear-cut reduction in defecation and urination under CDP in well-habituated home cages was also seen. The depressant effect of CDP upon the PAR is discussed in relation to the drug's inhibitory action upon the hippocampal theta activity.     

The effects of chlorpromazine on one-trial passive avoidance learning in mice: Further examination of pre- and post-learning administration

Chlorpromazine in doses of 0.5 mg/kg was administered to mice 0.5, 2, or 10 min after a one-trial passive avoidance learning experience. The drug produced effects on the magnitude and rate of extinction of the learned response dependent upon the injection, time, confirming results contained in an earlier report. In a second experiment with doses of 2.0 mg/kg, the effects of further injecion times were investigated. The drug had no effect when given 240 min before learning, but produced maximal blocking of response acquisition when given 120 and 8 min before learning. Drug injections 6 and 3 min before learning were suggested as having actions on post-learning memory traces. A distinction was noted between the effects of drug injections 1 and 1.5 min after learning and this was related to an effect on a rapidly decaying short-term memory trace. Chlorpromazine had no effect when given 20 min after learning.     

Cycloheximide and passive avoidance memory in mice: Time-response,dose-response and short-term memory

The greatest loss of memory shown by mice 24 hr after learning was found to occur with cycloheximide (CXM) (120 mg/kg) administered subcutaneously 30 min before training. With injection at this time the extent of the amnesia was done dependent (30–150 mg/kg) and the resultant amnesia was found to be relatively constant when tested at 1, 7 or 14 days. An attempt was made to follow the development of this amnesia with 100 and 120 mg/kg CXM. However, the saline controls showed an unexpectedly low avoidance 6 hr after training. This was interpreted as a possible interaction between the stress of the injection and the 6 hr interval. An experiment designed to test this possibility showed that mice injected with 0.1 ml of 1% lignocaine gave high avoidance at 6 hr but mice receiving only a needle puncture of the skin gave performances similar to mice receiving saline injections. It was felt that these findings cast doubt on the usefulness of the passive avoidance task in the assessment of drug action on short term memory.     

Disruptive effects of epinephrine on active avoidance behavior: alteration by scopolamine and d-amphetamine

Following intraperitoneal (ip) injection of either epinephrine (0.25 mg/kg) or saline, rats received treatment with either scopolamine (0.5 mg/kg), d-amphetamine (0.5 mg/kg) or saline, and they were subsequently tested in an open field activity task as well as in a shock motivated situation. Epinephrine effectively decreased both activity levels and avoidance behavior. Treatment with either scopolamine or d-amphetamine eliminated the disruptive effects of epinephrine in the avoidance task, but had negligible effects upon general activity in the absence of the drug treatment. Results were interpreted in terms of inhibitory properties of epinephrine and response disinhibitory effects of scopolamine and d-amphetamine.     

Effects of chlorpromazine and homofenazine upon a passive avoidance response in rats

Summary Both chlorpromazine and homofenazine at 2 mg/kg, i.p. were found to inhibit the rats' passive avoidance response in a two-compartment apparatus when the animals were given five electric shocks in the small compartment before testing. The same effect was reduced when they were given 10 shocks. The results could not be explained by such factors as sensory deficit, locomotor inhibition, drug-learning dissociation and loss of attention due to the drug injection.     

Effects of alpha methyl-para-tyrosine on the recall of a passive avoidance response.

Treatment with alpha methyl-para-tyrosine 4 hr before training on a passive avoidance task altered recall in mice tested 24 hr after training. The observed alterations were dependent on the intensity of the footshock used during training. Retention of the avoidance habit was reduced by drug treatment when a footshock of 1.6 milliamperes (mA) was employed, while retention by drug-treated mice was enhanced when a footshock of 0.16 mA was used. No significant differences in retention were noted when a footshock of 0.8 mA or no footshock was employed. These results could not be explained on the basis of drug-induced changes in activity or sensitivity to footshock, of to state-dependent learning.     

