Early life stress exacerbates cognitive dysfunction induced by d-amphetamine: amelioration by valproic acid.

It has been demonstrated that experiences taking place early in life have a profound influence on brain development, interacting with the genetic background and determining differences in the vulnerability to the onset of bipolar disorder when the individual is exposed to a second adverse event later in life. Here, we investigated the effects of exposure to an early adverse life event (maternal deprivation) and to a later adverse life event [D-amphetamine (AMPH)] on cognition in an animal model of mania. We have previously demonstrated that that repeated AMPH exposure produces severe and persistent cognitive impairment, which was more pronounced when the animals were maternal deprived, suggesting that the early adverse life event could be potentiating the effects of the exposure to the second adverse life event later in life. Here, we show that valproic acid ameliorated the cognitive deficits induced by AMPH, but it was not effective when the animals were exposed to both stressors: maternal deprivation and AMPH treatment.

Rescue of social behavior impairment by clozapine and alterations in the expression of neuronal receptors in a rat model of neurodevelopmental impairment induced by GRPR blockade.

We have previously shown that pharmacological blockade of the gastrin-releasing peptide receptor (GRPR) during the neonatal period in rats produces behavioral features of developmental neuropsychiatric disorders. Here, we show that social interaction deficits in this model are reversed by the atypical antipsychotic clozapine given in the adulthood. In addition, we analyzed the mRNA expression of three neuronal receptors potentially involved in the etiology of disorders of the autism spectrum. Rats were injected with the GRPR antagonist RC-3095 or saline (SAL) from postnatal days 1-10, and tested for social behavior and recognition memory in the adulthood. One hour prior to the behavioral testing, rats were given a systemic injection of clozapine or saline. The mRNA expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor, the epidermal growth factor receptor (EGFR), and GRPR was measured in the hippocampus and cortex of a separate set of rats given RC-3095 or SAL neonatally. Rats given neonatal RC-3095 showed decreased social interaction and impaired object recognition memory. Clozapine rescued the social interaction impairment. Neonatal treatment with RC-3095 also resulted in dose-dependent decreases in the expression of GRPR, NR1, and EGFR in the cortex, whereas all three receptor mRNAs were increased in the hippocampus in rats treated with the lower dose of RC-3095. The results contribute to further validate the novel rat model of neurodevelopmental disorders induced by GRPR blockade, and shows alterations in the expression of neuronal receptors in this model.

Early life stress decreases hippocampal BDNF content and exacerbates recognition memory deficits induced by repeated D-amphetamine exposure.

Adverse experiences early in life may have profound influences on brain development, for example, determining alterations in response to psychostimulant drugs, an increased risk of developing a substance abuse disorder, and individual differences in the vulnerability to neuropsychiatric disorders later in life. Here, we investigated the effects of exposure to an early adverse life event, maternal deprivation, combined with repeated d-amphetamine (AMPH) administration in adulthood, on recognition memory and brain-derived neurotrophic factor (BDNF) levels in rats' brain and serum. Rats were exposed to one of the following maternal rearing conditions from postnatal days 1 to 14: non-deprived (ND) or deprived (D). In adulthood, both groups received injections of saline (SAL) or AMPH (2.0mg/kg, i.p.) for 7 days. In Experiment I (performed 24h after the last AMPH injection), AMPH induced long-term memory (LTM) impairments in ND and D groups. The D+AMPH group also presented short-term memory (STM) impairments, indicating that the effects of AMPH on memory were more pronounced when the animals where maternally deprived. The group exposed to D+SAL (SAL) showed only LTM impairments. In Experiment II (performed 8 days after the last injection), AMPH detrimental effects on memory persisted in ND and D groups. BDNF levels were decreased in the hippocampus of D+SAL rats. In conclusion, AMPH produces severe and persistent recognition memory impairments that were more pronounced when the animals were maternally deprived, suggesting that an early adverse life event may increase the vulnerability of cognitive function to exposure to a psychostimulant later in life.

Modulatory influence of dopamine receptors on consolidation of object recognition memory.

