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PubMedDate not supplied

Neurobehavioral evaluation of rhesus monkey infants fed cow's milk formula, soy formula, or soy formula with added manganese.

The possible neurobehavioral effects of excess manganese in soy formula were studied. Male rhesus monkeys (n=8/group) were fed a commercial cow's milk based formula (Control), a commercial soy protein based formula (Soy), or the soy formula with added manganese (Soy+Mn) from birth to 4 months of age. Soy formulas naturally have higher manganese (Mn) content than cow's milk formulas. Monkeys received behavioral evaluations, growth measurements, and cerebrospinal fluid (CSF) sampling from birth to 18 months of age. Soy and Soy+Mn groups engaged in less play behavior and more affiliative clinging in social dyadic interactions. These groups also had shorter wake cycles and shorter periods of daytime inactivity than controls. An impulsivity test was sensitive to the Soy group diet. The Soy+Mn group also had a blunted response to the dopamine agonist apomorphine. Groups did not differ significantly in CSF dopamine and serotonin metabolite concentrations, but these concentrations were correlated with several tasks affected by experimental formula. This experiment suggests that components of soy formula, including Mn, may influence brain development as reflected in behavioral measures.

Activity Cycles↗

PubMed2004

Evaluation of antioxidant and neuroprotective effect of Ocimum sanctum on transient cerebral ischemia and long-term cerebral hypoperfusion.

Free radicals are implicated in causation of cerebral reperfusion injury and chronic cerebral hypoperfusion in rats is associated with functional and histopathological disturbances. Ocimum sanctum (OS), a plant widely used in Ayurveda, has been shown to possess anti-inflammatory, antioxidant and cognition-enhancing properties. In the present study, we investigated the effect of methanolic extract of OS leaves in cerebral reperfusion injury as well as long-term hypoperfusion. Occlusion of bilateral common carotid arteries (BCCA) for 30 min followed by 45 min reperfusion caused increase in lipid peroxidation and up-regulation of superoxide dismutase (SOD) activity accompanied by fall in tissue total sulfhydryl groups (TSH) in rat forebrains. Ascorbic acid levels were unchanged, however. OS pretreatment (200 mg/kg/day for 7 days) prevented this reperfusion-induced rise in lipid peroxidation and SOD activity. OS pretreatment also stabilized the levels of TSH during reperfusion. Long-term cerebral hypoperfusion (a model of cerebrovascular insufficiency and dementia) induced by permanent occlusion of BCCA for 15 days demonstrated altered exploratory behavior in open-field testing and memory deficits as tested by Morris' water maze. Histopathological examination of hypoperfused animals revealed reactive changes, like cellular edema, gliosis and perivascular inflammatory infiltrate. OS treatment (200 mg/kg/day for 15 days) significantly prevented these hypoperfusion-induced functional and structural disturbances. The results suggest that OS may be useful in treatment of cerebral reperfusion injury and cerebrovascular insufficiency states.

Animals↗

PubMed2005

Alterations in GABAergic function following forced swimming stress.

Forced swimming induces alterations in the GABA brain concentration and could change the sensitivity of the GABA/benzodiazepine receptor-chloride ionophore complex to benzodiazepines. This change in sensitivity could be explained by the allopregnanolone release that takes place during stress. The current study was carried out to determine whether forced swimming is able to modify the anti-anxiety effect of diazepam and to explore the possible relation of this change to allopregnanolone, the GABA concentration or/and the GABA/benzodiazepine receptor density. Unstressed and stressed mice, injected with the vehicle or diazepam, were evaluated in the exploratory behavior test. Diazepam induced clear anxiolytic actions at all doses in unstressed animals, but such an effect was not observed in stressed animals. The injection of allopregnanolone 24 h before the anxiety test blocked the effect of this benzodiazepine. Forced swimming decreased GABA concentrations in the hippocampus and the thalamus-hypothalamus region, besides decreasing the [(3)H]flunitrazepam labeling in both the hypothalamus and amygdala. These results show that forced swimming abolishes the anti-anxiety effect of diazepam.

