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Systemic injection of pirenzepine induces a deficit in passive avoidance learning in rats.

When injected IP, the M1 muscarinic receptor antagonist pirenzepine dose-dependently induced a deficit in passive avoidance learning in rats. This activity was optimal at 75 mg/kg injected 1 h before the acquisition session. The deficit induced by pirenzepine was antagonized by oxotremorine (0.03-0.3 mg/kg SC) and physostigmine (0.1 mg/kg SC), but not neostigmine. By comparison, under the same experimental conditions, physostigmine and oxotremorine also antagonized the deficit induced by an equipotent dose of scopolamine (0.5 mg/kg IP), although the activity of physostigmine appeared stronger against scopolamine than against pirenzepine. These results suggest that pirenzepine could produce a centrally-mediated behavioural disruption when injected systemically.

Animals↗

Deficits in passive-avoidance learning following atropine in the developing rat.

The maturation of cholinergic inhibitory mechanisms that may be involved in passive-avoidance learning was studied in rats 14, 17, 21, 25, 28, and 34 days of age. Acquisition and extinction of the conditioned response were examined under saline and atropine sulfate (5 mg/kg). Learning was also tested following scopolamine hydrobromide injections (1, 4, 8 mg/kg) in rats 17 days of age and following alpha-methylatropine (5 mg/kg) in 17- and 34-day-old groups. In normal animals the rate of acquisition increased during ontogenesis, with a significant improvement between postnatal days 17 and 21, whereas the rate of extinction did not vary with age. Acquisition was impaired by atropine sulfate at all ages and even totally prevented in younger groups (14 and 17 days of age). It was also completely disrupted by scopolamine in 17-day-old rats. Extinction following acquisition under atropine was more rapid than after normal acquisition. Methyl-atropine was without effect. These results support the hypothesis of central cholinergic mechanisms involved in response suppression, already functioning in the rat 14 days of age and maturing mainly between the 17th and the 21st postnatal days.

Age Factors↗

Passive avoidance learning involves alpha2-noradrenergic receptors in a day old chick.

Day-old chicks were trained on one-trial passive avoidance task, using methyl-anthranilate (MeA) as an aversive substance. Bilateral pharmacological manipulation of the intermediate hyperstriatum ventrale was performed by intracerebral application of an alpha2-noradrenergic agonist, clonidine (5 microM), or an antagonist, rauwolscine (300 microM). Only rauwolscine application (pre- or post-training) induced significant memory impairment. Quantitative receptor autoradiography was used to determine the kinetic properties of the binding sites for [3H]clonidine or [3H]rauwolscine in MeA-trained or water-trained (control) chicks, in forebrain areas known to be involved in avoidance learning. Scatchard analysis revealed that MeA-training resulted in a significant bilateral upregulation in the number of [3H]rauwolscine binding sites (Bmax) in the area of hyperstriatum ventrale. These findings suggest the importance of activation of alpha2-noradrenergic receptors in aversive learning in chicks.

Adrenergic alpha-Agonists↗

Methylphenidate effects on avoidance learning at two ages in the rat.

The major purpose of this investigation was to assess the effects of methylphenidate on avoidance learning at two ages. The subjects were 96 naive albino rats, equally divided between the sexes. One-half received daily drug administrations beginning at 47 days of age; one-half began at 87 days of age. Both groups were divided into three drug dosage levels (0.5, 1.5 and 4.5 mg/kg) and a distilled water control group. Methylphenidate was administered s.c. for a total of 18 days. Following 3 days of drug administrations only, 10 daily trials on avoidance conditioning were administered approximately 10 min after drugging to a total of 150 trials. The major findings indicated that: (1) no significant difference in avoidance response acquisition was obtained in the comparison between drug and control groups, (2) a dose effect was obtained in that the M4.5 group made siginificantly more correct responses than the M1.5 group, and (3) animals drugged beginning at 87 days made significantly more correct responses than those drugged beginning at 47 days.

Aging↗

Effects of some beta-adrenoceptor blockers on avoidance learning in rats.

