Tetrahydroaminoacridine facilitates passive avoidance learning in rats with nucleus basalis magnocellularis lesions

The effect of bilateral ibotenic acid lesions of the nucleus basalis magnocellularis (NBM) on performance in a step-through passive avoidance task and the ability of tetrahydroaminoacridine (THA) to enhance learning were evaluated. Fischer 344 rats were used in a passive avoidance task in which footshock was replaced by ultrasound (30-62 K Hz, 125 dB) as the aversive training stimulus. THA was given immediately after each single daily training trial and retention was tested 24 hr later for 10 consecutive days. Although NBM lesions alone did not impair passive avoidance learning, THA at 5 mg/kg (i.p.), but not 1 mg/kg, significantly facilitated latency performance in NBM-lesioned rats.     

Effect of lysine vasopressin on pentylenetetrazol-induced retrograde amnesia in rats

Lysine vasopressin (1 microgram/rat SC) administered 1 hr prior to either the acquisition trial or 24 hr retention trial facilitated passive avoidance retention. Amnesia was produced when a single 50 mg/kg (IP) injection of pentylenetetrazol was given immediately following the passive avoidance acquisition trial. A single injection of lysine vasopressin (1 microgram/rat SC) administered 1 hr prior to either the acquisition trial or 24 hr retention trial antagonized the amnesia.     

Effects of nimodipine, felodipine and amlodipine on electroconvulsive shock-induced amnesia in the rat

The effects of various doses (0.03, 0.1, 0.3 or 1.0 mg/kg) of the Ca²⁺ channel blockers nimodipine, felodipine and amlodipine on the learning ability of rats exposed to electroconvulsive shock were examined. The animals were trained in a passive avoidance procedure. The drugs tested were injected 30 min before the learning trial started. The electroconvulsive shock was given immediately after the learning trial response had been acquired. A passive avoidance retention test was performed 24 h later. It was found that electroconvulsive shock strongly impaired the retention of the passive avoidance response. Nimodipine, felodipine and amlodipine did not influence the passive avoidance behavior in the sham electroconvulsive shock group, but significantly improved the retention deficits in the animals exposed to electroconvulsive shock. These findings support the hypothesis that perturbations in Ca²⁺ homeostasis can contribute to the memory deficits associated with electroconvulsive shock. The antiamnestic effects of the substances tested make them interesting candidates for clinical trials in patients with cognitive impairment caused by electroconvulsive shock therapy.     

Effect of fipexide on passive avoidance behaviour in rats

The effect of fipexide, administered at different intervals after the learning trial of a single step-through type passive avoidance situation was studied. The administration of fipexide immediately after the learning trial resulted in a long-lasting facilitation of passive avoidance behaviour. On the contrary, the administration of this compound 1 h prior to the retention test failed to influence passive avoidance behaviour. The results suggest that fipexide facilitates memory consolidation but does not influence retrieval processes.     

Vasopressin antagonists block peripheral as well as central vasopressin receptors

The aim of the present study was to differentiate between the postulated central behavioral effects of vasopressin and its pressor response, which is mainly mediated by peripheral vascular receptors. Thus, the interaction between the vasopressor antagonists dPTyr(Me)AVP (AAVPa) and d(CH2)5Tyr(Me)AVP (AAVPb) with the effects of [Arg8]vasopressin (AVP-(1-9)) and [pGlu4,Cyt6]AVP-(4-8) (referred to as AVP-(4-8)) was examined using passive avoidance behavior and the pressor response as parameters. AVP-(4-8) was approximately 4 and 200 times more potent than AVP-(1-9) in facilitating passive avoidance behavior after subcutaneous (SC) or intracerebroventricular (ICV) administration respectively. This effect of SC injected AVP-(1-9) and AVP-(4-8) could be prevented by both vasopressor antagonists following SC treatment. A similar antagonistic action was found when AVP-(1-9) or AVP-(4-8) and the antagonist AAVPb were administered ICV. SC injection of AAVPb prevented the behavioral effect of ICV administered AVP-(1-9) while ICV treatment with the antagonist blocked the behavioral action of systemically injected AVP-(1-9) and AVP-(4-8). In contrast to SC injected AVP-(1-9) which dose-dependently increased blood pressure and decreased heart rate, AVP-(4-8) injected SC in identical doses did not affect blood pressure and heart rate, neither did AVP-(1-9) and AVP-(4-8) when injected ICV in behaviorally active doses. A SC, but not an ICV injection of the antagonist AAVPb could prevent the blood pressure increase and bradycardia induced by SC AVP-(1-9).(ABSTRACT TRUNCATED AT 250 WORDS)     

