Cholecystokinin octapeptide, proglumide, and passive avoidance in rats

Rats were conditioned to avoid a darkened chamber using electric footshock (0.25 mA for 2 sec). Cholecystokinin octapeptide (CCK-8), a CCK-8 antagonist proglumide, or 0.9% NaCl solution was injected immediately following the footshock to study the effect upon passive avoidance behavior. The passive avoidance behavior was observed one day following the conditioning footshock and treatment. CCK-8 produced a reduction of the passive avoidance latency of rats at doses ranging from 30 micrograms/kg to 500 micrograms/kg. Proglumide (5 mg/kg) was able to block the CCK-8 effect on rat passive avoidance conditioning. Proglumide by itself at a dose of 2 mg/kg decreased the latency to enter the darkened chamber. Endogenous CCK-8 activity may be involved in passive avoidance conditioning in rats.     

Pituitary-adrenal influences on avoidance behavior of pigs

Pigs submitted to extinction of a signaled conditioned avoidance response were injected daily with various doses of dexamethasone (DX) or ACTH. Pigs treated with 0.2 mg/kg of DX showed a higher number of intertrial crosses, but the extinction rate was not modified by either treatment. The effects of ACTH and DX were further studied on the reaction to a Pavlovian conditioned fear signal presented to pigs having learned a continuous avoidance response in a shuttle-box. DX treatment before both the fear conditioning and the test sessions enhanced the reaction to the fear signal at intermediate doses (0.2 mg/kg) but had little effect at lower (0.1 mg/kg) and higher doses (0.5 and 1 mg/kg). ACTH 1–24 treatment induced the same behavioral changes as intermediate doses of DX. A behaviorally active ACTH 4–9 analog, Org 2766, did not modify behavioral reaction to fear signal presentations when administered before fear conditioning and/or test sessions. These results demonstrate that, in pigs, avoidance performance changes under fear signal presentations are modulated by corticosteroids.     

Effect of cadmium chloride on the processes of learning and memory in rats

Intraperitoneal injection of cadmium chloride (4 mg/kg) to rats before elaboration or reproduction of two-way avoidance conditioned reflex (TACR) disturbs both these processes. Deterioration of elaboration does not affect connections fixation and their subsequent reproduction. Injection of the substance before the elaboration of passive avoidance conditioned reflex (PACR) depresses elaboration and consolidation. Injection of cadmium chloride before testing of PACR preservation does not influence the processes of engrams reproduction. The observed disturbances cannot be connected with changes of animals motor activity.     

Dose-dependent action of corticosteroids on brain serotonin content and passive avoidance behavior.

Corticosterone, 1.0 and 5.0 mg/kg, improved passive avoidance behavior based on fear versus thirst-conflict situation. Corticosterone, 1.0 mg/kg, increased the serotonin (5-HT) content in the hypothalamus and mesencephalon; 5.0 mg/kg of corticosterone had no effect. Plasma corticosterone level increased in a dosedependent manner after corticosterone treatment. dl-Parachlorophenylalanine (PCPA) impaired passive avoidance behavior and decreased the hypothalamic and mesencephalic 5-HT level. After PCPA treatment, the plasma corticosterone level was slightly increased. PCPA pretreatment was able to prevent the action of 1.0 and 5.0 mg/kg of corticosterone on behavior as well as on brain 5-HT level. Corticosterone, 10.0 mg/kg, impaired passive avoidance behavior, decreased the hypothalamic and mesencephalic 5-HT content, and increased the plasma corticosterone level.Monoamine oxidase inhibitor (nialamide) treatment improved the passive avoidance behavior and increased the 5-HT level in the hypothalamus and mesencephalon. The plasma corticosterone level did not change significantly. Nialamide pretreatment abolished the behavioral action of 10.0 mg/kg of corticosterone as well as its action on brain 5-HT level. A large dose of corticosterone (25.0 mg/kg) and 2.5 mg/kg of 6-dehydro-16-methylenhydrocortisone (6DH) had a similar action on passive avoidance behavior and on brain serotonin level as 10.0 mg/kg of corticosterone; however, the plasma corticosterone level was increased only in corticosterone-treated animals and was significantly decreased after 6DH. 11-Deoxycorticosterone (DOC) at a dose of 25.0 mg/kg was ineffective on passive avoidance behavior and on brain serotonin content, whereas it slightly decreased the plasma corticosterone level. Data suggest that the corticosterone has dosedependent dual action on passive avoidance behavior, and its action is, at least partly, mediated via changed brain serotonin metabolism. The action seems to be a glucocorticoid-specific one since mineralocorticoid (DOC) is ineffective on this behavioral pattern.     

