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Juvenile stress induces a predisposition to either anxiety or depressive-like symptoms following stress in adulthood.

Epidemiological studies indicate that childhood trauma is predominantly associated with later emergence of several stress-related psychopathologies. While most 'early-stress' animal models focus on pre-weaning exposure, we examined the consequences of exposure to stress during the early pre-pubertal period, "juvenile stress", on adulthood stress responses. Following two different juvenile stress protocols, predator scent or short-term variable stress, we examined adulthood stress responses using the elevated plus-maze and startle response or exploration and avoidance learning. Employing Cut-off Behavioral Criteria analyses of clustering symptoms on the rats' altered stress responses discriminated between different patterns of maladaptive behaviors. Exposure to either juvenile stress protocols resulted in lasting alteration of stress responses with the majority of rats exhibiting anxiety-like behaviors, while the remaining third displayed depressive-like behaviors. The results suggest that the presented "Juvenile stress" model may be relevant to the reported predisposition to develop both anxiety and depression following childhood trauma.

Acoustic Stimulation↗

Intrahippocampal GMP administration improves inhibitory avoidance performance through GABAergic and glutamatergic mechanisms in rats.

Guanidino compounds play specific physiological and pathological roles in the central nervous system. We investigated the effect of an intrahippocampal infusion of GMP (a guanidino compound) administered immediately post-training on the inhibitory avoidance learning paradigm in rats. Bilateral intrahippocampal micro-injection of GMP (0-30 nmol) caused a dose-dependent increase in test step-down latencies which was completely reversed by intrahippocampal co-administration of muscimol or baclofen (GABA agonists) or preadministration (15 min pre-training, i.p.) of MK-801 (an NMDA antagonist). These results provide evidence for a participation of GABA and NMDA receptors in the GMP-induced increase in the test step-down latencies.

Animals↗

Age-related effects of aluminum ingestion on brain aluminum accumulation and behavior in rats.

Both aluminum and aging have been associated with neurobehavioral changes in mammals. This study assessed in young (21 day old), adult (8 months), and old rats (16 months) the effects of prolonged aluminum ingestion on open-field activity and passive-avoidance conditioning. Aluminum was administered in drinking water as aluminum nitrate at doses of 0, 50, and 100 mg Al/kg/day over a 6.5 month period. There were no aluminum effects on the horizontal and vertical activity in an open-field, or in passive-avoidance learning in any group. On the other hand, measurement of aluminum concentrations in a number of brain regions indicated that the olfactory bulb and the rhachidical bulb were the regions with the highest aluminum levels, while the cortex and the thalamus were the cerebral regions showing the lowest aluminum content. For most brain regions analyzed the highest aluminum concentrations were found in young rats, which would indicate that early stages of the life cycle must be considered for enhanced brain aluminum accumulation.

Aging↗

Effects of a new thyrotropin-releasing hormone derivative on behavioral changes after focal cerebral ischemia in rats.

We observed the effects of a new thyrotropin-releasing hormone derivative, YM-14673 (N alpha-[[(S)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide dihydrate), on behavioral changes in rats for 3 weeks after focal cerebral ischemia. Under halothane anesthesia, the left middle cerebral artery was occluded via a transretro-orbital approach. YM-14673 was administered just after the operation and once a day for 3 weeks. Neurologic deficits, including hemiplegia and abnormal posture, and disturbance of passive avoidance learning were present in solvent-treated control rats for the entire 3 weeks. YM-14673 at 0.1 or 0.3 mg/kg i.p. or 1 mg/kg p.o. significantly accelerated the recovery of neurologic deficits and ameliorated cognitive disturbance compared with the solvent-treated controls although the drug at 0.1 and 0.3 mg/kg i.p. did not influence the size of the ischemic infarct. YM-14673 mitigated the behavioral disturbances in this model of chronic focal cerebral ischemia. We also discuss the suitability of this model for the evaluation of drugs.

Animals↗

Effects of indeloxazine hydrochloride (YM-08054) on anoxia.

