Predatory Odor Exposure as a Potential Paradigm for Studying Emotional Modulation of Memory Consolidation-The Role of the Noradrenergic Transmission in the Basolateral Amygdala.

The pivotal role of the basolateral amygdala (BLA) in the emotional modulation of hippocampal plasticity and memory consolidation is well-established. Specifically, multiple studies have demonstrated that the activation of the noradrenergic (NA) system within the BLA governs these modulatory effects. However, most current evidence has been obtained by direct infusion of synthetic NA or beta-adrenergic agonists. In the present study, we aimed to investigate the effect of endogenous NA release in the BLA, induced by a natural aversive stimulus (coyote urine), on memory consolidation for a low-arousing, hippocampal-dependent task. Our experiments combined a weak object location task (OLT) version with subsequent mild predator odor exposure (POE). To investigate the role of endogenous NA in the BLA in memory modulation, a subset of the animals (Wistar rats) was treated with the non-selective beta-blocker propranolol at the end of the behavioral procedures. Hippocampal tissue was collected 90 min after drug infusion or after the OLT test, which was performed 24 h later. We used the obtained samples to estimate the levels of phosphorylated CREB (pCREB) and activity-regulated cytoskeleton-associated protein (Arc)-two molecular markers of experience-dependent changes in neuronal activity. The result suggests that POE has the potential to become a valuable behavioral paradigm for studying the interaction between BLA and the hippocampus in memory prioritization and selectivity.

Carotid Body: The Primary Peripheral Arterial Chemoreceptor.

The carotid body (CB) is a polymodal chemosensory organ that plays an essential role in initiating respiratory and cardiovascular adjustments to maintain blood gas homeostasis. Much of the available evidence suggests that chronic hypoxia induces marked morphological and neurochemical changes within the CB, but the detailed molecular mechanisms by which these affect the hypoxic chemosensitivity still remain to be elucidated. Dysregulation of the CB function and altered oxygen saturation are implicated in various physiological and pathophysiological conditions. Knowledge of the morphological and functional aspects of the CB would improve our current understanding of respiratory and cardiovascular homeostasis in health and disease.

History and Recent Progress in Carotid Body Studies.

This chapter describes the history of the carotid body (CB) and the subsequent research on its structure and function. The chronological development of ideas about its anatomical structure as a ganglion, the first descriptions of its glandular nature as a ball of highly vascular tissue (glomus), the discovery of its neural crest origin and relevant embryological views as a true paraganglion toward a more conclusive understanding of its sensory nature as a chemoreceptor for chemical changes in blood have been consistently demonstrated. The knowledge of the CB neurochemistry, physiology and pathophysiology has progressed immensely in the past century and a large and compelling body of evidence for the presence of a neurogenic niche in the CB has accumulated over the last two decades, thus underlying its function and possibility for the development of cell replacement therapies.

General Morphology of the Mammalian Carotid Body.

The carotid body (CB) is the main peripheral arterial chemoreceptor that registers the levels of pO2, pCO2 and pH in the blood and responds to their changes by regulating breathing. It is strategically located in the bifurcation of each common carotid artery. The organ consists of "glomera" composed of two cell types, glomus and sustentacular cells, interspersed by blood vessels and nerve bundles and separated by connective tissue. The neuron-like glomus or type I cells are considered as the chemosensory cells of the CB. They contain numerous cytoplasmic organelles and dense-cored vesicles that store and release neurotransmitters. They also form both conventional chemical and electrical synapses between each other and are contacted by peripheral nerve endings of petrosal ganglion neurons. The glomus cells are dually innervated by both sensory nerve fibers through the carotid sinus nerve and autonomic fibers of sympathetic origin via the ganglioglomerular nerve. The parasympathetic efferent innervation is relayed by vasomotor fibers of ganglion cells located around or inside the CB. The glial-like sustentacular or type II cells are regarded to be supporting cells although they sustain physiologic neurogenesis in the adult CB and are thus supposed to be progenitor cells as well. The CB is a highly vascularized organ and its intraorgan hemodynamics possibly plays a role in the process of chemoreception.

Structural Plasticity of the Carotid Body.