In experiments on male Wistar rats, we studied the effects of some beta-adrenoceptor blockers: nonselective-propranolol, pindolol and 3b (a new aminotetraline derivative); and cardioselective (beta 1)-acebutolol and talinolol, on avoidance learning. The nonselective beta-adrenoceptor blockers failed to deteriorate and in some cases even facilitated learning, estimated by the number of avoidance responses and their latencies, while the cardioselective blockers significantly impaired learning process. A significant learning-impairing effect was shown by the beta 2-adrenoceptor agonist salbutamol. Similar was the effect of the mixed alpha- and beta-adrenoceptor blocker labetalol. The results are interpreted in connection with the functional role of beta 1- and beta 2- adrenoceptors in the CNS and with the importance of their balance for learning process.

Adrenergic alpha-Antagonists↗

Active and passive avoidance learning in controls and schizophrenic patients on racemic propranolol and neuroleptics.

Normal controls and schizophrenic patients on propranolol as sole drug or combined with neuroleptics showed superior active and passive avoidance learning to schizophrenic patients who were medicated with conventional neuroleptics only. Active avoidance involved responding quickly, passive avoidance withholding a response to avoid an unpleasant noise and reacting to the appropriate stimulus. This may reflect an improvement brought about by propranolol in the limbic regulation of stimulus and response processes.

Adult↗

Influence of hippocampal kindling on avoidance learning in cats.

The formation of avoidance response and differentiation was studied in 13 control and 7 kindled cats with developed hippocampal epileptic focus and complex partial or secondary generalized tonic-clonic seizures. Conditioning sessions lasted from 15 to 20 min in a period following afterdischarges and seizures resulting from electrical stimulation of the hippocampal formation. In two out of seven kindled cats the conditioned reflex was established within time limits (9 and 20 days) comparable to the control cats. These two animals had relatively short-lasting afterdischarges (mean values: 17 and 19 s). In cats with longer-lasting afterdischarges and complex partial seizures (mean duration: 32 to 65 s, in different animals) criterion was not reached during parallel kindling-conditioning stage of 10 to 30 days. The level of correct responses was low and variable (0-70 percent), despite typical reactions to the unconditioned stimuli and clear orienting responses to the conditioning stimuli on more advanced stages of training. Four kindled animals entered the stage of secondary generalization of seizures after hippocampal stimulation. Reflex performance after tonic-clonic seizures was practically abolished. The termination of kindling resulted in acquisition of the conditioned reflex in all the animals. The results indicate, that in animals with long-lasting complex partial seizures the learning of the avoidance response is impaired. In contrast to the effects exerted by afterdischarges and complex partial seizures, intensive interictal hippocampal spiking did not seem to have a direct negative influence on, this particular type of learning.

Animals↗

Effects of alpha-adrenoceptor agonists and antagonists on histamine-induced impairment of memory retention of passive avoidance learning in rats.

The effect of alpha-adrenoceptor agents on the impairment induced by histamine was measured for memory retention of passive avoidance learning in rats. Post-training intracerebroventricular (i.c.v.) injection was carried out in all the experiments. Histamine (5, 10 and 20 microg/rat) reduced, while a histamine H(1) receptor antagonist, chlorpheniramine (0.1, 1 and 10 microg/rat), increased memory retention. The histamine H(2) receptor antagonist, ranitidine (0.1, 1, 10 and 20 microg/rat), did not elicit any response in this respect. Different doses of chlorpheniramine but not ranitidine reversed the histamine-induced impairment of memory. Clonidine and prazosin decreased, but yohimbine and phenylephrine increased, memory retention. Yohimbine decreased the inhibitory response to histamine. Phenylephrine, clonidine and prazosin did not alter the histamine effect. It is concluded that a histamine-induced impairment of memory retention through histamine H(1) receptors and an alpha(2)-adrenoceptor mechanism may be involved in the histamine response.

Adrenergic alpha-Agonists↗

Effects of GABAergic drugs on physostigmine-induced improvement in memory acquisition of passive avoidance learning in mice.