Experimental study of the effects of amiridin and tacrine on learning and memory

The authors studied the influence of amiridin and tacrine on learning and memory in mice and rat by passive avoidance conditioning test at norm and under scopolamine induced amnesia as well as of their effect on acetylcholine esterase (AChE) activity in brain cortex homogenates. Amiridin in doses 0.1 and 0.2 mg/kg showed a beneficial action on conditioning in untreated animals, its effect being comparable with that of piracetam. Tacrine was ineffective. In scopolamine treated animals amiridin and tacrine showed anti-amnestic action at dose of 0.1 mg/kg which was found ineffective with respect to AChE activity. The data suggests that the ameliorating effect of amiridin and tacrine on cognitive abilities in patients with senile dementia is not related their anticholinesterase properties.     

A Single Neonatal Injection of Ethinyl Estradiol Impairs Passive Avoidance Learning and Reduces Expression of Estrogen Receptor α in the Hippocampus and Cortex of Adult Female Rats

Although perinatal exposure of female rats to estrogenic compounds produces irreversible changes in brain function, it is still unclear how the amount and timing of exposure to those substances affect learning function, or if exposure alters estrogen receptor α (ERα) expression in the hippocampus and cortex. In adult female rats, we investigated the effects of neonatal exposure to a model estrogenic compound, ethinyl estradiol (EE), on passive avoidance learning and ERα expression. Female Wistar-Imamichi rats were subcutaneously injected with oil, 0.02 mg/kg EE, 2 mg/kg EE, or 20 mg/kg 17β-estradiol within 24 h after birth. All females were tested for passive avoidance learning at the age of 6 weeks. Neonatal 0.02 mg/kg EE administration significantly disrupted passive avoidance compared with oil treatment in gonadally intact females. In a second experiment, another set of experimental females, treated as described above, was ovariectomized under pentobarbital anesthesia at 10 weeks of age. At 15–17 weeks of age, half of each group received a subcutaneous injection of 5 μg estradiol benzoate a day before the passive avoidance learning test. Passive avoidance learning behavior was impaired by the 0.02 mg/kg EE dose, but notably only in the estradiol benzoate-injected group. At 17–19 weeks of age, hippocampal and cortical samples were collected from rats with or without the 5 μg estradiol benzoate injection, and western blots used to determine ERα expression. A significant decrease in ERα expression was observed in the hippocampus of the estradiol-injected, neonatal EE-treated females. The results demonstrated that exposure to EE immediately after birth decreased learning ability in adult female rats, and that this may be at least partly mediated by the decreased expression of ERα in the hippocampus.     

Pre-electroconvulsive shock administration of calcium channel blockers reduces retrograde amnesia induced by ECS

Effect of pre-electroconvulsive shock (ECS) administration of calcium channel blockers (CCBs) like verapamil, diltiazem, nifedipine, nimodipine, flunarizine and cinnarizine on retrograde amnesia induced by ECS was examined using passive avoidance paradigm in rats. The groups (Gr 1-7) of adult, male Wistar rats received true ECS with CCBs (5mg/kg; i.p) or vehicle (10 ml/kg; ip) and other groups (Gr 8-14) received sham ECS with CCBs (5mg/kg; i.p) or vehicle (10 ml/kg; i.p). The anti-amnestic activity of CCBs were evaluated using the passive avoidance paradigm in rats. Results showed that, the baseline latencies for all the groups did not differ significantly. Rats receiving true ECS produced significantly lower latencies. There was increase in the post ECS step through latencies of the rats administered CCBs before ECS. Therefore, pre-ECS administration of calcium channel blockers might reduce retrograde amnesia produced by ECS without altering seizure duration.     