Permanent facilitation of avoidance behavior by d-amphetamine and scopolamine

Scopolamine (0.3, 0.6, 1.2, 2.4, 4.8 mg/kg) or d-amphetamine (0.25, 0.50, 1.00, 2.00, 4.00 mg/kg) was administered daily to independent groups of rats 30 min prior to training in a discriminated, Y-maze avoidance task. A dose-dependent relationship was found between amount of avoidance facilitation and drug dosage. Discontinuation of the drug following asymptotic performance resulted in a decrement in avoidance which varied as a function of the acquisition dosage. Results from a second experiment using the same task indicated that gradually reducing the dosage on consecutive training days rather than abruptly discontinuing the drug was more effective in producing permanent avoidance facilitation in the non-drug condition.     

Effects of scopolamine on shuttle-box avoidance and go-no go discrimination: Response-stimulus relationships,pretreatment baselines,and repeated exposure to drug

Summary The effects of scopolamine on shuttle-box avoidance and go-no go discrimination in pretrained rats have been shown to vary as a function of performance baselines, of response-CS (or response-S⁺) relationships, and of previous experience in the drug condition. Scopolamine induced a slight depression of active avoidance responding in rats with high baselines when the CS was terminated by the response, while a significantly greater depression was observed when a CS of fixed duration was not immediately terminated by the response. Animals with low baselines were significantly facilitated by the drug when the CS was terminated by the response, but not when it had a fixed duration.As concerns go-no go discrimination, the overall impairment of performance provoked by scopolamine was about the same with a fixed or a variable duration of the S⁺. However, the impairment consisted entirely of an increase of errors of commission (punished crossing responses to S^–) when the S⁺ was terminated by the response. Both errors of commission and errors of omission (absence of response to S⁺) increased after treatment when the S⁺ had a fixed duration.The differences between the two groups of animals increased with repeated exposure to drug. In the group performing with an S⁺ of fixed duration the suppression of responses to S^– was often accompanied by a further marked increase of errors of omission. With repeated exposure most animals gradually compensated for the performance deficit induced by scopolamine in the go-no go situation. Repeated testing in the drug condition was shown to be necessary to obtain this desensitization, since neither overlearning per se, nor overlearning accompanied by repeated post-session administration of scopolamine caused a reduction of sensitivity to drug.The Authors wish to acknowledge the expert assistance of Mr. Luigi AmoricoFellow (1966/1967) of the Istituto Superiore di Sanità     

The effect of α-amanitin on passive and active avoidance acquisition in mice

-Amanitin, a specific and potent inhibitor of form II DNA-dependent RNA polymerase, produced greater than 98% inhibition of the enzyme in mouse brain within 2 h of intracerebroventricular (icv.) injection. Mice were given one trial passive avoidance training and retested on the task 4 h later. Mice treated with -amanitin 2 h before training or immediately after training demonstrated a retention deficit when compared to non-injected or saline injected controls.Active avoidance was trained for 1 h using a Sidman schedule with a drumturning response. Performance during the last 15 min of training was compared to performance in the first 15 min of a retesting session, 4 h after training. -Amanitin, 2 h prior to training reduced the number of responses, per cent escapes and per cent avoidances in the retesting session. Post-training injection of -amanitin significantly reduced the number of responses and per cent avoidances.Rotarod and spontaneous motor activity were not affected by -amanitin. Whole body temperature was slightly and transiently reduced in icv. administration of -amanitin.     

Role of stimulus locale on strain differences in active avoidance after scopolamine of D-amphetamine treatment.

Three strains of mice were trained in a shuttle avoidance task following treatment with scopolamine (2.0 mg/kg) or d-amphetamine (3.0 mg/kg). When required to run towards light (CS) to avoid shock, A/J mice acquired the response more readily than DBA/2J or C57BL/6J mice. However, when required to run away from the light, the strain differences were eliminated. Under both testing conditions scopolamine and d-amphetamine augmented the performance of A/J mice, but had no effect of even disrupted performance of C57BL/6J. In DBA/2J mice d-amphetamine augmented performance only in the toward condition. Results were interpreted to support the hypothesis that scopolamine and d-amphetamine improve performance by response-disinhibition and response excitation, respectively. The presence of associative difficulties limit the effects of these agents.     