Effects of indeloxazine hydrochloride [(+/-)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride, YM-08054] on anoxia were examined. Indeloxazine significantly prolonged survival time of mice subjected to anoxia and improved anoxia-induced impairment of the passive and active avoidance learnings in rats. Indeloxazine at doses inducing anti-anoxic actions showed no effect on cerebral blood flow in cats and pentobarbital sleeping time in mice. Therefore, anti-anoxic actions of indeloxazine are not attributable to cerebral vasodilative or central depressant activities. Calcium hopantenate (cerebral metabolic enhancer) also showed anti-anoxic actions, whereas neither viloxazine, amitriptyline (antidepressant) nor dihydroergotoxine (cerebral vasodilator) showed any effect on anoxia. These results suggest that indeloxazine possesses anti-anoxic activities similar to calcium hopantenate. The mode of anti-anoxic actions of indeloxazine is also discussed.

Amitriptyline↗

Hemophilus influenzae meningitis in the rat: behavioral, electrophysiological, and biochemical consequences.

Hemophilus influenzae is the most common cause of bacterial meningitis in children, and a high percentage of survivors are at risk for long-term sequelae. To explore the mechanisms responsible for these sequelae, a neonatal rat model was used to define the behavioral, electrophysiological, and biochemical changes following meningitis. Three days after inoculation of 6-day-old rats with a minimum of 1 X 10(7) colony-forming units of a virulent Hemophilus influenzae, type b, cerebrospinal fluid and blood were cultured to confirm the presence of meningitis and bacteremia, respectively. At this time, forebrain norepinephrine and dopamine levels were significantly elevated in meningitic rats when standardized on a wet-weight basis. No changes in brain serotonin or heart norepinephrine levels could be found in the 9-day-old rats. No residual changes were found in steady-state concentrations of norepinephrine or dopamine in surviving adult rats. However, survivors that had had meningitis as neonates showed significant impairment in active and passive avoidance learning tasks and demonstrated a significantly higher level of activity during a habituation period in circular photocell activity cages. No change in the flinch-jump threshold was detected. Brainstem auditory evoked potentials showed delays of various waves in 3 of 10 Hemophilus influenzae type b-treated adult rats tested. These rats also exhibited markedly augmented locomotory responses to d-amphetamine (1 mg/kg), suggesting a long-lasting perturbation of central monoamine neuronal transmission.

Age Factors↗

A caspase inhibitor blocks ischaemia-induced delayed neuronal death in the gerbil.

Caspases play a critical role in the cell death machinery in various cell types. Here we investigated the involvement of caspases in the delayed neuronal death after transient global forebrain ischaemia in the gerbil. Intrahippocampal injection of benzyloxycarbonyl-Asp-CH2-dichlorobenzene (zD), an irreversible inhibitor of caspases, saved hippocampal CA1 neurones from chromatin condensation and DNA fragmentation at post-ischaemia day 4, and these neurones maintained normal morphology at day 8 post-insult. Intrahippocampal injection of interleukin-1beta (IL-1beta) after ischaemic insults did not influence the neuroprotective effect of zD, suggesting that the neuroprotective effect does not depend on the inhibition of mature IL-1beta production. Animals that received zD-injection showed significant improvement in step-through and step-down passive avoidance learning at post-ischaemia days 4 and 5, suggesting that neural functions were preserved in these animals. At post-ischaemia day 4, the cleavage of poly(ADP-ribose)polymerase was observed, and this cleavage was almost completely suppressed in zD-injected hippocampus, suggesting involvement of caspase-3 and caspase-3-like caspase in the delayed neuronal death. Our findings indicate that caspases play important roles in the delayed neuronal death after transient global forebrain ischaemia in the gerbil, and suggest that ischaemia-induced brain damage can be blocked by caspase inhibitors.

Animals↗

Identification of a novel glial fibrillary acidic protein mRNA isotype related to memory retention in rats.

Using the polymerase chain reaction (PCR) differential display directed to cloning transcripts related to retention performance for the inhibitory avoidance learning task, we have isolated two rat cDNA fragments homologous to the 3' untranslated region (3'UTR) of glial fibrillary acid protein (GFAP) cDNA. The GFAP upper cDNA represents a new GFAP mRNA isotype which has a 7 bp insertion in the 3'UTR. Further analyses indicated that retention performance in rats containing only the new GFAP mRNA isotype was significantly better than that of rats containing both the new GFAP mRNA isotype and the standard GFAP mRNA simultaneously. These results suggest that expression of the GFAP isotypes may be related to memory retention in rats.