The mammalian carotid body (CB) exhibits considerable plasticity of its structure during development and aging and as a consequence of environmental, metabolic and inflammatory stimuli. The structural changes during maturation include an enlargement of the total and vascular volume of the CB. Conversely, aging results in a reduction in the number and volume of glomus cells with progressive cellular degeneration and an apparent increase in the surrounding connective tissue. Age-related structural alterations are similar to those during chronic hypoxia. Long-term hypoxic exposure and sodium nitrate treatment enlarge several-fold the size of the rat CB causing glomus cell hypertrophy and hyperplasia, and evoke changes in its vascular structure, inducing marked vasodilation and neovascularization. In humans, such structural CB adaptation responses to prolonged hypoxia occur during acclimatization to high altitudes. On the other hand, the hyperoxic CB is significantly smaller than those of age-matched normoxic controls. Morphological alterations in the CB in both hypertensive animals and humans are characterized by a slightly enlarged parenchyma without apparent vascular expansion and/or dilation. The CB structural plasticity depends on the existence of a population of multipotent neural crest-derived stem cells, which are activated during hypoxia to proliferate and differentiate into new both neuronal (glomus) and vascular cell types.

Mechanisms of Chemosensory Transduction in the Carotid Body.

The mammalian carotid body (CB) is a polymodal chemoreceptor, which is activated by blood-borne stimuli, most notably hypoxia, hypercapnia and acidosis, thus ensuring an appropriate cellular response to changes in physical and chemical parameters of the blood. The glomus cells are considered the CB chemosensory cells and the initial site of chemoreceptor transduction. However, the molecular mechanisms by which they detect changes in blood chemical levels and how these changes lead to transmitter release are not yet well understood. Chemotransduction mechanisms are by far best described for oxygen and acid/carbon dioxide sensing. A few testable hypotheses have been postulated including a direct interaction of oxygen with ion channels in the glomus cells (membrane hypothesis), an indirect interface by a reversible ligand like a heme (metabolic hypothesis), or even a functional interaction between putative oxygen sensors (chemosome hypothesis) or the interaction of lactate with a highly expressed in the CB atypical olfactory receptor, Olfr78, (endocrine model). It is also suggested that sensory transduction in the CB is uniquely dependent on the actions and interactions of gaseous transmitters. Apparently, oxygen sensing does not utilize a single mechanism, and later observations have given strong support to a unified membrane model of chemotransduction.

Neurochemical Plasticity of the Carotid Body.

A striking feature of the carotid body (CB) is its remarkable degree of plasticity in a variety of neurotransmitter/modulator systems in response to environmental stimuli, particularly following hypoxic exposure of animals and during ascent to high altitude. Current evidence suggests that acetylcholine and adenosine triphosphate are two major excitatory neurotransmitter candidates in the hypoxic CB, and they may also be involved as co-transmitters in hypoxic signaling. Conversely, dopamine, histamine and nitric oxide have recently been considered inhibitory transmitters/modulators of hypoxic chemosensitivity. It has also been revealed that interactions between excitatory and inhibitory messenger molecules occur during hypoxia. On the other hand, alterations in purinergic neurotransmitter mechanisms have been implicated in ventilatory acclimatization to hypoxia. Chronic hypoxia also induces profound changes in other neurochemical systems within the CB such as the catecholaminergic, peptidergic and nitrergic, which in turn may contribute to increased ventilatory and chemoreceptor responsiveness to hypoxia at high altitude. Taken together, current data suggest that complex interactions among transmitters markedly influence hypoxia-induced transmitter release from the CB. In addition, the expression of a wide variety of growth factors, proinflammatory cytokines and their receptors have been identified in CB parenchymal cells in response to hypoxia and their upregulated expression could mediate the local inflammation and functional alteration of the CB under hypoxic conditions.

Carotid Body Dysfunction and Mechanisms of Disease.