Animals↗

PubMed2005

Non-associative learning and anxiety in rats treated with a single systemic administration of the gastrin-releasing peptide receptor antagonist RC-3095.

The gastrin-releasing peptide receptor (GRPR) has been implicated in the modulation of emotionally-motivated memory. In the present study, we investigated the role of the GRPR on non-emotional, non-associative memory, and anxiety. Adult male Wistar rats were given a systemic injection of the GRPR antagonist [D-Tpi6, Leu(13) psi(CH2NH)-Leu14] bombesin (6-14) (RC-3095) (0.2, 1.0 or 5.0mg/kg) 30 min before exposure to an open field or an elevated plus maze. Habituation to the open field was tested in a retention trial carried out 24 h after the first exposure to the open field. Rats given RC-3095 at the doses of 1.0 or 5.0mg/kg showed impaired habituation. Animals treated with 5.0mg/kg of RC-3095 spent significantly more time in the closed arms of the elevated plus maze. No effects of RC-3095 on locomotion or exploratory behavior were observed. The results implicate the GRPR in the regulation of non-emotional, non-associative memory as well as in anxiety.

Animals↗

PubMed2005

Effects of chronic mild stress on sexual behavior, locomotor activity and consumption of sucrose and saccharine solutions.

Many symptoms of human depressive disorders are also observed in animals after exposure to unpredictable stressors. The chronic mild stress (CMS) paradigm was developed in order to better model the human situation by using chronic mild stressors over a longer period. It is claimed that the model induces anhedonia in the animals, a core symptom of depression in humans. Despite the fact that the CMS model has a high degree of face validity, there are a number of laboratories in which the establishment of the model is less reliably observed. We have examined behavior (sexual activity and open field activity) together with hedonic measures (sucrose and saccharine intake) after exposure to CMS. CMS decreased male sexual activity (e.g. reduced capability to ejaculate) and increased activity in an open field test. The hedonic measures showed diverging results after CMS in our laboratory. Sucrose consumption was reduced, while saccharine consumption did not show a comparable change. It is concluded that CMS induces comparable alterations to some depression-like symptoms in humans. Saccharine consumption is not a reliable indicator of the hedonic responsiveness to CMS.

Analysis of Variance↗

PubMed2005

Effects of AP5 infusion into the lateral ventricle on the activities and hippocampal electrical patterns of sleep episodes in rats.

Although N-methyl-D-aspartate (NMDA) receptors of the hippocampus are mainly associated with learning and memory that might occur "on-line" during sharp waves (SPWs) and theta-rhythm, the participation of hippocampal NMDA receptors in sleep-related processes has not been well studied. In this study, the activity of sleep episodes, hippocampal SPWs and theta-rhythm were recorded in rats received a repeated infusion of NMDA receptor antagonist, D,L-2-amino-5-phosphonopentanoic acid (AP5), into the lateral ventricle in a 5-h daytime sleep. The first trial AP5 infusion (30 mM/2 microl) did not change measures of the activity of slow wave sleep (SWS), paradoxical sleep (PS) and awake episodes, but induced a delay in the latency of the first onset of PS; in the hippocampal EEG, it increased the amplitude of SPWs within SWS and shifted the amplitude/spectral power of theta-rhythm from high to low frequency within PS. The repeated AP5 infusion augmented the activity of SWS, and impaired PS and awake episodes; in the EEG-sleep picture, it maintained high scores of SPWs with the complete blockade of theta-rhythm generation. When AP5 rat was woken, the theta-rhythm was seen during exploratory behavior. These findings provide evidence that hippocampal NMDA receptors via SPWs or directly associated with the synaptic events of theta-rhythm generation are critical for the PS activities.

2-Amino-5-phosphonovalerate↗

PubMed2000

A single social defeat experience selectively stimulates the release of oxytocin, but not vasopressin, within the septal brain area of male rats.

