Kynurenic acid antagonizes hippocampal quinolinic acid neurotoxicity: behavioral and histological evaluation

In the present study, we evaluate the ability of kynurenic acid to protect hippocampal neurons from the neurotoxicity of the N-methyl-D-aspartate (NMDA) agonist quinolinic acid. Bilateral intrahippocampal injection of quinolinic acid (120 nmol) led to severe behavioral disturbances and total loss of hippocampal neurons. Intrahippocampal co-injection of kynurenic acid (360 nmol) completely prevented cell loss and behavioral disturbances. However, the protection was incomplete when kynurenic acid was intraperitoneally injected (500 mg/kg, repeated during 4 days). These above results indicate that kynurenic acid can antagonize the neuronal degeneration mediated by excessive stimulation of NMDA receptors in vivo.     

GSA: behavioral, histological, electrophysiological and neurochemical effects

Renal insufficient patients suffer from a variety of complications as direct and indirect consequence of accumulation of retention solutes. Guanidinosuccinic acid (GSA) is an important probable uremic toxin, increased in plasma, urine, cerebrospinal fluid and brain of patients with uremia and supposed to play a role in the pathogenesis of some neurological symptoms. GSA, an NMDA-receptor agonist and GABA-receptor antagonist, is suggested to act as an excitotoxin and shown to be convulsive. The effect of hippocampal (i.h.) GSA injection on behavior and hippocampal volume in mice is presented here. In addition, hippocampal cGMP concentration after systemic injection of GSA was measured. The effect of co-application of NMDA-receptor antagonist CGP37849 with GSA was tested, in vivo, after hippocampal GSA injection and, in vitro, on GSA evoked currents in spinal cord neurons. A significant dose-dependent effect of i.h. injection of GSA on cognitive performance, activity and social exploratory behavior was observed. There was a protective effect of CGP37849 on GSA induced behavioral alterations. Volume of hippocampal cornu ammonis region decreased significantly and dose-dependently after GSA injection. Systemic GSA injection increased cGMP concentration in hippocampal formation. It can be concluded that GSA is an important neurotoxin. As GSA is increased in patients with uremia, it probably contributes to their neurological symptoms. Knowledge of neurotoxic effects and mechanisms of action of GSA and other uremic retention solutes could help in the development of more efficient treatment of uremic patients. Animal models like the 'GSA mouse model' are useful tools for research in this context.     

Comparison of ibotenate and kainate neurotoxicity in rat brain: a histological study

The neurotoxic properties of ibotenate and kainate after intracerebral application were compared in several regions of the rat brain. Ibotenate, being 5-10 times less toxic than kainate, caused lesions which were generally found to extend spherically from the tip of the injection cannula. In contrast, kainate injections often resulted in neuronal degeneration distant from the site of infusion, thus severely limiting its use as a tool for causing lesions in neurobiological studies. In some of the brain regions examined (hippocampus, septum), neurons appeared differentially susceptible to kainate but uniformly vulnerable to ibotenate. Some cell groups, such as those in the medial septum and the locus coeruleus, proved highly resistant to kainate but could be selectively ablated by ibotenate. These findings, together with differences between the two toxins in the evolution of neuronal degeneration (exemplified here in the hippocampal formation), appear to support previous suggestions that ibotenate and kainate exert their excitotoxic actions via different mechanisms. On the other hand, neuropathological changes caused in the cerebellum did not differ, since both ibotenate and kainate preferentially destroyed granule cells. Two nuclei, the arcuate nucleus of the hypothalamus and the nucleus of the fifth nerve, were found to be extremely resistant to either neurotoxin.     

