Are WAG/Rij rats with genetic absence epilepsy anxious?

Behavior of susceptible and non-susceptible to audiogenic (convulsive) seizures rats from inbred WAG/Rij strain, genetically predisposed to absence epilepsy, and outbred Wistar strain, genetically not predisposed to absence epilepsy, was compared to assess the level of anxiety (in open field, light-dark choice and elevated plus-maze tests) and the level of depressiveness (in the sucrose consumption and forced swimming tests). Increased level of anxiety was found only in susceptible to audiogenic seizures rats both from WAG/Rij and Wistar strain, but increased level of depressiveness was found only in WAG/Rij strain rats as compared with Wistar rats independently of their susceptibility to audiogenic seizures. Results suggest that increased depressiveness in WAG/Rij strain rats is associated with absence epilepsy but increased anxiety with susceptibility to audiogenic seizures.     

Increased Noradrenaline Levels in the Rostral Pons can be Reversed by M1 Antagonist in a Rat Model of Post-traumatic Stress Disorder

The dysregulation of hypothalamic–pituitary–adrenal axis and noradrenergic, serotonergic and glutamatergic systems are thought to be involved in the pathophysiology of post-traumatic stress disorder. The effect of selective M1 muscarinic receptor antagonist, pirenzepine on anxiety indices was investigated by using elevated plus maze, following exposure to trauma reminder. Upon receiving the approval of ethics committee, Sprague–Dawley rats were exposed to dirty cat litter (trauma) for 10 min and 1 week later, the rats confronted to a trauma reminder (clean litter). The rats also received intraperitoneal pirenzepine (1 or 2 mg/kg/day) or saline for 8 days. Noradrenaline (NA) concentration in the rostral pons was analyzed by HPLC with electrochemical detection. The anxiety indices of the rats subjected to the trauma reminder were increased when compared to control rats (p < 0.05). Pirenzepine treatment in traumatized rats displayed similar anxiety indices of non-traumatized rats treated with physiological saline. Although freezing time was prolonged with pirenzepine in traumatized groups the change was not found statistically significant. The NA level was 1.5 ± 0.1 pg/mg in non-traumatized rats and increased to 2.4 ± 0.2 pg/mg in traumatized rats. Bonferroni post hoc test revealed that the NA content of the rostral pons of the traumatized rats treated with physiological saline was significantly higher than the content of other groups (p < 0.01). We conclude that NA content in the rostral pons increases in respect to confrontation to a trauma reminder which can be reversed by M1 antagonist pirenzepine indicating the roles of M1 receptors.     

Influence of acoustic signal with ultrasonic components on the development of defensive conditioned reflex in Wistar rats

Short-term (90 s) effects of the complex acoustic signal (CAS) with ultrasonic components on the development of defensive conditioned reflex of two-way active avoidance in a shuttle-box were studied in female Wistar rats. The learning ability of rats was measured on a scale designed in our laboratory. It was shown that CAS stimulation triggered an audiogenic seizure of different strength in 59% of animals. The CAS was extremely stressful for Wistar rats: it prevented the active avoidance learning in early terms after its application (the first training session in 4 or 6 days). This effect did not depend on the presence or intensity of audiogenic seizures during CAS. In the second training session in 9 days (the first session was in 4 days), learning was impaired as compared to control without CAS. However, during repeated training procedure 1.5 months after the CAS (the first session in 6 days), rats rapidly reached the criterion of learning (10 consecutive avoidance reactions). On the other hand, if the CAS was presented with different time lags (immediately, in 3 or in 45 days) after the first training session, the ability of animals to learn during the second session was not impaired both in early and late terms after exposure to the stressor. The results suggest that exposure to CAS prevents development of short-term memory but does not affect consolidation process and long-term memory.     

Dependence of long-lasting effects of the ACTH(4-10) analogue semax on the time of its neonatal administration

Long-lasting behavioural effects of chronic administration of synthetic ACT(4-10) analogue Semax (MEHFPGP) during early neonatal life were studied. The peptide was injected daily intraperitoneally in dose 0.05 mg/kg during the first, second or second-third weeks of postnatal development. It was shown that the peptide injections during the first week lead to a decrease and during second or second-third weeks--to an increase of exploratory activity in 4-8-week aged rats. Furthermore, the peptide adminictration at all times diminished anxiety and improved learning ability of adult rats. The data obtained show that Semax neonatal administration during the first three weeks of life modulates development of brain structures involved in regulation of exploration, anxiety and learning.     