The naturally occurring social conflict situation to be confronted with an aggressive dominant conspecific was used to study the effects of emotional stress on the release of oxytocin (OXT) and arginine vasopressin (AVP) within the mediolateral septum of the rat brain. Male rats were chronically implanted with a microdialysis probe into this brain area. Local release patterns of both, OXT and AVP were monitored in response to a 30 min social defeat. Social defeat caused a significant increase in the release of OXT (to 254%+/-43%, P<0.01). In contrast, the release of AVP was not affected. In a preliminary experiment, to assess the physiological significance of stress-induced intraseptal OXT release, a separate group of animals received the OXT receptor antagonist des-Gly-NH(2)d(CH(2))(5)[Tyr(Me)(2)Thr(4)]OVT into the mediolateral septum via inverse microdialysis prior to and during the social defeat procedure. However, no difference could be observed in submissive freezing (passive coping) or in exploratory behavior (active coping) when compared to vehicle-treated animals, neither acutely nor 24 h after antagonist administration. Taken together, our results demonstrate that emotional stress activates the septal oxytocinergic, but not vasopressinergic, system. The physiological significance of intraseptally released OXT remains unclear and has to be elucidated in future studies.

Adaptation, Psychological↗

PubMed2002

Estrogen and progesterone treatment: effects on muscarinic M(4) receptor subtype in the rat brain.

We investigated the effect of ovariectomy (OVX) and hormonal treatment for 10 weeks by estradiol and progesterone on muscarinic M(4) receptor subtype in different brain areas of female rats. Moreover, motor activity of OVX and hormone-treated rats was measured by automated open field exploration boxes. Receptor quantification in the hippocampus, frontal cortex, parietal cortex, amygdala and hypothalamus was done by receptor autoradiography using a selective ligand for muscarinic M(4) receptors. Ovariectomy up-regulated M(4) receptors in the dentate gyrus, CA1, CA3, frontal cortex and hypothalamus whereas the estrogen treatment restored M(4) binding to that of the sham group. Progesterone treatment had no effect on the ovariectomy-induced up-regulation of M(4) receptors. Ovariectomy significantly decreased the exploratory activity of the rats compared to the sham group. Estrogen treatment restored the exploratory behavior of the ovariectomized rats to that of the sham group whereas the progesterone-treated rats were less alert to the surrounding when compared to the sham and estrogen supplemented rats. The effect of estrogen on the hippocampal muscarinic M(4) receptor subtype is a novel finding and may have functional significance for cholinergic receptors especially in relation to postmenopausal memory problems and neurodegenerative disease like Alzheimer's disease.

Amygdala↗

PubMed1998

The frequency of rat's hippocampal theta rhythm is related to the speed of locomotion.

Hippocampal EEG activity was recorded in rats during locomotion, spontaneous or induced by electrical stimulation of subthalamic locomotor region (SLR) and posterior hypothalamus (PH). Spontaneous locomotion was associated with the theta frequency (6-8.5 Hz). Electrically induced locomotion was also associated with theta rhythm, frequency of which depended on the site of stimulation. Theta frequency during SLR evoked locomotion was almost the same as during spontaneous locomotion (7-9 Hz). PH induced locomotion was accompanied by higher theta frequency (9-11 Hz). Theta frequency and the speed of locomotion were positively correlated during spontaneous locomotion. During electrically induced locomotion the theta frequency was much higher than expected when related to the speed of spontaneous locomotion. The electrically evoked locomotion may result from activation of various systems. Stimulation of the SLR activates system responsible for the exploratory behavior, while stimulation of PH evokes locomotion related to aversive behavior. Thus, we conclude that the theta rhythm frequency may depend not only on the speed of locomotion but also on the rats' motivational-emotional state, associated with locomotion performed by the animal.

Animals↗

PubMed1999

Reduced anxiety-like and cognitive performance in mice lacking the corticotropin-releasing factor receptor 1.