ACTH4-9 analog (ORG 2766) facilitates acquisition of an inhibitory avoidance response in rats.

These experiments examined the effects of an ACTH4-9 analog (ORG 2766) on an inhibitory avoidance response in rats. Graded doses of ORG 2766 were administered either 1 hr prior to training, immediately after training, or 1 hr prior to the retention test. The animals were tested 24 hr after training. A 5.0 mg/kg dose was administered prior to training significantly facilitated acquisition of the response. ORG 2766 did not significantly affect retention when administered after training or prior to the retention test. Since ORG 2766 only affected acquisition of the response, it is suggested that the drug acts by influencing sensory, motivationl or attentional variables rather than directly affecting memory consolidation or retrieval processes.     

Parallel changes in behaviour and hippocampal monoamine metabolism in rats after administration of ACTH-analogues.

Application of footshock during the acquisition trial of a one-trial passive avoidance test is associated with a rise in the concentration of serotonin in the hippocampi of rats 24 hr after termination of the acquisition trial. Rats subjected to amnesic treatment with carbon dioxide (CO2) immediately after footshock do not show this rise in the hippocampal concentration of serotonin. The ACTH-analogues, ACTH 4-10 and ACTH 4-10 (7D-Phe), alleviate CO2-induced amnesia for the passive avoidance response when administered 1 hr before retrieval test 24 hr after acquisition. These peptides do not have anti-amnesic activity when given before acquistion. Another ACTH-analogue, ACTH 11-24 does not affect amnesia, given before either the acquisition or the retrieval test. The anti-amnesic effect of ACTH 4-10 AND ACTH 4-10 (7D-Phe), was correlated with a rise in the hippocampal serotonin concentration similar to that observed in non-amnesic animals. Pre-acquisition treatment with ACTH 4-10 or administration of ACTH 11-24 did not affect hippocampal serotonin concentrations. Changes in the hippocampal concentrations of noradrenaline, dopamine, tryptophan and tyrosine were not related to the behavioural activity of any of the peptides. It is suggested that alterations in hippocampal serotonin metabolism 24 hr after acquisition of a passive avoidance response are associated with the retrieveability of the passive avoidance response.     

Cholinergic drugs reverse AF64A-induced impairment of passive avoidance learning in rats

The cholinergic neurotoxin AF64A was administered to rats in order to produce learning impairment to test the effect of cholinergic drugs. Seven days after receiving an intracerebroventricular injection of AF64A (2.5–7.5 nmol), rats were subjected to one-trial passive avoidance acquisition and tested 24 h later. Learning was significantly impaired at 3.75 nmol AF64A, a dose at which significant reduction in acetylcholine level and choline acetyltransferase and acetylcholinesterase activity in the hippocampus was observed but changes in monoamine levels in the hippocampus, general behavior, or sensory sensitivity were not observed. Arecoline (4 mg/kg, IP) and physostigmine (0.1 mg/kg, IP) significantly decreased the learning impairment produced by AF64A (3.75 nmol) when given before the acquisition of passive avoidance learning but not when given after the acquisition or before the 24 h retention test. These drugs and oxotremorine (0.1 mg/kg, IP) given immediately after the acquisition, however, improved passive avoidance retention when the interval between the acquisition and the test was shortened to 1 h. These results indicate that the impairment of learning in AF64A-treated rats is caused by a memory retention deficit and suggest that such impairment can be effectively ameliorated by cholinergic drugs.     