The role of dopamine receptors in regulating the formation of recognition memory remains poorly understood. Here we show the effects of systemic administration of dopamine receptor agonists and antagonists on the formation of memory for novel object recognition in rats. In Experiment I, rats received an intraperitoneal (i.p.) injection of vehicle, the selective D1 receptor agonist SKF38393 (1.0 and 5.0mg/kg), or the D2 receptor agonist quinpirole (1.0 and 5.0mg/kg) immediately after training. In Experiment II, rats received an injection of vehicle, the dopamine receptor antagonist SCH23390 (0.1 and 0.05 mg/kg), or the D2 receptor antagonist raclopride (0.5 and 0.1mg/kg) before training, followed by an injection of vehicle or the nonselective dopamine receptor agonist apomorphine (0.05 mg/kg) immediately after training. SKF38393 at 5mg/kg produced an enhancement of novel object recognition memory measured at both 24 and 72 h after training, whereas the dose of 10mg/kg impaired 24-h retention. Posttraining administration of quinpirole did not affect 24-h retention. Apomorphine enhanced memory in rats given pretraining raclopride, suggesting that the effect was mediated by selective activation of D1 receptors. The results indicate that activation of D1 receptors can enhance recognition memory consolidation. Importantly, pharmacological activation of D1 receptors enhanced novel object recognition memory even under conditions in which control rats showed significant retention.

Neonatal gastrin-releasing peptide receptor blockade reduces maternal odor preference in rats.

Alterations in attachment behavior might play a role in the dysfunction in social behavior displayed by autistic infants. Here we show that neonatal gastrin-releasing peptide receptor (GRPR) blockade induces a reduction in maternal odor preference, a task involving attachment behavior, in infant rats. These findings provide the first evidence that the GRPR regulates odor preference, supporting the view that the GRPR is involved in attachment and social behaviors.

Desferoxamine reverses neonatal iron-induced recognition memory impairment in rats.

We have previously demonstrated that rats given iron neonatally presented memory deficits. The aim of the present study was to evaluate the effect of desferoxamine, a metal chelating agent, on memory deficits in an iron overload model in rats. Male rats received vehicle or iron orally at postnatal days 12-14 and desferoxamine (30 or 300 mg/kg) in the adulthood. After desferoxamine treatment, they were trained in a novel-object recognition task. Iron-treated rats showed recognition memory impairments when compared to controls. Iron-treated rats that received desferoxamine 300 mg/kg, showed normal recognition memory, suggesting that desferoxamine can reverse recognition memory deficits associated with iron accumulation. Further research is required to examine whether the findings from animal models of iron overload have implications for humans.

Adrenergic enhancement of consolidation of object recognition memory.

Extensive evidence indicates that epinephrine (EPI) modulates memory consolidation for emotionally arousing tasks in animals and human subjects. However, previous studies have not examined the effects of EPI on consolidation of recognition memory. Here we report that systemic administration of EPI enhances consolidation of memory for a novel object recognition (NOR) task under different training conditions. Control male rats given a systemic injection of saline (0.9% NaCl) immediately after NOR training showed significant memory retention when tested at 1.5 or 24, but not 96h after training. In contrast, rats given a post-training injection of EPI showed significant retention of NOR at all delays. In a second experiment using a different training condition, rats treated with EPI, but not SAL-treated animals, showed significant NOR retention at both 1.5 and 24-h delays. We next showed that the EPI-induced enhancement of retention tested at 96h after training was prevented by pretraining systemic administration of the beta-adrenoceptor antagonist propranolol. The findings suggest that, as previously observed in experiments using aversively motivated tasks, epinephrine modulates consolidation of recognition memory and that the effects require activation of beta-adrenoceptors.

Differential effects of low and high doses of topiramate on consolidation and retrieval of novel object recognition memory in rats.

Topiramate is a new antiepileptic drug proposed to facilitate synaptic inhibition and block excitatory receptors. However, little is known about the effects of topiramate on memory. In the first experiment, intraperitoneal injection of topiramate at doses of 10.0 and 100.0 mg/kg, immediately after training, induced a deficit in short-term memory (STM) of a novel object recognition (NOR) task tested 1.5 hours after training in rats. In a long-term memory (LTM) test given to the same rats 24 hours after training, topiramate 0.1mg/kg enhanced, whereas 10.0 and 100.0 mg/kg impaired, NOR retention. In the second experiment, administration of topiramate 0.01 and 0.10 mg/kg 1 hour prior to the LTM retention test improved NOR retention, whereas 10.0 and 100.0 mg/kg produced retrieval deficits. The results indicate that low doses of topiramate improve, whereas high doses impair, consolidation and retrieval of recognition memory in rats.