Corticotropin-releasing factor (CRF) has been hypothesized to be involved in the pathophysiology of anxiety, depression, cognitive and feeding disorders. Two distinct CRF receptor subtypes, CRFR1 and CRFR2, are thought to mediate CRF actions in the CNS. However, the role for each receptor subtype in animal models of neuropsychiatric disorders remains to be determined. Using CRFR1 deficient mice, the present study investigated the functional significance of this CRF receptor subtype in anxiety-like and memory processes. CRFR1 knockout mice displayed an increased exploratory behavior in both the Elevated Plus-maze (EPM) and the Black and White (B-W) test box models of anxiety, indicating an anxiolytic-like effect of the CRFR1 gene deletion. In contrast, during the retrieval trial of a two-trial spatial memory task wild type mice made more visits to and spent more time in the novel arm as opposed to the two familiar ones of a Y-maze apparatus. No increase in the level of exploration of the novel arm by the CRFR1 deficient mice was observed. This indicates that CRFR1 knockout mice are impaired in spatial recognition memory. These results demonstrate that genetic deletion of the CRFR1 receptor can lead to impairments in anxiety-like and cognitive behaviors, supporting a critical role for this receptor in anxiety and cognitive biological processes.

Animals↗

PubMed2000

The dopamine D(4) receptor: one decade of research.

Dopamine is an important neurotransmitter involved in motor control, endocrine function, reward, cognition and emotion. Dopamine receptors belong to the superfamily of G protein-coupled receptors and play a crucial role in mediating the diverse effects of dopamine in the central nervous system (CNS). The dopaminergic system is implicated in disorders such as Parkinson's disease and addiction, and is the major target for antipsychotic medication in the treatment of schizophrenia. Molecular cloning studies a decade ago revealed the existence of five different dopamine receptor subtypes in mammalian species. While the presence of the abundantly expressed dopamine D(1) and D(2) receptors was predicted from biochemical and pharmacological work, the cloning of the less abundant dopamine D(3), D(4) and D(5) receptors was not anticipated. The identification of these novel dopamine receptor family members posed a challenge with respect to determining their precise physiological roles and identifying their potential as therapeutic targets for dopamine-related disorders. This review is focused on the accomplishments of one decade of research on the dopamine D(4) receptor. New insights into the biochemistry of the dopamine D(4) receptor include the discovery that this G protein-coupled receptor can directly interact with SH3 domains. At the physiological level, converging evidence from transgenic mouse work and human genetic studies suggests that this receptor has a role in exploratory behavior and as a genetic susceptibility factor for attention deficit hyperactivity disorder.

Amino Acid Sequence↗

PubMed2000

Effects of prenatal stress on development in mice: maturation and learning.

Female CD-1 mice were stressed during the final week of gestation. Beginning 3 days after birth, until weaning, their pups were examined for eye opening, startle response, tooth eruption, surface righting, ability to cling to and climb an incline, tail pull reflex, rotation, linear movement and exploration. At 3 months of age, they were tested in a Morris Water Maze. Stressed animals were significantly lighter and shorter than non-stressed animals the first week after birth. By 3 days after birth, significantly fewer stressed animals could rotate or right themselves. By 6 days after birth, significantly fewer stressed animals could cling to or climb an inclined screen, or show the tail pull reflex. By 9 days of age, significantly fewer stressed animals had teeth. In contrast, by day 12 of age, significantly more stressed animals demonstrated exploratory behavior than did non-stressed animals. There were no sex differences in the ability of animals to perform these tasks at the same age. Stressed animals were significantly slower than non-stressed animals to reach the hidden platform in the water maze on all trials, and this difference was due to stressed females being slower to find the platform than non-stressed females, with no main effect of stress on males. This study supports and expands previous findings in rodents that prenatal stress can cause deficiencies in some early indices of physical maturation and also that these deficiencies can be continued into adulthood.

Animals↗

PubMed2003

Time-dependent effects of neuropeptide Y infusion in the paraventricular hypothalamus on ingestive and associated behaviors in rats.