1. The effect of gamma-aminobutyric acid (GABA) receptor agonists and antagonists on acquisition of a step-down passive avoidance learning in mice was measured in the presence and absence of physostigmine. 2. Intraperitoneal injection of different doses of the anticholinesterase drug physostigmine (0.1-0.3 mg/kg) increased acquisition in mice dose dependently. The maximum response was obtained with 0.3 mg/kg of the drug. Higher doses of the drug impaired acquisition of the learned response. To show the effect of the GABAergic system on acquisition, GABAA receptor agonists and antagonists were challenged against 0.2 mg/kg of physostigmine. 3. Administration of the GABAA receptor agonist muscimol but not the GABAB receptor agonist baclofen decreased the acquisition of the learned task. However, the improvement induced by physostigmine (0.2 mg/kg) was decreased by both muscimol and baclofen. A combination of both agonists caused a higher inhibitory effect on the physostigmine response. 4. Pretreatment of animals with the higher doses of GABAA receptor antagonists bicuculline and picrotoxin but not the GABAB receptor antagonist phaclofen impaired learning. Both the GABAA and GABAB receptor antagonists reduced the learning improvement induced by physostigmine. The inhibitory effects of the GABAA and GABAB receptor antagonists are lost when combined together. 5. Bicuculline, picrotoxin or phaclofen increased the impairment of learning induced by muscimol, whereas a combination of either of the antagonists with baclofen did not alter the learning. The GABAA antagonists reduced the inhibitory effect of muscimol, whereas a higher dose of phaclofen increased the inhibition of the physostigmine response induced by muscimol and baclofen on physostigmine-induced learning improvement. 6. Phaclofen decreased but a higher dose of bicuculline increased the baclofen-induced inhibition of physostigmine effect. 7. It is concluded that both GABAA and GABAB activation inhibit improvement of acquisition induced by physostigmine.

Animals↗

Phencyclidine and behavior: II. Active avoidance learning and radial arm maze performance.

Rats with injections of 4 or 8 mg/kg of phencyclidine (PCP) are impaired in the acquisition of active avoidance learning and radial arm maze performance. This impairment was not due to a change in detectability of aversive stimuli or the inability to perform the correct response. The primary deficit appears to be the inability of PCP injected animals to encode the appropriate attributes (e.g., environmental context, response selection, and emotion) associated with each task.

Animals↗

Substance P enhancement of inhibitory avoidance learning: mediation by the N-terminal sequence.

Experiments were performed to investigate the effects of intraperitoneally administered undecapeptide substance P (SP), its N-terminal fragment SP(1-7) (SPN) and the C-terminal analog [pGlu6]-SP(6-11) (SPC) on inhibitory avoidance learning, using a one-trial up-hill avoidance task. In Experiment 1 rats were injected with either SP (50 micrograms/kg), SPN (3.3, 33, 167, 333 micrograms/kg) or SPC (2.7, 27, 134, 268 micrograms/kg) immediately after the training trial. Controls received the diluent vehicles. When tested 24 hr later, rats injected with 50 micrograms/kg SP (37 nmol/kg) and 167 micrograms/kg SPN (185 nmol/kg) exhibited longer step-up latencies than vehicle-treated controls. None of the other doses of SPN nor of the C-terminal fragment influenced performance. In Experiment 2, 167 micrograms/kg SPN or vehicle was injected posttrial either immediately or 5 hr after the training trial. Retention latencies 24 hr later were longer for rats treated with 167 micrograms/kg SPN immediately after the training trial. Performance of the SPN 5-hr delay group did not differ from that of the vehicle-injected controls, ruling out proactive effects of SPN on recall.

Animals↗

Effects of low doses of physostigmine on avoidance learning and EEG in two strains of mice.