Animals↗

Dissociation between the effects of pre-weaning and/or post-weaning social isolation on prepulse inhibition and latent inhibition in adult Sprague--Dawley rats.

Human attentional impairments can be modelled in the rat using the prepulse inhibition (PPI) or the latent inhibition (LI) paradigm. The present study investigated the consequences of a combination of pre-weaning maternal separation (MS) and post-weaning social isolation (SI) on both PPI and LI in male and female Sprague--Dawley rats tested as adults. We report here a double dissociation between the effects of MS (repeated 4 h daily separations) and SI on PPI and LI: MS did not modify PPI, but enhanced LI. In contrast, SI disrupted PPI, the deficits being restricted to male rats, but left LI intact. There were no additive effects of MS and SI on PPI or LI. While MS improved avoidance learning, SI impaired it. Although both PPI and LI assess processes of selective attention, our results support the contention, already stated in the literature, that they involve differing neuro-psychological mechanisms. Furthermore, the fact that only males exhibited PPI deficits following SI has implications for the well-known differential vulnerability of human males to certain psychiatric disorders (e.g. schizophrenia). Finally, the combination of MS and SI could represent a relevant animal model for some aspects of schizophrenia, since both PPI and LI were altered.

Animals↗

Effects of delta 9-THC on pregnancy and offspring in rats.

Pregnant rats were intubated with increasing doses of delta 9-THC (5-50 mg/kg/day) up to gestation day 5. On gestation day 5, these animals continued to receive either 50 or 150 mg/kg/day of delta 9-THC. Animals receiving the 50 mg/kg/day dose and a control group of vehicle (olive oil) treated animals were pair-fed and pair- watered to animals given the 150 mg/kg/day dose. A second control group served as nontreated, ad lib control animals. Animals were tested postnatally for spontaneous alteration, avoidance learning and rotarod behavior to determine if delta 9-THC was behaviorally teratogenic. Drug treatments produced a dose-related decrease in pregnancies carried to term, weight gain during pregnancy, and birth weight. However, since no viable litters were born to animals in the high dose-group, their data was not included in statistical analyses. Nevertheless, the effects of drug treatment (50 mg/kg/day) were still statistically significant for weight gain during pregnancy and birth weight. Drug treatment (50 mg/kg/day) did not affect litter size or weight at 21 days of age, nor did it affect any of the behavioral tests.

Animals↗

Post-lesion administration of 5-HT1A receptor agonist 8-OH-DPAT protects cholinergic nucleus basalis neurons against NMDA excitotoxicity.

Recent evidence indicates that serotonin (5-HT)1A receptor agonists may abrogate excitotoxic brain damage. We investigated whether a single i.p. injection of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), at a dose of 2.5 mg/kg, protects cholinergic neurons of the rat magnocellular nucleus basalis (MBN) against NMDA excitotoxicity when administered at post-injury intervals ranging from 6 to 96 h. Drug effects on passive avoidance learning and on the density of cortical cholinergic innervation, a measure of neuronal survival in the damaged MBN, were analyzed. Our results demonstrate that 8-OH-DPAT, when administered up to 24 h post-lesion, significantly attenuates both behavioral and neuroanatomical consequences of NMDA excitotoxicity on cholinergic MBN neurons; and support the hypothesis that 5-HT1A receptor agonists may interfere with delayed neuronal death in vivo that is of significance in the pharmacological treatment of neurological disorders associated with excitotoxic neuronal damage.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

[Changes in the content of water-soluble brain proteins-antigens during bilateral avoidance training of rats].

The levels of water-soluble brain antigens have been studied during bilateral avoidance learning in Wistar rats. With the help of cross and rocket immunoelectrophoresis the content of antigens was measured in the brain structures an hour and a week after training. It was shown that the content of one of six antigens in the auditory cortex correlated with the number of tone-shock combinations. The antigen was not found in the liver and its amount was higher in the brain stem, as compared to cerebral cortex and cerebellum. The results suggest that this antigen may be involved in the processes of memory build-up.

Acoustic Stimulation↗

State dependent and/or direct memory retrieval by morphine in mice.