Characterization of carbon disulfide neurotoxicity in C57BL6 mice: behavioral, morphologic, and molecular effects

Female C57BL6 mice were exposed to 0 or 800 ppm carbon disulfide (CS2), 6 h/d, 5 d/wk for 20 weeks. The neurologic function of all mice was assessed once at the end of exposures using a functional observational battery. General health effects included a decrease in body weight gain, piloerection, hunched body posture, and ptosis. Treatment-related effects included altered gait (uncoordinated placement of hind limbs and ataxia) and impaired function on an inverted screen test. In addition, rearing and locomotor movement were decreased in treated mice. Focal to multifocal axonal swelling was seen predominantly in the muscular branch of the posterior tibial nerve, and occasionally giant axonal swelling was detected in the lumbar segment of the spinal cord. Electron microscopic examination revealed swollen axons with massive accumulation of neurofilament proteins within the axoplasm. Covalent cross-linking of erythrocyte spectrin (surrogate protein to neurofilament protein) was demonstrated in mice exposed to CS2 but not in mice receiving filtered air. These data provide supportive evidence that covalent cross-linking of neurofilament proteins is a significant feature of the axonal swellings in mice produced by inhalation exposure to CS2.     

Dopamine receptor blockade and extinction differentially affect behavioral variability

Dopamine (DA) neurons respond to unexpected food delivery and are inhibited during the omission of expected reward. DA receptor blockade mimics some, but not all, aspects of non-reward (extinction) conditions. It was therefore of interest to ask whether DA receptor blockade produces extinction-like increases in behavioral variability in addition to its well-known operant response-suppressing effects. In the current experiment, rats were trained drug-free on an operant task in which they pressed on a keyboard. Two of the keys led to food on a continuous reinforcement schedule. Both response rates and behavioral variability were measured. Test day administration of D(1) and D(2) antagonists SCH23390 and raclopride, like extinction, suppressed responding but, unlike extinction, did not lead to an increase in variability.     

Dopamine receptor hetero-oligomerization: a hypothesis for behavioral sensitization to psychostimulants

Repeated psychostimulant pretreatment can induce behavioral sensitization. Many previous studies have demonstrated that receptors of the dopamine and other neurotransmitter systems are involved in the sensitization process, however, the precise mechanism of this interaction is still unknown. We propose the hypothesis that oligomerization of the dopamine receptors and analogs from other neurotransmitter systems may contribute, at least in part, to psychostimulant-induced behavioral sensitization. Psychostimulant exposure can enhance central dopamine release, which can increase oligomerization of the dopamine receptors with their analogs. Receptor oligomerization can enhance the functional properties of the receptors and affect receptor degradation, which may be related to the behavioral augmentation which characterizes the sensitized state and produces the persistence of behavioral sensitization. The proposed receptor hetero-oligomerization model may provide a new direction in the exploration of the functionally critical sensitization phenomenon.     

Dopamine antagonists produce an age-dependent increase in the responding of the young chick

In three experiments the effects of dopamine receptor antagonists on response-contingent punishment and autoshape learning of 1- and 4-day-old chicks were determined. In the first two experiments, 1- or 4-day-old chicks (N = 120) were trained to key-peck for heat reward and then injected intraperitoneally (ip) with either haloperidol (1.5, 2.5, or 5.0 mg/kg) or saline (Experiment 1) and with either haloperidol (2.0 mg/kg), sulpiride (50 mg/kg) or saline (Experiment 2) 30 min before a 96-trial response-contingent punishment session. In Experiment 3, 1- and 4-day-old chicks (N = 48) were injected ip with saline or haloperidol (2.0 mg/kg) 30 min prior to a 30-trial autoshape learning session. In both the punishment and appetitive tasks 1-day-old chicks pretreated with either haloperidol (1.5 to 2.5 mg/kg) or sulpiride showed a significant increase in key-peck responding compared with their saline injected controls. In contrast, 4-day-old chicks given either haloperidol (2.0 mg/kg) or sulpiride did not differ significantly from saline treated chicks on the punishment task, and on the autoshape task haloperidol-treated 4-day-old chicks responded on fewer trials than did their saline controls. These results indicate that dopaminergic synaptic transmission in the young chick as measured by dopamine D2 receptor blockers is functionally different at 1 compared with 4 days of age.     