The effects of the cholinomimetic drug, physostigmine (0, 0.01, 0.025, 0.05 and 0.1 mg/kg, i.p.), on shuttle-box avoidance learning and electroencephalographic (EEG) activity were investigated, in two separate studies, in mice belonging to the inbred C57BL/6 (C57) and DBA/2 (DBA) strains. The results of the behavioral investigation showed a consistent, significant enhancement of avoidance performance, on the whole of 5 daily training sessions, in C57 mice treated with the lowest dose (0.01 mg/kg) and in DBA mice treated with the highest doses (0.05 and 0.1 mg/kg) of the drug. Doses higher than 0.01 mg/kg, in C57 mice, and lower than 0.05 mg/kg, in DBA mice, had no significant effect. The avoidance improvements induced by physostigmine cannot be ascribed to general behavioral activation, since the doses that increased avoidance responses did not affect or even depressed spontaneous locomotor activity. The same doses of treatment which increased avoidance responding, also induced, in the same strains, consistent enhancement of 4-7 Hz (theta) EEG band power and decrease of 7-12 Hz (alpha) band power. Results suggest that the effects induced by physostigmine on the EEG and on the shuttle-box performance of mice are related to the same neurochemical systems, and are dependent upon the interaction of the dose with specific strain sensitivity.

Animals↗

Effects of histamine and opioid systems on memory retention of passive avoidance learning in rats.

The present study investigated the effect of interactions between histamine receptor agents and the opioid peptidergic system on memory retention of passive avoidance learning in rats. Post-training intracerebroventricular (i.c.v.) injections were carried out in all the experiments. Administration of histamine (20 micro g/rat) reduced, but the histamine H(1) receptor antagonist, pyrilamine (20 and 50 micro g/rat), and the histamine H(2) receptor antagonist, cimetidine (10 and 50 micro g/rat), increased memory retention in rats. The histamine receptor antagonists decreased the response induced by histamine. Morphine (1-10 micro g/rat) reduced, while pentazocine (5 and 10 micro g/rat) or the opioid receptor antagonist, naloxone (5 and 15 micro g/rat), increased memory retention. The combination of histamine with morphine showed potentiation. Effects of pyrilamine and cimetidine were attenuated by morphine. The responses to pentazocine and naloxone also were decreased by histamine. It is concluded that the histaminergic system has an interaction with opioidergic system that is involved in the memory retention process.

Animals↗

Serotonin receptor involvement in the avoidance learning deficit caused by p-chloroamphetamine-induced serotonin release.

The receptor involvement in the p-chloramphetamine (PCA, 2.5 mg kg-1) induced impairment of active avoidance acquisition was examined in the male rat. The avoidance deficit was blocked at low doses by serotonergic (5-HT)-receptor blocking agents but not by alpha-adrenergic-, beta-adrenergic-, opiate-, muscarinic- or dopamine D2-receptor antagonists. The potency of the 5-HT antagonists to block the PCA-induced deficit correlated with their affinity in displacing [3H]ketanserin but not [3H]5-HT binding in the frontal cortex. The potencies of the 5-HT antagonists to block the action of PCA could not be related to their action on muscarinic-, histaminergic H1- or dopaminergic D2-receptor binding in vitro. It is concluded that the avoidance learning deficit caused by PCA-induced 5-HT release is related to activation of 5-HT receptors in the frontal cortex having the characteristics of a 5-HT2 receptor.

Adrenergic alpha-Agonists↗

Nimodipine on shuttle-box avoidance learning in mice: no impairment but slight improvement.

The dihydropyridine calcium channel antagonist nimodipine was tested in mice of CD-1, C57BL/6, and DBA/2 strains subjected to shuttle-box avoidance training. In contrast with some findings of other authors showing impairment of shuttle-box avoidance learning by low doses of the drug in rats, nimodipine given IP before each training session at doses of 0.25, 0.5, 1, 2.5, or 5 mg/kg never impaired avoidance acquisition in mice. On the contrary, one dose of nimodipine (1 mg/kg) significantly improved avoidance acquisition in mice of the DBA/2 strain. The drug failed to impair avoidance performance in DBA/2 mice even if given acutely in the middle (third session) or at the end (fifth session) of the training period. The results contradict studies showing cognitive impairment induced by calcium channel blockers, and may provide some limited evidence in support of improved cognitive function in normal animals, although this effect is much less evident than in aged or brain-damaged subjects.

Animals↗

Effects of anisomycin on brain protein synthesis and passive avoidance learning in newborn chicks.