Antiepileptic effects of cerebellar nucleus dentatus electrical stimulation under different conditions of brain epileptisation

It was shown in acute experiments on cats that high frequency (100-300 Hz) electrical stimulation of dentate nucleus led to the solitary epileptic foci of relatively weak intensity suppression and at the same time caused the activation of stronger focal epileptic activity. Electrical stimulation of nucleus dentatus suppressed the epileptic activity of grand mal type and increased seizures in rats with petit mal form of epileptogenesis which was formed in rats during pentylenetatiozol kindling. It was concluded that there is a relation between the antiepileptic effects of nucleus dentatus irritation and intensity as well as the form of epileptic activity induced experimentally.     

The dynamics of latent inhibition in rats under the action of substance P]

The role of substance P in latent inhibition was studied in experiments on rats. Administration of neuropeptide during pre-exposition of conditioned stimulus and before conditioning disturbed all signs of latent inhibition: level of reproduction, retention and resistance to amnestic action of conditioned reaction in the task of passive avoidance. Single administration of haloperidol before learning prevented the disturbance. Significance of hyperfunction of substance P in selective attention and pathogenesis of schizophrenia is discussed.     

Erythropoietin prevents the increase in blood-brain barrier permeability during pentylentetrazol induced seizures

Recombinant human erythropoietin (r-Hu EPO) has been shown to exert neuroprotection in ischemic, excitotoxicity, trauma, convulsions and neurodegenerative disorders. Blood-brain barrier (BBB) leakage plays a role in the pathogenesis of many pathological states of the brain including neurodegenerative disorders. This study aimed to investigate the effects of r-Hu EPO on BBB integrity in pentylentetrazol (PTZ) induced seizures in rats. Seizures were observed and evaluated regard to latency and intensity for an hour. Macroscopical and spectrophotometrical measurement of Evans Blue (EB) leakage were observed for BBB integrity. r-Hu EPO was given intraperitoneally 24 h prior to seizure induction. Total seizure duration of 720+/-50 s after single PTZ administration (80 mg/kg i.p.) was declined to 190+/-40 s in r-Hu EPO pretreatment. A typical BBB breakdown pattern (i.e. staining in cerebellum, cerebral cortex, midbrain, hippocampus, thalamus and corpus striatum) was observed in rat brains with PTZ induced seizures; whereas, EPO pretreatment confined BBB leakage to cerebellum and cortical areas, and lessened the intensity of tonic-clonic seizures observed in PTZ seizures. The protective effect of r-Hu EPO on BBB permeability in seizures is a new and original finding. The protective action of r-Hu EPO in seizures and some of CNS pathologies warrant further investigations.     

Non-classic effects of luliberin confirming the pleiotropy of neuropeptides

The effects of synthetic neuropeptide LH-RH and its analogues were studied in experiments on 174 white male rats. The influence of the substances was shown on instrumental avoidance learning in Y-shaped maze. Convulsive and anticonvulsive effects of the preparations were studied on experimental model of corasol seizures. The analgetic effect of the substances was evaluated by behavioural pain reaction to electrical stimulation of the tail root. Analgetic, anticonvulsive, and psychostimulating LH-RH properties confirm polyfunctionality and "pleiotropy" of neuropeptides as a class of new endogenous informational compounds.     

Impairement of estimation of the inner time and the emotional behavior in rats with the lesioned striatum and hippocampus

Bilateral lesion of the striatum delayed time conditioning in rats, induced anxiety, rearranged normal correlation between the anxiety level and autochronometrical ability. These shifts progressed along with an augmentation of the striatum lesion extent. Combined striat- and hippocampectomy as well as the latter alone resulted in a complete absence of time counting learning irrespective of the brain lesion extent. In these animals anxiety was also more obvious.     

Modulation of Learning and Neuronal Membrane Composition in the Rat by Essential Fatty Acid Preparation: Time-Course Analysis

Previous studies have shown that chronic administration of SR-3 (a 1:4 mixture of -linolenic and linoleic acid) affects spatial learning, thermoregulation, pain threshold and protection from seizures. The mode of action is unknown. One possible explanation is that the preparation induces changes in the fatty acids profile and in the cholesterol level in the neuronal membrane. This study used 15 independent groups of rats (n = 12) which were given either saline, mineral oil (vehicle) or SR-3 (25 mg/kg) for 0, 1,2, 3, or 4 weeks. The learning performance was measured in the Morris Water tank and the fatty acids profile and the cholesterol level were examined by the GC method in synaptosomes obtained from the frontal cortex of the rats. SR-3 improved the learning performance and induced major changes in the neuronal membrane composition, such as an increase in the total level of fatty acids, an increase in the level of essential fatty acids and a decrease in the cholesterol level. Those changes occurred after 3 weeks of treatment. The biochemical variables can predict the behavioral variables but not vice versa. The changes in the neuronal membrane may result in a modification of the membrane fluidity, which may, in turn, enhance cognitive and neuropharmacological effects.     