Neuroprotective effect of baicalein against MPTP neurotoxicity: behavioral, biochemical and immunohistochemical profile

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes the damage of dopaminergic neurons as seen in Parkinson's disease (PD). Oxidative stress has been implicated in the pathogenesis of PD. Baicalein, isolated from the traditional Chinese herbal medicine Huangqin (Scutellaria baicalensis Georgi), has been shown to have antioxidant effects. Here we investigated the effect of baicalein on MPTP-induced neurotoxicity in mice. Pretreatment with baicalein for a week was followed by challenge with MPTP for 4 consecutive days; the subsequent behavioral, biochemical and immunohistochemical manifestations in mice were determined and compared to those in untreated mice and mice challenged only with MPTP. The present study showed that baicalein could improve the abnormal behavior in MPTP-treated mice. The protective effect may be caused by increasing the levels of DA and 5-HT in the striatum, increasing the counts of dopaminergic neurons, inhibiting oxidative stress and the astroglia response. These results suggest that baicalein possesses potent neuroprotective activity and may be a potential anti-Parkinson's disease drug that is worthy of further study.     

Potential age-dependent effects of estrogen on neural injury

In 2000, approximately 10 million women were receiving hormone replacement therapy (HRT) for alleviation of menopausal symptoms. A number of prior animal studies suggested that HRT may be neuroprotective and cardioprotective. Then, in 2003, reports from the Women's Health Initiative (WHI) indicated that long-term estrogen/progestin supplementation led to increased incidence of stroke. A second branch of the WHI in women with prior hysterectomy found an even stronger correlation between estrogen supplementation alone and stroke incidence. Follow-up analyses of the data, as well as data from other smaller clinical trials, have also demonstrated increased stroke severity in women receiving HRT or estrogen alone. This review examines the studies indicating that estrogen is neuroprotectant in animal models and explores potential reasons why this may not be true in postmenopausal women. Specifically, age-related differences in estrogen receptors and estrogenic actions in the brain are discussed, with the conclusion that animal models of disease must closely mimic human disease to produce clinically relevant results.     

Dopamine receptor activation reveals a novel, kynurenate-sensitive component of striatal N-methyl-D-aspartate neurotoxicity

The N-methyl-d-aspartate (NMDA) subtype of glutamate receptors plays an important role in brain physiology, but excessive receptor stimulation results in seizures and excitotoxic nerve cell death. NMDA receptor-mediated neuronal excitation and injury can be prevented by high, non-physiological concentrations of the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA). Here we report that endogenous KYNA, which is formed in and released from astrocytes, controls NMDA receptors in vivo. This was revealed with the aid of the dopaminergic drugs d-amphetamine and apomorphine, which cause rapid, transient decreases in striatal KYNA levels in rats. Intrastriatal injections of the excitotoxins NMDA or quinolinate (but not the non-NMDA receptor agonist kainate) at the time of maximal KYNA reduction resulted in two- to threefold increases in excitotoxic lesion size. Pre-treatment with a kynurenine 3-hydroxylase inhibitor or with dopamine receptor antagonists, i.e., two classes of pharmacological agents that prevented the reduction in brain KYNA caused by dopaminergic stimulation, abolished the potentiation of neurotoxicity. Thus, the present study identifies a previously unappreciated role of KYNA as a functional link between dopamine receptor stimulation and NMDA neurotoxicity in the striatum.     

Dopamine D(4) receptors in rat forebrain: unchanged with amphetamine-induced behavioral sensitization

Dopamine D(2) receptors are implicated in stimulant-induced behavioral sensitization.(7,10) Studies using selective receptor antagonists also implicate the D(4) receptor, a member of the dopamine D(2)-like receptor family.(3) Accordingly, dopamine D(4) and D(2)-like receptor levels in rat forebrain were examined by computed autoradiography after repeated (+)-amphetamine treatment that induced behavioral sensitization. Receptor binding was quantified in critical brain regions including caudate-putamen, nucleus accumbens septi, medial prefrontal cortex and hippocampus. No significant differences in D(4) or D(2)-like receptor levels were detected among rats sensitized to amphetamine, those exposed to amphetamine but killed before behavioral sensitization emerged or vehicle-treated controls. The findings indicate that expression of amphetamine-induced behavioral sensitization is not associated with altered D(4) (or D(2)) receptor density in rat forebrain.     

Environmental enrichment and crowding: behavioral and hormonal effects.