Emerging evidence shows that the carotid body (CB) dysfunction is implicated in various physiological and pathophysiological conditions. It has been revealed that the CB structure and neurochemical profile alter in certain human sympathetic-related and cardiometabolic diseases. Specifically, a tiny CB with a decrease of glomus cells and their dense-cored vesicles has been seen in subjects with sleep disordered breathing such as sudden infant death syndrome and obstructive sleep apnea patients and people with congenital central hypoventilation syndrome. Moreover, the CB degranulation is accompanied by significantly elevated levels of catecholamines and proinflammatory cytokines in such patients. The intermittent hypoxia stimulates the CB, eliciting augmented chemoreflex drive and enhanced cardiorespiratory and sympathetic responses. High CB excitability due to blood flow restrictions, oxidative stress, alterations in neurotransmitter gases and disruptions of local mediators is also observed in congestive heart failure conditions. On the other hand, the morpho-chemical changes in hypertension include an increase in the CB volume due to vasodilation, altered transmitter phenotype of chemoreceptor cells and elevated production of neurotrophic factors. Accordingly, in both humans and animal models CB denervation prevents the breathing instability and lowers blood pressure. Knowledge of the morphofunctional aspects of the CB, a better understanding of its role in disease and recent advances in human CB translational research would contribute to the development of new therapeutic strategies.

Stem Cell Niche in the Mammalian Carotid Body.

Accumulating evidence suggests that the mammalian carotid body (CB) constitutes a neurogenic center that contains a functionally active germinal niche. A variety of transcription factors is required for the generation of a precursor cell pool in the developing CB. Most of them are later silenced in their progeny, thus allowing for the maturation of the differentiated neurons. In the adult CB, neurotransmitters and vascular cytokines released by glomus cells upon exposure to chronic hypoxia act as paracrine signals that induce proliferation and differentiation of pluripotent stem cells, neuronal and vascular progenitors. Key proliferation markers such as Ki-67 and BrdU are widely used to evaluate the proliferative status of the CB parenchymal cells in the initial phase of this neurogenesis. During hypoxia sustentacular cells which are dormant cells in normoxic conditions can proliferate and differentiate into new glomus cells. However, more recent data have revealed that the majority of the newly formed glomus cells is derived from the glomus cell lineage itself. The mature glomus cells express numerous trophic and growth factors, and their corresponding receptors, which act on CB cell populations in autocrine or paracrine ways. Some of them initially serve as target-derived survival factors and then as signaling molecules in developing vascular targets. Morphofunctional insights into the cellular interactions in the CB stem cell microenvironment can be helpful in further understanding the therapeutic potential of the CB cell niche.

Neurochemical Anatomy of the Mammalian Carotid Body.

Carotid body (CB) glomus cells in most mammals, including humans, contain a broad diversity of classical neurotransmitters, neuropeptides and gaseous signaling molecules as well as their cognate receptors. Among them, acetylcholine, adenosine triphosphate and dopamine have been proposed to be the main excitatory transmitters in the mammalian CB, although subsequently dopamine has been considered an inhibitory neuromodulator in almost all mammalian species except the rabbit. In addition, co-existence of biogenic amines and neuropeptides has been reported in the glomus cells, thus suggesting that they store and release more than one transmitter in response to natural stimuli. Furthermore, certain metabolic and transmitter-degrading enzymes are involved in the chemotransduction and chemotransmission in various mammals. However, the presence of the corresponding biosynthetic enzyme for some transmitter candidates has not been confirmed, and neuroactive substances like serotonin, gamma-aminobutyric acid and adenosine, neuropeptides including opioids, substance P and endothelin, and gaseous molecules such as nitric oxide have been shown to modulate the chemosensory process through direct actions on glomus cells and/or by producing tonic effects on CB blood vessels. It is likely that the fine balance between excitatory and inhibitory transmitters and their complex interactions might play a more important than suggested role in CB plasticity.

Carotid Body and Cell Therapy.

During the past decade, the carotid body (CB) has been considered an innovative therapeutic target for the treatment of certain cardiorespiratory and metabolic diseases most of which are sympathetically mediated. It has recently been revealed that CB stem cells provide new target sites for the development of promising cell-based therapies. Specifically, generation of CB progenitors in vitro which can differentiate into functionally active glomus cells may be a useful procedure to produce the cell mass required for replacement cell therapy. Due to their dopaminergic nature, adult glomus cells can be used for an intrastriatal grafting in neurodegenerative brain disorders including Parkinson's disease. The beneficial effect of throphic factors such as glial cell-derived neurotrophic factor synergistically released by the transplanted cells then enables the transplant to survive. Likewise, intracerebral administration of CB cell aggregates or dispersed cells has been tested for the treatment of an experimental model of stroke. The systematic clinical applicability of CB autotransplants following glomectomy in humans is under investigation. In such autotransplantation studies, cell aggregates from unilaterally resected CB might be used as autografts. In addition, stem cells could offer an opportunity for tissue expansion and might settle the issue of small number of glomus cells available for transplantation.