Dehydroevodiamine.HCl prevents impairment of learning and memory and neuronal loss in rat models of cognitive disturbance

We previously reported that dehydroevodiamine.HCl (DHED) has anticholinesterase and antiamnesic activities. To verify the effects of DHED on cognitive deficits further, we tested it on the scopolamine-induced amnesia model of the rat using the passive avoidance and eight-arm radial maze tests. A single (20 mg/kg p.o.) and repeated (10 mg/kg p.o.) administrations of DHED could significantly reverse the latency time shortened by scopolamine (1 mg/kg i.p.) to control level. The impaired spatial working memory induced by scopolamine (1 mg/kg i.p.) was also improved significantly by a single injection (6.25 mg/kg i.p.) and repeated administrations of DHED (10 mg/kg p.o.) in the eight-arm radial maze test. In addition, we examined the effects of DHED on the memory impairment and the histological changes of the brain after unilateral electrolytic lesion of the entorhinal cortex (EC) and middle cerebral artery occlusion in rats. The cognitive deficits caused by EC lesion and middle cerebral artery occlusion were improved significantly by repeated administrations of DHED (6.25 mg/kg i.p.) after EC lesion or ischemic insult once a day for 7 days in the passive avoidance test. Histological analysis showed that the neuronal loss in the DHED-treated group was notably reduced in the hippocampal area (CA1) of ischemic rats and in the dentate gyrus and hippocampal area (CA1 and CA3) of EC-lesioned rats compared with the nontreated group. The infarction area was decreased significantly by a single administration of DHED (6.25 mg/kg i.p.) 30 min before ischemic insult for 6 h. These results suggest that DHED might be an effective drug for not only the Alzheimer's disease type, but also the vascular type of dementia.     

Intraseptal injection of scopolamine increases the effect of systemic diazepam on passive avoidance learning and emotionality in rats.

This experiment was designed to assess the role of the septo-hippocampal cholinergic (ACh) system in the deleterious effects produced by systemic benzodiazepine injection on learning processes in rats. Retention of a step through passive avoidance task was analysed after systemic injection of increasing doses of either scopolamine or diazepam applied alone 30 min before the acquisition phase. Results indicated a dose related impairment of retention by each drug: in addition, sub-threshold doses of scopolamine and diazepam applied in combination (diazepam: 2mg/kg plus scopolamine: 0.3mg/kg) produced a decrease of retention latencies, thus showing an additive effect of the combined treatment. Secondly, a sub-threshold dose of scopolamine (15microg/0.5microl) was also administered into the medial septal area, together with an i.p. injection of 2mg/kg of diazepam. This combined treatment produced a severe impairment of retention, in parallel with a large reduction in emotionality (number of faeces). The data are consistent with the hypothesis that peripheral administration of behaviorally effective doses of diazepam on passive avoidance learning might act partially via a septal ACh-GABA/benzodiazepine mechanism. It is also suggested that this mechanism subserves both anxiety and the memorisation of contextual stimuli associated with passive avoidance acquisition, through the modification of the septo-hippocampal activity.     

Effects of dehydroepiandrosterone on passive avoidance in ovariectomized female rats of different age

The aim of the present work was to study the influence of long-term treatment with dehydroepiandrosterone (DHEA) in doses of 0.1 and 0.7 mg/kg, i.p. on the passive avoidance performance in the ovariectomized female rats of 5- and 18-month old. The results obtained indicated that DHEA administration during 7 days in dose of 0.1 mg/kg normalized the passive avoidance performance in the ovariectomized rats of 5-month old while DHEA administration during 7 days in dose of 0.7 mg/kg restored passive avoidance performance in the ovariectomized rats of 18-month old.     

Is "scopolamine-induced amnesia" in rats the result of state-dependent learning?

The effects of a single and repetitive administration of m-cholinoblocker scopolamine (Sc) to male rats on retention of step-through passive avoidance (PA) or active avoidance (AA) in a shuttle-box were compared. In case of PA Sc (1 mg/kg) was injected i.p. only 30 min before training, only 30 min before testing, or both before training and before testing. In case of AA Sc (0.5 mg/kg/day) was injected i.p. only 15 min before each training session or both before training and before testing (44 days after achievement of learning criterion). The PA and AA retention were impaired only in the experiments, where the drug was administered before training, but did not differ from control, when Sc was injected twice. The Sc-induced amnesia (like many other cases of memory deficits) is suggested to be a manifestation of state-dependent learning. Similarity between the brain state during memory consolidation and during the retention test is necessary for recollection.     