The effects of anisomycin (ANM) on newborn chicks have been studied with respect to brain protein synthesis, growth, EEG, toxicity, and several passive avoidance learning tasks. It was found that intracerebral ANM (80 nmol) gave a maximum inhibition of brain protein synthesis of 30%, while a combination of subcutaneous (10 mumol; 53 mg/kg) plus intracerebral (80 nmol; 21 mug) ANM inhibited by 91% in the first 2 hr and by 75% in the subsequent 2 hr period. Cycloheximide (CXM) also in combined injections at the same doses as ANM, inhibited by 97% in the 4 hr that followed injection. However, all the CXM-injected chicks were dead by 18 hr, while the lethality of ANM did not differ from that of saline. ANM also did not affect EEG measured at 1, 3, 5, or 24 hr following the subcutaneous plus intracerebral injections, nor did ANM affect body or brain growth curves or brain protein accretion. In the learning experiments, animals were initially trained to peck at water-coated metal spheres (type A learning) or at water imbibed birdseed (types B and C learning) in less than 1 sec, and were exposed to the same lures treated with the aversant methylanthranilate (MeA) one day later on one occasion (types A and B learning) or exposed twice (type C learning) and tested for learning retention one day later. Learning criterion was set as failure to peck at the lure during the first 20 sec of presentation. If ANM was injected 1 hr prior to MeA exposure, large and highly significant memory deficits were found during the retention test, as compared with saline injected controls. No effect of ANM was seen, however, if it was injected one day after learning, indicating that it did not interfere with retrieval mechanisms. ANM also decreased the external manifestations of fear or displeasure that chicks express during retention testing. Such manifestations have a high correlation with pecking suppression (r = 0.88, P less than 0.001).

Amino Acids↗

Inhibitory avoidance learning alters the amygdala calcium/calmodulin-dependent protein kinase II activity in rats.

This study investigated the role of amygdala CaM-kinase II (calcium/calmodulin-dependent protein kinase II) in affective learning and memory. In Experiment I, two groups of rats were trained on a one-trial step through inhibitory avoidance learning task. The experimental group received a high intensity foot shock contingent upon the stepping-through behavior, whereas the control group received a series of non-contingent low intensity foot shock during training. The experimental rats showed significantly higher retention scores than the control rats. Correspondingly, rats in the experimental group showed significantly higher Ca2+-independent activity of CaM-kinase II than the controls. Intra-amygdala injection of a specific CaM-kinase II inhibitor, KN-62, before the training trial disrupted affective learning. In comparison with the vehicle-injected controls, pretraining injection of KN-62 impaired the acquisition of affective specific learning. These results, taken together, indicated that the activation of amygdala CaM-kinase II in the amygdala is associated with the affective learning behavior, and may be one of the neural mechanisms underlying formation of affective memory.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

Observation learning in day-old chicks using a one-trial passive avoidance learning paradigm.

We tested the hypothesis that day-old chicks, Gallus gallus domesticus, can learn to avoid an aversive stimulus if they observe the responses of another chick. In experiment 1, one of a pair of chicks (the actor) was allowed to peck at a bead coated in the bitter-tasting substance methylanthranilate (MeA), while we prevented the other chick (the observer) from pecking the bitter-tasting bead by separating the chicks with a piece of wire mesh. Both chicks avoided pecking at a similar but dry bead 0.5, 3 and 24 h after the observer chick saw the actor chick peck at an MeA-coated bead. By contrast, when the actor chick had pecked at a water-coated bead, both chicks continued to peck at a dry bead at 0.5, 3 and 24 h after training. Experiment 2 investigated whether observer chicks showed avoidance if they were prevented (by the insertion of an opaque barrier) from observing their companion pecking at the MeA-coated bead during either training or testing. Observer chicks that could not see their companion during training but could observe the actor chicks at test showed no subsequent avoidance whereas chicks that observed the actor chick at training, but not during testing, showed high levels of avoidance. Although the sensory cues (visual, auditory or olfactory) or types of behaviour (i.e. levels of pecking or head shaking) that the observer chick used to maintain avoidance remain unclear, the results show that chicks can learn about an aversive object by observing the responses of a conspecific. (c) 1998 The Association for the Study of Animal Behaviour.

Journal Article↗