Opposite effects induced by low and high doses of apomorphine on single-trial passive avoidance learning in mice

The effects of apomorphine (0.0125-1 mg/kg, SC), a dopamine (DA) agonist, on passive avoidance learning were assessed in mice which received brief and long foot-shocks in a training test. At low doses, apomorphine stimulates DA autoreceptors. With a shock of brief duration, apomorphine at a low dose (0.05 mg/kg), enhanced the avoidance learning when it was administered 20 min before the training test or the retention test. At high doses, apomorphine stimulates postsynaptic DA receptors. With a shock of long duration, apomorphine at a high dose (1 mg/kg), impaired the avoidance learning when it was administered 20 min before the training test or the retention test. However, apomorphine (0.05 and 1 mg/kg) given immediately after the training test did not have any effect on the avoidance behavior with shocks of either brief or long durations. Apomorphine-induced enhancement of passive avoidance learning was antagonized by sulpiride, but not by haloperidol. These results show that apomorphine induced the opposite effects on the passive avoidance learning depending on the dose or on the reinforcement intensity and suggest that the central DA system may play an important role in modulating memory processes.     

Potency and duration of action of the ACTH 4-9 analog (ORG 2766) as compared to ACTH 4-10 and [D-Phe7] ACTH 4-10 on active and passive avoidance behavior of rats

Experiments were performed to examine the potency and duration of action of various ACTH analogs on active and passive avoidance behavior of rats. ACTH 4-10 and the ACTH 4-9 analog (ORG 2766) delayed extinction of pole-jumping avoidance behavior and facilitated passive avoidance responding. [D-Phe7] ACTH 4-10 facilitated extinction of pole-jumping avoidance behavior and facilitated passive avoidance responding. [D-Phe7] ACTH 4-10 facilitated extinction of pole-jumping avoidance behavior and facilitated passive avoidance responding. ORG 2766 was a thousand times more active than ACTH 4-10. The effect of ORG 2766 on extinction of pole-jumping avoidance behavior and on passive avoidance behavior was of longer duration than that of ACTH 4-10. As determined more precisely in the passive avoidance test it appeared that the action of ACTH 4-10 lasted 3 to 6 hours, while that of ORG 2766 amounted to at least 24 hours. Although [D-Phe7] ACTH 4-10 was a thousand times less active than ORG 2766 in the passive avoidance paradigm, its duration of action was of the same magnitude. In view of this, the marked increase in potency of the ACTH 4-9 analog cannot be explained only on the basis of its metabolic stability but also by an increased intrinsic activity.     

The effects of dexmedetomidine, an alpha 2 agonist, on learning and memory, assessed using passive avoidance and water maze tasks in rats.

The effects of dexmedetomidine, a specific and potent alpha 2 agonist, on the performance of rats in passive avoidance and water maze tasks were studied. Pre-training administration of subanaesthetic dose (9.0 micrograms/kg) of dexmedetomidine impaired the retention of the passive avoidance task (assessed 24 hr after training) but it did not affect the training of this task. Smaller doses (0.3, 0.9 and 3.0 micrograms/kg) did not affect the training or retention of this aversively motivated task. On the other hand, pre-training administration of 0.3 and 0.9 microgram/kg dexmedetomidine impaired the acquisition of the water maze task, whereas larger doses (3.0 and 9.0 micrograms/kg) had no significant effect on spatial learning. Pre-training administration of dexmedetomidine (0.3-9.0 micrograms/kg) increased swimming speed in rats. Only a large dose (300 micrograms/kg) of dexmedetomidine, administered immediately after training, impaired the retention of the passive avoidance task and the acquisition of the water maze task. These data agree with previous findings that pharmacological manipulation of the noradrenergic system affects the retention of aversively-motivated (passive avoidance) tasks. The present results suggest that the dose-response curve of dexmedetomidine for impairment of learning/memory differs between the passive avoidance and water maze tasks.     