Male and female gerbils lived from weaning to adulthood in Enriched Crowded, Plain Crowded, Dense Crowded, or Paired conditions. Daily observations, social interaction tests with one animal from each of the 4 groups, and anatomical measures were made, and levels of cortisol and testosterone were determined by radioimmunoassay. In the social interaction tests Paired gerbils marked and fought the most. Home cage observations estabished that Enriched animals failed to pair bond or establish nests in the small cubicles provided. They also reproduced no more successfully than did other crowded groups, while all crowded groups reproduced less than Paired animals. All groups of crowded animals had lighter testes and adrenal glands than Paired animals, although their cortisol levels were consisderably higher than Paired animals'. This inverse relationship of cortisol and adrenal weight was interpreted as a sign of extreme adrenal activity on the part of crowded animals. Enriched animals had cortisol levels intermediate between those of Paired and of Dense and Plain crowded animals, and their testosterone levels were as high as those of Paired males, indicating some diminution of hormonal effects of crowding. There was, however, little evidence of diminished behavioral and reproductive effects of crowding by environmental enrichment.     

Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice

Apoptosis, or programmed cell death, is a cellular pathway involved in normal cell turnover, developmental tissue remodeling, embryonic development, cellular homeostasis maintenance and chemical-induced cell death. Caspases are a family of intracellular proteases that play a key role in apoptosis. Aberrant activation of caspases has been implicated in human diseases. In particular, numerous findings implicate Caspase-6 (Casp6) in neurodegenerative diseases, including Alzheimer disease (AD) and Huntington disease (HD), highlighting the need for a deeper understanding of Casp6 biology and its role in brain development. The use of targeted caspase-deficient mice has been instrumental for studying the involvement of caspases in apoptosis. The goal of this study was to perform an in-depth neuroanatomical and behavioral characterization of constitutive Casp6-deficient (Casp6-/-) mice in order to understand the physiological function of Casp6 in brain development, structure and function. We demonstrate that Casp6-/- neurons are protected against excitotoxicity, nerve growth factor deprivation and myelin-induced axonal degeneration. Furthermore, Casp6-deficient mice show an age-dependent increase in cortical and striatal volume. In addition, these mice show a hypoactive phenotype and display learning deficits. The age-dependent behavioral and region-specific neuroanatomical changes observed in the Casp6-/- mice suggest that Casp6 deficiency has a more pronounced effect in brain regions that are involved in neurodegenerative diseases, such as the striatum in HD and the cortex in AD.     

Neonatal hypothyroidism: behavioral, thyroid hormonal and neuroanatomical effects

Neonatal hypothyroidism was induced in albino rats by adding propylthiouracil for 30 days to the lactating mother's food and water. Behavioral evaluation of offspring on a 6-item battery occurred from 70–114 days of age. Results indicated long lasting behavioral changes in the hypothyroid subjects characterized by increased activity and decreased performance on avoidance and escape learning. Serum thyroxine levels were reduced in the hypothyroid animals until 120 days of the age. These animals also had fewer synaptic contacts in the cerebellar cortex.     

Separation-induced early malnutrition: Maternal,physiological and behavioral effects

Rats were malnourished during the first 3 weeks of life by separation from their dams for 12 hours per day. Half of these litters were exposed to a nonlactating “aunt” during this separation, while half were housed in a warm incubator. The dams whose pups underwent daily separation behaved differently from control dams, although comparably to each other. The two separation procedures produced pups with biochemical and physiological differences from control groups, and some differences from each other. When tested as adults, the malnourished and control groups performed equivalently on a number of behavioral tests (e.g. footshock sensitivity, spatial alternation), but the previously malnourished groups differed from each other and from control groups on some open field and passive avoidance measures. Thus, these procedures for producing malnutrition in offspring of adequately nourished dams can have both brain and behavioral effects. The influence of the different early environments was evident since the two experimental groups exhibited some brain and behavioral differences although their nutritional histories and contacts with lactating dams were similar.     