Sensitiveness to social stress in female rats with alteration of the pituitary-adrenal axis stress reactivity

The sensitiveness of female rats to social stress induced by increasing group density, was investigated. It was shown that female rats were housed in groups of 9-10 animala per cage in pubertal period and demonstrated significant alteration of oestrous cycle duration and anxiety level. This housing condition increased basal level of corticostcrone in prenatal stressed female rats who have high stress reactivity of the hypothalamic-pituitary-adrenal axis, as well as a more profound effect on anxiety level and oestrous cycle. Prenatal stressed rats retained impairment of oestrous cycle and behavior after optimization of housing condition, whereas control rats demonstrated normalization of oestrous cycle duration and anxiety level. These data suggest that high stress reactivity females rats are more sensitive to crowding-induced stress.     

Sex differences in modulating blood brain barrier permeability by NO in pentylenetetrazol-induced epileptic seizures

Susceptibility to epilepsy as well as BBB dysfunction in some pathological conditions varies depending on sex difference. It has recently been shown that systemically given NO donor and antagonists modify the nature of seizures induced by PTZ (pentylenetetrazol) differently in male and female rats. This study investigates the role of NO on BBB permeability in PTZ seizures with sex differences using NO donor, sodium nitroprusside (SNP), and NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). Nitrite+nitrate levels as indices of NO generation in the brain were also assessed. L-NAME prolonged seizure latency in male rats, seizure intensity and seizure duration were lessened. L-NAME depicted opposite effects in seizure nature in female rats. SNP prolonged seizure latency, while seizure intensity and duration were lessened only in female rats. L-NAME in male rats increased L-NAME use in female rats (not in male rats) which resulted in a more leaky BBB especially in midbrain, thalamus, hippocampus, corpus striatum and cerebellum whereas SNP use in male rats and not in female rats resulted in pronounced BBB opening in all brain regions studied than PTZ per se. L-NAME while decreasing nitrite+nitrate levels in male rat brains, acted in an opposite fashion in females. SNP use depicted an inverse picture with respect to L-NAME, with an opposite action in different sexes. This study reveals that NO effect on BBB in PTZ-induced seizures depends unequivocally on sex difference. The sex-dependent action of NO in seizures and in CNS pathologies warrants further investigation.     

The role of individual characteristics and learning in the manifestation of motor asymmetry in rats

Relative role was studied of the "initial" preference (caused by animals individual properties) and learning in real preference of one limb in rats. After a short-time learning to get food from a narrow horizontal pipe only by the left paw a retrograde amnesia was evoked in rats. At preference determination after three weeks, in conditions which allowed to get food by any paw, in the group of animals without amnesia the number of the left-handed rats was 5.7 times more than of the right-handed ones. In the group of animals with amnesia the numbers of the left-handed, right-handed and ambidextrous were approximately equal. Correlation was revealed between the speed of learning to get food by the left paw and the number of attempts to use the right paw. It has been shown that the initial preference may be stably changed even by a short-time learning (3 food seizures). By the degree of manifestation of the initial preference the rats form a continuum with a gradual transition from pronounced right-handed animals to pronounced left-handed ones. The weaker is the initial preference, the greater the role of learning in the real preference of one of the paws.     

Effect of a change in the effectiveness of a benzodiazepine-GABA-ionophore complex blockade on the reproduction of an amnesic memory trace in mice after preliminary diazepam administration

The paper deals with the results of analysis of the influence of blocked of BD-GABA-ionophore complex and its separate components on recover of memory trace amnesia during BD-receptors activation in experiments on elaboration of CR of passive avoidance in mice. It is shown that at "neurochemical tuning" the improvement of conditioned reaction reproduction on the 2-nd and 21-st day after learning and amnestic action was observed only at GABAA receptor blockade by bicuculline, while the blockade of BD-receptor by flumazepil and of chlorine channel by picrotoxin was ineffective. Simultaneous blockade of all BD-GABA-ionophore complex components was not more effective in comparison with the blockade of its separate links in the recovery of conditioned reaction reproduction. The presented data allow to suppose that "psychogenic" amnesia development is determined by the functional state of neurotransmitter brain systems at learning and amnestic action which stipulates subsequent possibility of memory trace retrieval.     