The Carotid Body: A Tiny Structure with Many Roles.

Over the last century, the structure of the mammalian carotid body (CB) has repeatedly been studied, and our present understanding of its normal morphology is comprehensive. It has been demonstrated that the CB has an intricate internal structure and a remarkable ability to release a wide variety of neurotransmitters and neuromodulators in response to different chemical stimuli. The advances in modern cellular/molecular biological methods and newly developed single-cell electrophysiological techniques have provided an additional insight into the precise working mechanisms and roles of the CB in health and disease. Emerging experimental evidence has also shown that the CB exhibits an extraordinary structural and functional plasticity as a consequence of various environmental stimuli. Lately, the CB has attracted much clinical interest because its dysfunction relates to a number of cardiovascular and respiratory disorders. Expanding knowledge about the pathophysiological mechanisms that alter the CB cell function would certainly help to facilitate the translational research. Recent progress in cell fate experiments has further revealed that the CB is a neurogenic center with a functionally active germinal niche. This may lead to the development of promising new candidate therapies to combat these diseases and improve the quality of human life. Thus, the CB has entered the twenty-first century with its actual designation.

Sexual dimorphism in shape and size of the neurocranium.

Sex identification is a primary step in forensic analysis of skeletal remains. The accuracy of sex estimation methods greatly depends on the sexual dimorphism manifested by the target anatomical region. The study aims to evaluate the sexual dimorphism in shape and size of the neurocranium and to compare the potential of shape and size of different cranial regions to classify correctly the male and female crania. The study was carried out on computed tomography images of 373 Bulgarian adults (161 males and 212 females). Three-dimensional coordinates of 32 landmarks were acquired. The landmarks were arranged in 4 configurations: neurocranium, frontal bone, parietotemporal region, and occipital bone. For each configuration, the presence of significant sex differences in shape and size was tested. Principal component analysis (PCA) was applied to explore the shape variation. The classification power of size and shape was tested using discriminant analysis and k-means clustering. The neurocranium shows significant sex differences in shape and size. The parietotemporal region is the most dimorphic neurocranial part in size and the frontal bone is the most differing one in shape. The size of the parietotemporal region and frontal bone classifies correctly more than 80% of the crania. The discrimination ability based on shape is rather low as the highest values of about 70% are obtained for the frontal and occipital bone. The PCA plots show large overlapping of the male and female crania. It can be inferred that the sex-specific size differences in the neurocranium are more important than the shape differences.

Machine learning approaches for sex estimation using cranial measurements.

The aim of the present study is to apply support vector machines (SVM) and artificial neural network (ANN) as sex classifiers and to generate useful classification models for sex estimation based on cranial measurements. Besides, the performance of the generated sub-symbolic machine learning models is compared with models developed through logistic regression (LR). The study was carried out on computed tomography images of 393 Bulgarian adults (169 males and 224 females). The three-dimensional coordinates of 47 landmarks were acquired and used for calculation of the cranial measurements. A total of 64 measurements (linear distances, angles, triangle areas and heights) and 22 indices were calculated. Two datasets were assembled including the linear measurements only and all measurements and index, respectively. An additional third dataset comprising all possible interlandmark distances between the landmarks was constructed. Two machine learning algorithms-SVM and ANN and a traditional statistical analysis LR-were applied to generate models for sex estimation. In addition, two advanced attribute selection techniques (Weka BestFirst and Weka GeneticSearch) were used. The classification accuracy of the models was evaluated by means of 10 × 10-fold cross-validation procedure. All three methods achieved accuracy results higher than 95%. The best accuracy (96.1 ± 0.5%) was obtained by SVM and it was statistically significantly higher than the best results achieved by ANN and LR. SVM and ANN reached higher accuracy by training on the full datasets than the selection datasets, except for the sample described by the interlandmark distances, where the reduction of attributes by the GeneticSearch algorithm improved the accuracy.

Sagittal suture maturation: Morphological reorganization, relation to aging, and reliability as an age-at-death indicator.