Behavioral effects of propentofylline (HWA 285) on ambulatory activity, discrete avoidance response and passive avoidance response in mice

Behavioral effects of propentofylline (HWA 285) were investigated by means of ambulatory activity, discrete lever-press avoidance and step-through type passive avoidance response in mice. Single administration of HWA 285 produced no marked change in the bodily condition and also produced no changes in ambulatory activity at 1.25-20 mg/kg, s.c.; the discrete avoidance response at 2.5-40 mg/kg, s.c.; and the passive avoidance response at 10-30 mg/kg, s.c. However, 5-20 mg/kg of HWA 285 attenuated the ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) and scopolamine (0.5 mg/kg, s.c.). HWA 285 tended to attenuate the avoidance-suppressing effect of chlorpromazine (2 mg/kg, s.c.) and physostigmine (0.1 mg/kg, s.c.) at 2.5 mg/kg, while it enhanced the effect of chlorpromazine at 10-40 mg/kg. The mice treated with HWA 285 (10-30 mg/kg) at 30 min before or immediately after the acquisition trial did not show a marked change in the passive avoidance response when the retention trial was done 24 hr after the acquisition trial. The treatment with scopolamine (2 mg/kg, s.c.) at 30 min before the acquisition trial suppressed the passive avoidance response, eliciting a marked shortening of the step-through latency and decrease in % of mice to the 300 sec criterion of latency. The effect of scopolamine was attenuated by combined administration of HWA 285 (30 mg/kg) and treatment with HWA 285 (30 mg/kg) after the end of the acquisition trial. The present results suggest that HWA 285 demonstrates complex behavioral effects which vary dependently on the doses and types of behaviors.     

Reversal of ECS-induced amnesia by post-ECS injections of amphetamine.

Water deprived rats were trained to drink from a water spout within an apparatus on each of 2 days. On the third day, passive avoidance of the spout was induced by giving the animal a 0.3 sec, 5 mA footshock after 1 lick at the spout. A test for retention of the avoidance learning was given 48 hr following training. ECS administered through cortical electrodes at 15 sec following the footshcok impaired retention. The amnesia was attenuated when amphetamine (1 mg/kg) was injected immediately but not at 6 hr following the ECS. In a second experiment, attentuation of amnesia by amphetamine was not found when the ECS occured at 4 sec instead of 15 sec following the footshock. The results are interpreted in terms of reactivation by amphetamine of a consolidation process that was interrupted by ECS.     

The improvement of memory retention and retrieval of a novel vasopressin fragment analog NC-1900

The effects of a novel vasopressin (AVP) fragment analog NC-1900 (pGlu-Asn-Ser-Pro-Arg-Gly-NH2 acetate) were studied on the performance of memory retention and retrieval in mice. NC-1900 of one time application of 1 hr after the acquired trial (electric shock) extended the latent period of passive avoidance task 21 days after the acquired trial. Though the extended response was also recognized with AVP4-9, the potency was approx. 1/1000 of NC-1900. The potentiation wasn't recognized with vasopressin. NC-1900 showed a significantly high correct answer after 21 days after the last trial in the search task. While, V1 antagonist Pmp1-Tyr (Me)2-AVP shortened the latent period of passive avoidance task. On the other hand, NC-1900 extended the reaction latency 21 days after the acquired trial by the application 1 hr before the retention trial. Though this improvement of memory retrieval was recognized with vasopressin and AVP4-9, the potency was 1/100-1/1000. NC-1900 improved the retrieval 24 h after the CO2 exposure. V1 antagonists Pmp1-Tyr-Me2-AVP or Deamino-Pen1, O-Me-Tyr2-AVP, and PMA had no effects on the retrieval 21 days after the acquired trial. These results suggest that NC-1900 may have the memory retention and retrieval potentiating action, and that phospholipase C-protein kinase C system may be involved in the former action, and the latter action not be involved.     