Ninjin-yoei-to (Ren-Shen-Yang-Rong-Tang) and Polygalae radix improves scopolamine-induced impairment of passive avoidance response in mice

We investigated the effect of Ninjin-yoei-to (Ren-Shen-Yang-Rong-Tang), a Japanese herbal medicine, and found that 1000 mg/kg p.o. improved the scopolamine-induced impairment of passive avoidance response in mice. Further, the same dose of Ninjin-yoei-to enhanced oxotremorine-induced tremors in mice. The water extract of Polygalae radix, one of the constituent herbs of Ninjin-yoei-to, at a dose of 100 mg/kg significantly improved the scopolamine-induced impairment of passive avoidance response and enhanced oxotremorine-induced tremors in mice. Moreover, the enhancement of oxotremorine-induced tremors by Ninjin-yoei-to (1000 mg/kg) and Polygalae radix (100 mg/kg) was completely antagonized by pretreatment of scopolamine hydrobromide (0.5 mg/kg). These results suggest that Ninjin-yoei-to may improve the scopolamine-induced impairment of passive avoidance response by enhancing the cholinergic system and that Polygalae radix may be involved in the action of Ninjin-yoei-to.     

A rapid assessment of stimulus properties of morphine

The difficulty in assessing stimulus properties of drugs becomes apparent when the test drug, like morphine, carries both aversive and reinforcing effects at certain doses. Mice (ICR Crj strain) were trained in a passive avoidance conditioning using a two-compartment shuttle-box. On alternate days, morphine (3.0 mg/kg) was paired with shock in one compartment and saline with shock in the other compartment. A total of 3 morphine/saline pairings were given. Animals were then tested 7 times, one test per day, with saline and different doses of morphine (0.75, 1.12, 1.32, 0.93, 1.50, 3.0 mg/kg) to reveal the stimulus properties of morphine. The preference for the morphine-conditioned safe compartment after morphine injections was used to indicate that the animals associated some “stimulus” or “motivational” properties of morphine with the cues of the safe compartment. The animals discriminated very well between saline and low doses of morphine on the one hand and higher doses of morphine (close to that given during conditioning) on the other. The discontinuity between injections responded to as saline and those responded to as morphine was virtually complete between 1.12 and 1.32 mg/kg of morphine. These findings demonstrate that the present method can be used to establish an association between some stimulus properties of morphine and avoidance of shock. Accordingly, the successful discrimination of the animals between the two compartments revealed some stimulus properties of morphine.     

Effects of D2 receptor agonist and antagonist on behavior of intact and ovariectomized rats

The involvement of D2 dopaminergic receptors in behavioral responses during ovary cycle was assessed in adult intact female rats and ovariectomized (OVX) female rats. Quinperole (0.1 mg/kg), D2 receptor agonist and sulpiride (10.0 mg/kg), D2 receptor antagonist were injected chronically to adult intact and ovariectomized (OVX) female rats either separately or in combination with 17beta-estradiol (0.5 microg) within 14 days. Behavior of these animals was assessed in the "open field" test, whereas passive avoidance performance served as a model of learning. In intact rats, the passive avoidance performance was observed only in metestrous and diestrous. Chronic quinperole administration to intact females resulted in the appearance of the passive avoidance performance in proestrous and estrous, as distinct from the control animals. The passive avoidance performance was not reproduced in OVX rats. Quinperole per se or in combination with 17beta-estradiol completely restored the passive avoidance performance in OVX rats. Moreover, quinperole or sulpiride administration to OVX rats increased horizontal locomotor activity, exploratory behavior, and grooming behavior.     

Leu-enkephalin actions on avoidance conditioning are mediated by a peripheral opioid mechanism

Leu-enkephalin (100 micrograms/kg, i.p.) administered to mice 5 min before training in a one way active avoidance task significantly reduced the number of avoidances observed in the peptide treated animals. This impairing action of Leu-enkephalin was partially attenuated by methylnaloxonium (naloxonium), a quarternary form of naloxone with a limited ability to penetrate the blood brain barrier. Passive immunization (i.v.) of mice with a Leu-enkephalin antiserum 4 hrs before training produced an effect on avoidance conditioning that was the opposite to that observed with Leu-enkephalin alone. That is, passive immunization increased the number of avoidances observed in the treated mice. The results suggest that Leu-enkephalin actions on avoidance conditioning are mediated by a peripheral opioid mechanism, that leu-enkephalin may have a primary site of action outside the blood brain barrier, and that peripheral Leu-enkephalin systems may normally operate to influence conditioned avoidance behavior.     