Mice were trained in step-down and step-through type passive avoidance learning tasks and given retention tests. Pre-training administration of morphine impaired retention, the effect recovering completely after an additional injection of the same dose of morphine given 30 min before the retention test. Amnesia produced by scopolamine, cycloheximide and electroconvulsive shock was also reversed by pre-test morphine. Pre-test saline also reversed the morphine-induced memory impairment to some extent, indicating that the recovery may partially be due to the state dependent effect. Thus, it is demonstrated that pre-test morphine not only state dependently but also directly reversed memory impairment in mice.

Amnesia↗

Modulation of memory processing by glutamic acid receptor agonists and antagonists.

Recent hypotheses suggesting a critical role of glutamate receptors in hippocampal long-term potentiation and memory processing suggested a closer examination of this transmitter's effect on memory processing in an in vivo setting. New pharmacological antagonists allow for a separation and examination of various glutamate receptors and their role in memory processing. Mice were trained on a shock avoidance learning paradigm and injected intracerebroventricularly after training with agonists and antagonists of various classes of glutamate receptors. Retention was tested 1 week after training. N-Methyl-D-aspartate (NMDA) receptor agonists enhanced retention in a dose-dependent manner. The enhancement of retention by the non-NMDA agonist kainic acid and quisqualic acid was dose-dependent. L-Glutamic acid, but not D-glutamic acid, enhanced retention. Both NMDA and non-NMDA receptor antagonists produced dose-dependent impairment of retention for footshock training. Administration of the antagonists 24 h after training did not impair memory retention.

Animals↗

Altering a dominant response: performance of psychopaths and low-socialization college students on a cued reaction time task.

The passive avoidance learning deficits of disinhibited Ss have been attributed to their difficulty inhibiting dominant responses. To date, evidence for this hypothesis has been derived from complex tasks. In two experiments, a cued reaction time task requiring no learning or memory was used to evaluate the degree to which groups of disinhibited Ss inhibit simple dominant responses. Disinhibited groups were incarcerated psychopaths identified with Hare's (1985) Psychopathy Checklist and undergraduate males who scored low on the Socialization Scale. Both disinhibited groups committed more errors than controls on trials containing misleading cues, but in both samples, findings were limited to trials in which Ss expected to make right-hand responses. Although alternative interpretations are possible, these data are consistent with the proposal that disinhibited individuals are less likely to inhibit well-established dominant responses.

Adult↗

CRF increases protein phosphorylation and enhances retention performance in rats.

This study examines the roles of PKC and protein phosphorylation in the retention performance of a passive avoidance learning (PAL) task in rats. Results revealed that H7 injected into the dentate gyrus (DG) of the hippocampus impaired retention in a dose-dependent manner. Corticotropin-releasing factor (CRF) injected into the DG improved retention and this facilitation was antagonized by H7 pretreatment. CRF increased phosphorylation of five proteins, whereas H7 decreased phosphorylation in three of these proteins in both the cytosol and the membrane fractions of hippocampus. These effects were shown not to be associated with stress. These results demonstrate that CRF increased protein phosphorylation associated with enhanced retention of PAL task in rats.

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

Inhibition of long-term memory formation in the chicken by anti chick Thy-1 antibody.

Anti-chick Thy-1 antibodies administered close to a single trial passive avoidance learning task in day-old chicks resulted in inhibition of long-term memory formation. The retention time course was comparable to that obtained with the protein synthesis inhibitor anisomycin. The amnestic effect of the anti-chick Thy-1 antibody appears to be mediated solely by immunoglobulin G, and is species specific since anti-rat Thy-1 antibodies did not produce amnesia. The results are consistent with a three stage model of memory formation, suggest a role for glycoproteins in long term memory formation, and emphasise the potential of neuroimmunological tools for investigating the neurological bases of memory formation.

Animals↗

Isolation-stress-induced facilitation of passive avoidance memory in the day-old chick.

This study showed that facilitation of recall of a weak version of the 1-trial passive avoidance learning task could be achieved by behavioral "stressing" of day-old chicks after training. Recall, usually retained for less than 9 hr, was extended by socially isolating the chicks for 1 hr immediately after training. There was a brief 3-fold increase in plasma corticosterone levels 10 min after isolation. Facilitated recall was not evident when chicks were isolated 2 hr after training, and it was blocked by intracerebral administration of 2-ng RU 38486, a specific glucocorticoid receptor antagonist, per chick. Male chicks responded more to isolation than did female chicks, presumably a consequence of the additional stress of the injection procedure.

Analysis of Variance↗