In this study the role of neuropeptide Y (NPY) in the paraventricular nucleus of the hypothalamus (PVN) in the daily regulation of feeding, drinking, locomotor activity, and nestbox occupation was investigated. These behaviors were recorded during and after bilateral infusion of NPY into the PVN of rats during the early (E) or late (L) part of the light phase. Administration of NPY caused a significant increase in feeding behavior at E, but not at L. In contrast to the feeding at E, L feeding was associated with increased water intake following NPY infusion. While locomotor activity was similar in sCSF- and NPY-infused rats at all times of the daily cycle, administration of NPY at L, but not at E increased nestbox occupation during the first few hours of the dark phase. This increased nestbox occupation was not associated with altered food intake or drinking behavior, implying that NPY-treated rats made frequent excursions between nestbox and food hopper/water bottle. Thus, feeding-associated drinking and explorative behavior are time-dependently modulated by NPY in the PVN, independent of locomotor activity.

Animals↗

PubMed2000

Cocaine and morphine-induced place conditioning in adolescent and adult rats.

The periadolescent period in the rat is characterized by alterations in novelty seeking and exploratory behavior, as well as changes in the behavioral responsiveness to many drugs of abuse. These alterations may be predictive of alterations in the reward value of drugs of abuse. The present experiments examined whether adolescent rats (34-37 days old) differ from their adult counterparts in the expression of drug-induced place conditioning for morphine (0, 2.5, or 5 mg/kg; Experiment I) and cocaine (0, 5, or 10 mg/kg; Experiments II and III). Animals received multiple conditioning days, followed 24 h later by a drug-free CPP test. All drugs were given intraperitoneally immediately prior to confinement in the CS+ compartment, while vehicle injections were given prior to exposure to the CS- chamber. For both drugs, there were no significant differences between adolescents and adults in amount of place conditioning seen when drug exposure was paired with the nonpreferred chamber. When cocaine was paired with either the preferred or nonpreferred compartment (Experiment III), again, the magnitude of the place conditioning observed did not differ between adolescents and adults. The lack of age differences in expression of drug-induced place conditioning in the present experiments is not likely a result of ceiling effects, because the data suggest that the doses used included near-threshold doses. Although these findings need to be confirmed using other approaches for assessing drug reward before concluding that adolescent and adult rats exhibit similar sensitivity to the rewarding effects of morphine and cocaine, the current data revealed no differences between adolescents and adults in the magnitude of place conditioning expressed for morphine or cocaine.

Aging↗

PubMed2002

Modification of dendritic development.

Since 1890 Ramón y Cajal strongly defended the theory that dendrites and their processes and spines had a function of not just nutrient transport to the cell body, but they had an important conductive role in neural impulse transmission. He extensively discussed and supported this theory in the Volume 1 of his extraordinary book Textura del Sistema Nervioso del Hombre y de los Vertebrados. Also, Don Santiago significantly contributed to a detailed description of the various neural components of the hippocampus and cerebral cortex during development. Extensive investigation has been done in the last Century related to the functional role of these complex brain regions, and their association with learning, memory and some limbic functions. Likewise, the organization and expression of neuropsychological qualities such as memory, exploratory behavior and spatial orientation, among others, depend on the integrity and adequate functional activity of the cerebral cortex and hippocampus. It is known that brain serotonin synthesis and release depend directly and proportionally on the availability of its precursor, tryptophan (TRY). By using a chronic TRY restriction model in rats, we studied their place learning ability in correlation with the dendritic spine density of pyramidal neurons in field CA1 of the hippocampus during postnatal development. We have also reported alterations in the maturation pattern of the ability for spontaneous alternation and task performance evaluating short-term memory, as well as adverse effects on the density of dendritic spines of hippocampal CA1 field pyramidal neurons and on the dendritic arborization and the number of dendritic spines of pyramidal neurons from the third layer of the prefrontal cortex using the same model of TRY restriction. The findings obtained in these studies employing a modified Golgi method, can be interpreted as a trans-synaptic plastic response due to understimulation of serotoninergic receptors located in the hippocampal Ammon's horn and, particularly, on the CA1 field pyramidal neurons, as well as on afferences to the hippocampus which needs to be further investigated.