Hormonal modulation of extinction responses induced by sexual steroid hormones in rats

A functional interrelation between the nervous and endocrine systems has been established. However, few studies have dealt with the effects of sexual steroids on learning and memory. The aim of this work was to determine whether sexual steroid hormones could modulate the extinction response of a passive avoidance conditioning in rats. Male Wistar rats, randomly assigned to five groups, two controls and three experimental groups, were submitted to a one-trial passive avoidance conditioning and tested for their retention 24 hr after and during 10 weeks. One control group received no treatment at all, the other received vegetable oil, and the three experimental received 20 mg of testosterone enanthate, 0.8 mg estradiol valerate, or 4 mg nandrolone decanoate, respectively. All substances were applied in a 0.3 ml volume, 24 hours before training and before testing for retention each week during 10 weeks. Results indicate that the extinction process is modulated by these hormones, since testosterone and estradiol facilitate extinction, whereas the anabolic androgen produced a resistance to the extinction process.     

Angiotensin II--derived peptides devoid of phenylalanine in position 8 have full psychotropic activity of the parent hormone.

In this work we compared in rats the influence of heptapeptide 1-7-angiotensin II, hexapeptide 2-7-angiotensin II, pentapeptide 3-7-angiotensin II and angiotensin II on motility, stereotypy, learning of conditioned avoidance responses and recall of passive avoidance behaviour allowing to avoid aversive stimulation. The 4 peptides administered 15 min before the experiment, tended to increase the number of crossings, rearings and bar approaches in open field, significantly accelerated acquisition of conditioned avoidance responses and improved recall of the passive avoidance. All the peptides applied immediately before the experiment intensified stereotypy evoked by apomorphine in the dose 1 mg/kg and amphetamine in the dose 6.5 mg/kg given intraperitoneally. These results show full psychotropic activity of the examined fragments of angiotensin II, comparable with the activity of the parent octapeptide. Our previous hypothesis that the Val-Tyr-Ile-His-Pro fragment of angiotensin II is responsible for the psychotropic activity evoked by angiotensins in rats is thus confirmed.     

Effects of stress and of amphetamine on passive avoidance conditioning in rats

This study examined the effects of immobilization stress combined with water immersion (ICS) and/or amphetamine (AM) on different memory phases in the passive avoidance task in rats. The performance of rats was evaluated in the retention tests 24 and 48 h after a single acquisition trial. ICS exposure lasting 1 h impaired retention of the learned avoidance response if applied 2 to 4 h before or immediately after training. The stressor did not affect retrieval if presented 5 or 2 h before the retention test. AM was used i.p. at the dose of 8 or 1 mg/kg. Neither 8 mg AM administered 4 h before nor 8 or 1 mg doses given after training did not impair the retention performance in unstressed rats. The 1 mg AM prevented the impairment of retention in animals exposed to the stressor 3 or 4 h before training but had no effect when the stronger impairment was induced by ICS 2 h before training. However, when given 1 h before retention testing, 1 mg AM attenuated even the severe impairment induced by the pre-training stressor exposure. Our results suggest that ICS impairs primarily the early phase of memory consolidation and a low dose of AM can prevent this effect.     

Effect of drugs of the nootropic class on rat behavior after deprivation of the paradoxical stage of sleep

Pharmacological analysis was used for studying the influence of 24-hour deprivation of paradoxical sleep by Jouvet method on retention of conditioned reaction of passive avoidance in rats. Psychotropic substances of different action were used for the analysis: nootropes as anti-amnestic--pyracetam (400 mg/kg), kleregil (100 mg/kg), centrofenoxin (50 mg/kg) and watersoluble salt of 3-oxypiridin derivative (3-OP) (50 mg/kg) and tranquilizer of bensodiazepine series phenazepam (1 mg/kg) as antistress and antiphobic. It was established that 24-hour deprivation disturbed the elaborated reaction but did not change the rate of emotionality and orienting-investigating behaviour of rats in the open field. Nootropes effectively restored the conditioned passive avoidance reaction while phenazepam had no effect. This allows to suggest that Jouvet method of paradoxical sleep deprivation elicits amnesia and its cause is not only stress but deficit of paradoxical sleep.