Alterations of behavior and spatial learning after unilateral entorhinal ablation of rats

The entorhinal cortex (EC) is the key input and output structure of the hippocampus. It plays a crucial role in sensory processing, memory and learning, as well as in mechanisms of epileptic seizures. Our previous studies on the 4-aminopyridin induced epilepsy model of rats showed that ablation of unilateral EC prompted weakening of limbic seizure manifestation, thus the possibility of therapeutical benefit of this kind of surgery can be risen. Open field, elevated plus-maze and Morris water-maze test were performed to analyze changes of the basal activity level, exploratory behavior, and spatial memory capacity, respectively, of adult Wistar rats having undergone left EC excision. Compared with the sham-operated control group, rats with lesions of the EC showed enhanced locomotor activity in the open-field test. The elevated plus-maze test revealed higher frequency of entries and more time spent in the open arms. Morris water-maze test suggested impairment of the spatial learning capacity following left lateral EC lesion. Therefore, our data showed that EC lesions induced hyperactivity, increased exploratory behavior, and impaired spatial learning. Entorhinal cortex ablation, as a potential method for controlling epileptic seizures has multiple effects on animals' behavior and spatial learning. To determine the cost-benefit ratio of a potential surgical intervention needs further experimental and human investigations.     

Level of neuroactive steroids in the brain and sex-related peculiarities of formation and extinction of conditioned reflex in rats

Sex-related peculiarities of dynamics of brain sex steroids in the process of learning and extinction of the conditioned reflex of passive avoidance have been studied in model experiment. Prior to learning of the conditioned reflex, female rats were found to be distinguished by manifestation of anxiety and fear as compared with male rats. At formation of the conditioned reflex, no significant sex-related differences were detected between males and females, whereas extinction of the conditioned reaction of passive avoidance in males occurred by 2–3 days faster than in females. At learning of conditioned reaction of passive avoidance, in sexually mature male rats there was revealed an increase of the testosterone content in various brain structures, especially in hippocampus and frontal cortex, while its level in blood plasma remained unchanged. Also shown was an elevation of estradiol concentration in female amygdale, whereas at extinction of the conditioned reaction of passive avoidance, a rise of estradiol values was noted in hippocampus and cingular cortex. At the same time, the testosterone level in blood plasma did not change, whereas after extinction of the conditioned reflex the estradiol concentration decreased statistically significantly. Different dynamics of changes of the sex steroid levels in brain and blood plasma can indicate a possibility of their formation in the nervous tissue. The performed correlation analysis confirms the concept of selective involvement of testosterone and estradiol of individual brain structures in realization of processes of learning and memory in sexually mature male and female rats.     

Reproduction of a memory trace in amnesia and forgetting following alteration in the activity of pre- and postsynaptic dopamine receptors

The paper deals with analysis of the action of enantiomers 3-PPP on memory trace reproduction disturbed by amnestic effects and spontaneous forgetting in mice. A considerable antiamnestic effect is shown of (+)3-PPP and (-)3-PPP in 10 mg/kg doze changing the activity of postsynaptic dopamine receptors. The influence of drugs in 2 mg/kg doze changing the activity of presynaptic receptors consisted in recovery of conditioned habit only in situation of a weak amnestic effect and at forgetting, when the level of reproduction was like a weak amnesia. The range of enantiomers 3-PPP action on reproduction processes disturbed by amnesia or forgetting is determined by the possibility of specific activation of pre- and postsynaptic receptors at different depth of disturbances of memory trace reproduction causing differentiation of 3-PPP effects.     

The effect of gonadal hormones and gender on anxiety and emotional learning

Disorders of anxiety and fear dysregulation are highly prevalent. These disorders affect women approximately 2 times more than they affect men, occur predominately during a woman's reproductive years, and are especially prevalent at times of hormonal flux. This implies that gender differences and sex steroids play a key role in the regulation of anxiety and fear. However, the underlying mechanism by which these factors regulate emotional states in either sex is still largely unknown. This review discusses animal studies describing sex-differences in and gonadal steroid effects on affect and emotional learning. The effects of gonadal hormones on the modulation of anxiety, with particular emphasis on progesterone's ability to reduce the responsiveness of female rats to corticotropin releasing factor and the sex-specific effect of testosterone in the reduction of anxiety in male rats, is discussed. In addition, gonadal hormone and gender modulation of emotional learning is considered and preliminary data are presented showing that estrogen (E2) disrupts fear learning in female rats, probably through the antagonistic effect of ERalpha and ERbeta activation.