OBJECTIVES: The sagittal suture (SS) is assumed to be an initial site for the commencement of cranial suture closure as well as the most frequent spot of isolated craniosynostosis. The present study aimed to inspect the reorganization of the SS at the microlevel to assess the relation between its closure and aging and to establish whether it could be used as a reliable indicator in age-at-death prediction. MATERIALS AND METHODS: The SS was investigated in 68 dry contemporary adult male skulls of known age-at-death. An additional series of 20 skulls was used for verification. The skulls were scanned using a micro-computed tomography system. The SS closure degree was assessed along the three bone layers on cross-sectional tomograms by using a scoring scale. RESULTS: In the entirely open SS, the bone edges consist of compact bone and are widely separated. With SS maturation, the bone edges come into contact, and the remodeling process leads to a decrease in the sutural area and bone homogenization across all three layers. SS closure is an irregular process roughly related to aging, beginning in the early 20s, reaching its peak at about 30 years of age and abating in the late 40s. DISCUSSION: Although related to aging, SS closure is not a simple function of it. Rather, the underlying factors inducing and managing this process are multifaceted and complex. Although the etiology of SS maturation remains unclear, it is reasonable to use SS closure cautiously and only as a supportive method for age prediction.

Chronic agomelatine treatment prevents comorbid depression in the post-status epilepticus model of acquired epilepsy through suppression of inflammatory signaling.

Inflammatory signal molecules are suggested to be involved in the mechanism underlying comorbid depression in epilepsy. In the present study, we tested the hypothesis that the novel antidepressant agomelatine, a potent melatonin MT1 and MT2 receptor agonist and serotonin 5HT2C receptor antagonist, can prevent depressive symptoms developed during the chronic epileptic phase by suppressing an inflammatory response. Chronic treatment with agomelatine (40 mg/kg, i.p.) was initiated an hour after the kainate acid (KA)-induced status epilepticus (SE) and maintained for a period of 10 weeks in Wistar rats. Registration of spontaneous motor seizures was performed through a video (24 h/day) and EEG monitoring. Antidepressant activity of agomelatine was explored in the splash test, sucrose preference test (SPT) and forced swimming test (FST) while anxiolytic effect was observed through the novelty suppression-feeding test (NSFT) during chronic phase in epileptic rats. The frequency of motor seizures detected by video and EEG recording did not differ between vehicle and Ago group. Rats with registered spontaneous motor seizures showed symptoms typical for depressive behavior that included decreased grooming, anhedonia during the dark period and hopeless-like behavior. Epileptic rats exhibited also anxiety with novelty-induced hypophagia. This behavioral deficit correlated with increased signal markers of inflammation (plasma levels of interleukin (IL)-1ß and activated glia in brain), while plasma corticosterone levels were not changed. Agomelatine treatment during epileptogenesis exerted a clear antidepressant effect by suppressing all behavioral hallmarks, reducing plasma IL-1ß levels and preventing microgliosis and astrogliosis in specific limbic regions. The present results suggest that agomelatine treatment starting after SE can provide an effective therapy of comorbid depression in chronic epileptic condition through suppression of inflammatory signaling.

Digital radiomorphometric analysis of the frontal sinus and assessment of the relation between persistent metopic suture and frontal sinus development.

OBJECTIVES: This study aimed to establish the frequency of the frontal sinus (FS) aplasia, to compare metopic and nonmetopic series and thus to assess the relationship between the preservation of metopic suture and FS development. MATERIALS AND METHODS: FSs were investigated in 230 dry skulls of adult males distributed into control (137) and metopic (93) series. They were visualized through industrial digital radiography. RESULTS: In the control series, the FS aplasia was observed in 12.41% of the skulls, and it was mostly unilateral (8.76%) than bilateral (3.65%). The left-sided aplasia (5.11%) slightly prevailed over the right-sided one (3.65%). In the metopic series, the aplasia was observed with a frequency of 19.35%, and the bilateral aplasia (7.53%) was rarer that the unilateral one (11.83%), while the right-sided aplasia was clearly predominant (9.68%) compared to the left-sided one (2.15%). DISCUSSION: The significant differences between both series showed a tendency for the persistence of metopic suture to be frequently related with FS underdevelopment in the vertical plate of the frontal bone, but in cases of pneumatization, it was preferentially on the left side. Taking into account that the cranial hypertension leads to suture diastasis and hinders development of the FS, it could be suggested that persistence of the metopic suture along with underdevelopment of the FS in nonsyndromic adults could be an expression of an elevated intracranial pressure during early development as an after-effect of certain condition.