Effects of vasopressin,des-glycinamide vasopressin and amphetamine on a combined passive and active avoidance task

The effects of peripherally injected arginine vasopressin (AVP), its des-glycinamide derivative (DGAVP), which has limited pressor activity, and d-amphetamine (AMP) were studied on a combined passive and active avoidance task (Carew 1970). In this procedure, the rat experiences mild foot-shock in one of two distinctively coloured compartments, followed by drug treatment. On the next day, re-entry latency into either of the two compartments is measured (latency index), and the actual compartment chosen is noted (choice index).Both measures were affected by the intensity of the shock. A moderate dose of AVP (25 g/kg) increased latencies, but only when a relatively low shock intensity was used; choice was not markedly affected. DGAVP did not significantly affect performance under any condition. AMP affected latency scores as well as choice behaviour at the lower shock level but, presumably due to ceiling effects, did not exert an effect in the high shock condition.The negative DGAVP findings suggest that the behavioural potency of peripherally injected AVP was due to pressor activity, rather than any direct action on cognitive mechanisms. Moreover, this indirect AVP effect on mnemonic performance was relatively weak, since only the latency, but not choice, measure was significantly affected. It is concluded that the Carew paradigm provides a more comprehensive assessment of behaviour than traditional passive or active avoidance procedures.     

The comparative effects of benzodiazepines,progabide and PK 9084 on acquisition of passive avoidance in mice

Acquisition of passive avoidance following aversive conditioning to a dark compartment was measured in mice under the influence of one of seven bezodiazepines, the GABA-mimetic drug progabide or PK 9084, a nonbenzodiazepine ligand on benzodiazepine receptors.The drugs were administered prior to the training trial and retention was measured in the absence of the drug 24 h later. Oral administration (dose in mg/kg in parentheses) of flunitrazepam (0.1), lorazepam (1.0), nitrazepam (3.0), diazepam (10), flurazepam (10) and chlordiazepoxide (30), all prevented retention whereas progabide (100–800) and PPK 9084 (10–100) were ineffective. In comparison to effects on motor capacity none of the benzodiazepines was outstanding in its acquisition interfering effects.     

Acute dose-effects of scopolamine on false recognition

RATIONALE: Recently, there has been increased research interest in the phenomenon of false recognition, in which participants claim to recognize words that had not been presented during an initial study phase but that are associatively related to presented words. Acute administration of the benzodiazepine hypnotic triazolam has been shown to decrease false recognition rates. However, no false recognition studies have examined the effects of scopolamine, an anticholinergic drug that might produce a different profile of memory-impairing effects than the benzodiazepines due to its distinct neurochemical profile. OBJECTIVE: This study was designed to examine the acute dose-effects of scopolamine on false recognition. METHODS: The effects of subcutaneously administered scopolamine (0.3 and 0.6 mg/70 kg) on performance in the Deese/Roediger-McDermott false recognition paradigm were examined in a repeated-measures placebo-controlled double-blind design in 18 healthy volunteers. RESULTS: Scopolamine produced dose-related reductions in both true and false recognition rates, and induced a more conservative response bias relative to placebo for recollection-based ("remember") responses to studied words. CONCLUSIONS: While scopolamine's effects on false recognition are similar to those observed previously with triazolam, its effects on response bias may differ from those of triazolam.     

Effects of antimuscarinic cholinergic drugs injected systemically or into the hippocampo-entorhinal area upon passive avoidance learning in young rats

Passive avoidance learning was significantly impaired by atropine (5 mg/kg, IP) or scopolamine (0.5 mg/kg), but not by methyl-atropine (5 mg/kg) or methyl-scopolamine (0.5 mg/kg), from postnatal day 15 on. In contrast, an improvement was observed, not significant at 11 days and significant at 13 days, probably due to nonspecific effects. Retention of the response increased from 6 h at 13 days, to 24 h at 17 days. In treated rats, retention was abolished at 13 and 15 days, and impaired at 17 and 20 days. Acquisition of the response was also significantly impaired by bilateral injections of atropine (1, 5, and 20 g) into the posteroventral hippocampo-entorhinal (VHE) area, from day 15 on. Concomitantly, extinction was accelerated. At 14 days, atropine had no influence. At 13 days, a facilitatory action was observed, with better acquisition and greater resistance to extinction, possibly linked to affective changes. The results conform that central muscarinic cholinergic mechanisms are involved in passive avoidance learning from postnatal day 15 on, and demonstrate that some pathways of this system are located in the VHE area, become efficient at 15 days, and improve markedly between 17 and 18 days.     