8-Hydroxy-2-(di-n-propylamino)tetralin, a 5-HT1A receptor agonist, impairs performance in a passive avoidance task.

The effects of various subcutaneous doses (30, 100 and 300 micrograms/kg) of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a serotonin (5-HT)1A receptor agonist, were studied on the performance of rats in a one-trial passive avoidance task. When administered 30 min before the training trial and the retention test, 8-OH-DPAT significantly reduced retention latencies at all doses. Similar results were obtained when 8-OH-DPAT was administered before either the training trial or the retention test. When administered 5 min after the training trial, 100 and 300 micrograms/kg 8-OH-DPAT significantly reduced the retention latencies whereas 30 micrograms/kg caused a non-significant tendency to a reduction. A dose of 300 micrograms/kg 8-OH-DPAT significantly raised the thresholds for various responses (flinch, jump and vocalization) elicited by electric shock applied to the grid floor while 30 and 100 micrograms/kg had no effect. When administered 30 min before the retention test to rats that could choose between a punished and unpunished compartment, 8-OH-DPAT at 100 and 300 micrograms/kg facilitated re-entry to either compartment but, like control animals, most 8-OH-DPAT-treated animals preferred the unpunished compartment. Although the effects of 8-OH-DPAT on pain perception, general activity or emotional behavior may interfere with the performance of rats in the passive avoidance task, the results suggest that at 100 and 300 micrograms/kg 8-OH-DPAT interferes with mechanisms related to the acquisition and consolidation of memory.     

Beneficial effect of idebenone (CV-2619) on cerebral ischemia-induced amnesia in rats

An experimental model of amnesia induced by cerebral ischemia after one-trial passive avoidance learning was established to test the effects of a novel compound, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone, CV-2619), and some commonly used drugs in rats. One day after the vertebral artery was electrocauterized bilaterally, the common carotid artery was transiently occluded bilaterally to produce cerebral ischemia. The amnesia was estimated by the response latency for a rat to step from a light safety compartment to a dark compartment in which a foot-shock was given. The results of the retention test given 24 hr after the ischemia indicated that amnesia was successfully produced when the 200-600 sec ischemia was provided within 20 min after the avoidance learning. The effects of drugs on the amnesia induced by a 200-sec ischemia immediately after the avoidance learning were as follows: CV-2619 (10, 30 mg/kg, i.p. or p.o.) given before the retention test significantly increased the response latency, indicating a reversal effect on the amnesia. Physostigmine (0.1, 0.2 mg/kg, i.p.) and arginine-vasopressin (10 micrograms/kg, s.c.) were also effective, and calcium hopantenate (500 mg/kg, p.o.) showed a slight reversal action. Furthermore, CV-2619 (10 mg/kg, i.p.), given before or after the ischemia, significantly inhibited the appearance of amnesia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vasopressin antagonizes retrograde amnesia in rats following electroconvulsive shock

Rats given an electroconvulsive shock immediately following training in a passive avoidance task showed amnesia when tested 24 hr after training. This amnesia was prevented if lysine vasopressin was injected either one hr before the training trial or one hr before the first test trial. The results indicate that it is unlikely that either electroconvulsive shock or lysine vasopressin affect memory storage.     

DOPAMINERGIC PROJECTION TO THE CENTRAL AMYGDALA MEDIATES THE FACILITATORY EFFECT OF CCK-8US AND CAERULEIN ON MEMORY IN RATS

The involvement of dopaminergic projection to the central amygdala in the facilitatory effect of cholecystokinin unsulphated octapeptide (CCK-8US) and caerulein (CER) on memory motivated affectively was investigated in male rats. CCK-8US and CER were administered subcutaneously at the doses of 10 micrograms kg-1and 0.5 microgram kg-1, respectively, immediately after a single learning trial in a passive avoidance situation, after bilateral 6-OHDA lesions to the central amygdala. Bilateral 6-OHDA lesions to the central amygdala totally abolished the facilitatory effect of CCK-8US and CER on retention of passive avoidance behaviour evaluated 24 h after the learning trial. These results may indicate that the facilitatory effect of CCK-8US and CER on memory motivated affectively is mediated by dopaminergic projection from ventral tegmental area to the central amygdala.     