Dopamine neurons of the monkey midbrain: contingencies of responses to stimuli eliciting immediate behavioral reactions

1. This study investigates the behavioral conditions in which dopamine (DA) neurons of substantia nigra and adjoining areas A8 and A10 respond with impulses to visual and auditory trigger stimuli eliciting immediate arm- and eye-movement reactions. 2. In a formal task, the rapid opening of the door of a small, food-containing box located at eye level ahead of the animal served as visible and audible trigger stimulus. Most DA neurons on the contralateral side responded to this stimulus with a short burst of impulses with median onset latency of 50 ms and duration of 90 ms (75% of 164 neurons). Similar responses were seen in a comparable fraction of DA neurons during ipsilateral task performance, suggesting that responses were not specific for the limb being used. 3. When the sensory components of the door opening stimulus were separated, DA neurons typically responded in a similar manner to the moving visual stimulus of the opening door, the low-intensity sliding noise of the opening door, and the 1-kHz sound of 90-92 dB intensity emitted from a distant source at the onset of door opening. Responses to each component alone were lower in magnitude than to all three together. 4. In a variation of the task, a neighboring, identical food box opened in random alternation with the other box but without permitting animals to reach out (asymmetric, direct-reaction go/no-go task). With each sensory component, DA neurons typically responded both to opening of go and no-go boxes. Responses were enhanced when stimuli elicited limb movements in go trials. 5. Monkeys reacted to door opening with target-directed saccadic eye movements in the majority of both go and no-go trials. Neuronal responses were equally present during the occasional absence of eye movements. Thus responses were not specific for the initiation of individual arm or eye movements. 6. Neuronal responses were absent when the same stimuli occurred outside of the behavioral task with target-direct arm and eye movements lacking. This shows that responses were not of purely sensory nature but were related to the capacity of the stimulus for eliciting behavioral reactions. 7. In a variation of the go/no-go task, an instruction light illuminated 2-3 s before door opening prepared the animal to perform the reaching movement on door opening or to refrain from moving (asymmetric, instruction-dependent go/no-go task).(ABSTRACT TRUNCATED AT 400 WORDS)     

Influence of dizocilpine (MK-801) on neurotoxic effect of dexamethasone: behavioral and histological studies

Elevated levels of endogenous glucocorticoids (GCs) or prolonged treatment with high doses of dexamethasone (DEX) or other GCs preparations are frequently associated with psychosis as well as cognitive deficits, such as the impairment of memory and learning. GCs potentiate stress or ischemia-induced accumulation of excitatory amino acids in the extracellular space of hippocampus. The antagonism of glutamate receptors may potentially improve safety profile of therapy with GCs. The purpose of the present study was to investigate the effect of dizocilpine maleate (MK-801), non-competitive NMDA glutamate receptor antagonist, on neurotoxic effect of the prolonged treatment with the high dose of DEX. The results showed that DEX (120 mg/kg/day for 7 days) impaired the long-term memory and the motor coordination, reduced the body weight and induced the lethality of mice. The morphological and ultrastructural study have confirmed damage to hippocampal neurons especially in the CA3 region after the prolonged treatment with DEX alone. Damaged pyramidal neurons showed robust changes in the shape of the nucleus and cytoplasm condensation. MK-801 alone (at non-toxic dose of 0.3 mg/kg/day), changed neither the behavior of mice nor morphology of the hippocampal neurons. However, it did not prevent the neurotoxic effects of DEX. On the contrary, it intensified DEX-induced neurotoxicity.     

Sensation-seeking: electrodermal and behavioral effects of stimulus content and intensity

Although a number of studies support an arousal theory interpretation of differential sensation-seeking behavior, the conditions under which arousal correlates of this personality dimension are manifest is as yet unclear. Both theory and research suggest that among the external factors affecting the differential arousal response are stimulus relevance and stimulus intensity. The present study assessed the impact of these factors on both psychophysiological and behavioral responses. Subjects were preselected to represent the extremes of the sensation-seeking dimension, then exposed to auditory and visual presentations of a series of sexual and aggressive stimuli of systematically varied intensity. High sensation seekers gave larger amplitude SCRs to violent stimuli and larger initial responses to sexual stimuli presented visually, while verbal response intensities showed an opposite pattern. Overall, results provided support for an arousal theory interpretation of sensation-seeking, but suggested that the probability and magnitude of group differences is a somewhat complex function of stimulus intensity, stimulus modality, and perhaps other factors not yet assessed.