Afferent Pathways↗

PubMed1998

A new approach to the light/dark test procedure in mice.

The effect of the known anxiolytic agents diazepam and alprazolam and a putative anxiogenic agent, FG 7142, were assessed in a fully automated and computer-integrated two-compartment light/dark apparatus. In addition, psychostimulant drugs (amphetamine, adrafinil, amineptine, and caffeine) were tested to determinate the influence of increasing locomotor activity on the indices of anxiety. Some modifications, such as using a soiled apparatus, have been made from the initial model to reduce any neophobic response to the test situation. These results have been compared to results obtained after cleaning between trials. In addition, strain differences have been assessed by comparing the effect of Swiss mice with the C57Bl/6J strain. The role of each parameter as an index of anxiety is discussed. The time spent in the lit area and exploratory behaviors seemed to be the most reliable parameter for assessing anxiolytic-like activity. Diazepam and alprazolam were found to have an anxiolytic profile. FG 7142 did not demonstrate any intrinsic effect. Amphetamine was reported to be anxiogenic, and amineptine, adrafinil, and caffeine only had a psychostimulant profile. We conclude that the light/dark test may be useful for identifying putative anxiolytic and anxiogenic agents, but an additional test such as an open field or an actimeter test must be performed as a control with regard to the problem of sedation and change in exploration. The Swiss strain of mice has been found a suitable strain to be used in the test.

Alprazolam↗

PubMed1998

Maternal exposure to low doses of delta9-tetrahydrocannabinol facilitates morphine-induced place conditioning in adult male offspring.

The possible existence of an increased susceptibility to the reinforcing properties of morphine was analyzed in male and female rats born from mothers exposed to delta9-tetrahydrocannabinol (THC, 1, 5, or 20 mg/kg) during gestation and lactation. Maternal exposure to low doses of THC (1 and 5 mg/kg), relevant for human consumption, resulted in an increased response to the reinforcing effects of a moderate dose of morphine (350 microg/kg), as measured in the place-preference conditioning paradigm (CPP) in the adult male offspring. These animals also displayed an enhanced exploratory behavior in the defensive withdrawal test. However, only females born from mothers exposed to THC 1 mg/kg exhibited a small increment in the place conditioning induced by morphine. The possible implication of the hypothalamo-pituitary-adrenal axis (HPA) was analyzed by monitoring plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone in basal and moderate-stress conditions (after the end of the CPP test). Female offspring perinatally exposed to THC (1 or 5 mg/kg) displayed high basal levels of corticosterone and a blunted adrenal response to the HPA-activating effects of the CPP test. However, male offspring born from mothers exposed to THC (1 or 5 mg/kg) displayed the opposite pattern: normal to low basal levels of corticosterone, and a sharp adrenal response to the CPP challenge. The present study reveals that maternal exposure to low doses of THC results in an increased sensitivity to the reinforcing effects of morphine in the adult male offspring, and in sexually dimorphic behavioral and endocrine alterations in the adaptative responses to stressors such as novelty or place-preference testing. These results support the growing evidence of the importance of monitoring the long-term consequences of maternal consumption of cannabis derivatives.

Adrenocorticotropic Hormone↗

PubMed1999

Pharmacological evaluation of ricinine, a central nervous system stimulant isolated from Ricinus communis.

The extract of the pericarp of castor bean (Ricinus communis) showed some typical central nervous system stimulant effects when administered to mice. The animals became exophthalmic, presented tremors and clonic seizures and died a few minutes after receiving larger doses of the extract. At lower doses the extract improved memory consolidation and showed some neuroleptic-like properties, such as a decrease in exploratory behavior and catalepsy. The memory-improving effect and the seizure-eliciting properties of the extract were also observed with the administration of ricinine, a neutral alkaloid isolated from the extract. However, the neuroleptic-like properties of the extract were not observed with ricinine. As the therapeutic index of ricinine is of the order of 200, the compound may be considered as a promising cognition-enhancing drug that may be used for the treatment of human amnesias.

Alkaloids↗