Effects of scopolamine,physostigmine and chlordiazepoxide on punished and extinguished water consumption in rats

It has been postulated that behavioral inhibition due to punishment or extinction may be mediated by brain acetylcholine, and drugs which have disinhibitory action are thought to interact with this system. This notion was tested by comparing the effects of scopolamine, physostigmine and chlordiazepoxide on punished and extinguished water consumption. Scopolamine hydrobromide (0.3, 0.5 mg/kg, i.p.), a centrally and peripherally acting antimuscarinic agent and physostigmine sulfate, (0.3 mg/kg, i.p.), a centrally and peripherally acting acetylcholinesterase inhibitor, lowered both non-punished and punishment suppressed water intake and lick rate, whereas their quaternary analogs which primarily act in the periphery, had no significant effect at comparable dose levels. Scopolamine and physostigmine suppressed punished water consumption at lower dose levels than nonpunished intake. In contrast, chlordiazepoxide (5.0, 10.0, 20.0 mg/kg, i.p.) enhanced punished as well as non-punished water intake. In a further experiment comparing punishment and extinction suppression, scopolamine and physostigmine did not affect punished or extinguished water intake; chlordiazepoxide (5.0, 10.0, 20.0 mg/kg) reliably increased punished, but not extinguished licking on the water nozzle. These results suggest (1) that scopolamine and chlordiazepoxide do not act via a common mechanism, and (2) that punishment and extinction suppression are not a pharmacological entity.     

Baclofen disrupts passive avoidance retention in rats

Baclofen (Lioresal, Ciba-Geigy) is an analog of the inhibitory neurotransmitter GABA and is used clinically to control spasticity. Recent studies have demonstrated that this compound produces a marked inhibition of synaptically evoked responses in area CA3 of the hippocampal slice, suggesting that this drug could influence behavior mediated by the limbic system. In the present study, male rats of the Fischer-344 strain were trained on a one-trial passive avoidance task and tested for retention 1 week later. After the training trial, separate groups of rats received either 5 or 10 mg/kg/4 ml IP of baclofen or the distilled H₂O vehicle immediately, 10 min, or 60 min after training. One week later, the rats that received baclofen immediately after training reentered the test chamber with a significantly higher frequency than controls, although no differences in vacillatory responses were observed between groups. Similar effects were observed following posttrial administration of chlordiazepoxide. In a separate experiment rats were tested for locomotor activity after receiving the same doses of baclofen. Although baclofen decreased activity during a 30-min period after dosing, rats exposed to baclofen showed no significant change in activity relative to controls 1 week later. These data are consistent with the interpretation that baclofen may interfere with memory consolidation or retention.     

Effects of diazepam and scopolamine on storage,retrieval and organizational processes in memory

The effects of intramuscular injections of diazepam (0.3 mg/kg) and scopolamine (8 g/kg) on memory processes and subjective moods were studied in 36 volunteers. Subjects (Ss) were tested in groups of four in a double blind procedure with treatments distributed according to a Latin square design. Lists of words were presented to Ss who were then tested with an immediate free recall test prior to drug administration. Following injection delayed free recall and recognition tests were given. Subsequently two sets of lists were presented separately and tested in the same fashion. Two of the lists in the last set were composed of words falling into distinct categories. Memory was additionally analyzed by testing immediate recall of digit sequences and employing a visual recognition test. Subjective moods were evaluated with a rating questionnaire.Both diazepam and scopolamine impaired memory functions although the action of the latter drug was more pronounced and prolonged. The deficit appeared to be in the storage process leaving retrieval processes unaffected. Scopolamine in addition interfered with organizational processes. Subjectively, scopolamine also produced a larger sedative effect than diazepam.