Naltrexone-insensitive facilitation and naltrexone-sensitive inhibition of passive avoidance behavior of the ACTH-(4-9) analog (ORG 2766) are located in two different parts of the molecule

Subcutaneous injection of the ACTH-(4-9) analog (OG 2766) in ng amounts prior to the retention test facilitated, while microgram doses attenuated passive avoidance behavior. The inhibitory effect could easily be overcome by treatment with ACTH-(1-10) either before or after ORG 2766 administration. Thus, inhibition of passive avoidance behavior by ORG 2766 probably was not due to competition with ACTH-like peptides or a functional antagonistic influence on brain structures sensitive to ACTH-like peptides. Intracerebroventricular administration of ACTH-(4-10) in a wide dose range (0.5-10.0 micrograms) and of ORG 2766 in low doses (0.5-1.0 ng) facilitated passive avoidance behavior, whereas 'high' doses of ORG 2766 (5.0 and 10.0 ng) and graded doses of COOH terminal tripeptide of ORG 2766 (Phe-D-Lys-Phe; PDLP; 0.5-10.0 ng) attenuated passive avoidance behavior. The NH2 terminal tetrapeptide of ORG 2766 (H-Met/O2/-Glu-His-Phe) facilitated passive avoidance behavior, whereas the NH2 terminal tripeptide (H-Met/O2/-Glu-His) was ineffective. Naltrexone pretreatment antagonized the attenuating effect of ORG 2766 and PDLP. Following pretreatment with this opiate antagonist both 'low' and 'high' doses of ORG 2766 and the NH2 terminal tetrapeptide of ORG 2766 induced facilitation of passive avoidance behavior, while PDLP was ineffective in the presence of naltrexone. Thus, ORG 2766 exerts a dual effect on passive avoidance behavior. The facilitating effect of ORG 2766 resides in the NH2 terminal part and is unrelated to naltrexone-sensitive brain opiate receptor sites, whereas the inhibiting influence is located in the COOH terminal part of the peptide and depends on naltrexone-sensitive brain opiate receptor sites.     

Bilateral 6-OHDA lesions to the hippocampus attenuate the facilitatory effect of CCK-8 us and caerulein on memory in rats.

The involvement of dopaminergic projection to the hippocampus in the facilitatory effect of cholecystokinin-unsulphated octapeptide (CCK-8 us) and caerulein (CER) on memory motivated affectively was investigated in male rats. CCK-8 us and CER were given subcutaneously at the doses of 10 microg kg(-1)and 0.5 microg kg(-1), respectively, immediately after a single learning trial in a passive avoidance situation, after bilateral 6-OHDA lesions to the dentate gyrus of the hippocampus. In order to protect noradrenergic neurones against destruction by neurotoxin, 30 min before surgery rats were pre-treated intraperitoneally with 25 mg kg(-1)of desmethylimipramine, an inhibitor of noradrenaline uptake. Bilateral 6-OHDA lesions to the hippocampus significantly attenuate the facilitatory effect of CCK-8 us and CER on retention of passive avoidance behaviour evaluated 24 h after the learning trial. Neither, destruction of dopaminergic endings in the hippocampus, nor application of CCK-8 us and CER changed the spontaneous psychomotor activity of rats estimated in an 'open field' test. These results may indicate that the facilitatory effect of CCK-8 us and CER on memory motivated affectively is, in part, mediated by dopaminergic projection from the ventral tegmental area to the dentate gyrus of the hippocampus. 2000 Academic Press@p$hr Copyright 2000 Academic Press.