Agomelatine protects against neuronal damage without preventing epileptogenesis in the kainate model of temporal lobe epilepsy.

Recent studies about the novel antidepressant agomelatine, which is a mixed MT1 and MT2 melatonin receptor agonist and 5HT2C serotonin receptor antagonist possessing an anticonvulsant and neuroprotective action, suggest that it may have potential to contribute against epileptogenesis and epilepsy-induced memory impairment. In order to ascertain whether protection of some brain structures could suppress epileptogenesis, in the present study, we evaluated the effect of chronic post-status treatment with agomelatine on epileptogenesis, behavioral and neuronal damage induced by kainate acid (KA) status epilepticus (SE). Agomelatine/vehicle treatment (40mg/kg, i.p.) started one hour after SE and continued up to 10weeks in Wistar rats. Latency for onset of spontaneous motor seizures (SMS) and their frequency was detected by a 24-h video-recording. Locomotor activity, anxiety and hippocampus-dependent spatial memory in open field (OF), elevated plus maze (EPM), light-dark test (LDT) and radial arm maze (RAM) test, respectively, were evaluated during the last two weeks after SE. Agomelatine significantly decreased the latency for onset of SMS and increased the seizure frequency during the 2nd and the 3rd week of treatment. The MT1 and MT2 receptor agonist and serotonin 5HT2C receptor antagonist exacerbated the KA-induced hyperlocomotion and impulsive behavior and it was unable to prevent spatial memory impairment of epileptic rats. However, agomelatine induced a neuroprotection in the dorsal hippocampus, specifically in the CA1, septal CA2 and partially in the CA3c region, the hilus of the dentate gyrus, piriform cortex and septo-temporal and temporal basolateral amygdala. Our findings suggest that the beneficial impact against SE-induced neuronal loss exerted by agomelatine is not crucial for the suppression of epileptogenesis and its deleterious consequences in KA model of temporal lobe epilepsy.

Incidence of a Bifid Mandibular Condyle in Dry Mandibles.

BACKGROUND: A bifid mandibular condyle (BMC) is a rare anatomical variation with an etiology not fully understood. Although there are numerous case reports regarding it, purposeful epidemiological investigations on the BMC frequency among different groups are scarce. This study aims to investigate the incidence and laterality of BMC among series of adult males from Bulgaria and perform a morphometric analysis of it. MATERIALS AND METHODS: A series of 500 dry intact mandibles from adult males was investigated. The condyles were macroscopically observed and when skulls were available, the corresponding mandibular fossae were also inspected. In the cases when bifid condyles were found, 27 measurements were taken. RESULTS: Bifid mandibular condyle was observed in 4 (0.8%) mandibles. All of the cases were unilateral, 2 on the right side (0.4%) and 2 on the left (0.4%). The condyles were divided into medial and lateral heads by a sagittal fissure or a notch. CONCLUSION: The established frequency of BMC was comparable with those reported in Turkish and Korean populations. The lack of injury marks and traces implies a developmental etiology of this condition.

Long-Term Treatment with Losartan Attenuates Seizure Activity and Neuronal Damage Without Affecting Behavioral Changes in a Model of Co-morbid Hypertension and Epilepsy.

Over the last 10 years, accumulated experimental and clinical evidence has supported the idea that AT1 receptor subtype is involved in epilepsy. Recently, we have shown that the selective AT1 receptor antagonist losartan attenuates epileptogenesis and exerts neuroprotection in the CA1 area of the hippocampus in epileptic Wistar rats. This study aimed to verify the efficacy of long-term treatment with losartan (10 mg/kg) after kainate-induced status epilepticus (SE) on seizure activity, behavioral and biochemical changes, and neuronal damage in a model of co-morbid hypertension and epilepsy. Spontaneous seizures were video- and EEG-monitored in spontaneously hypertensive rats (SHRs) for a 16-week period after SE. The behavior was analyzed by open field, elevated plus maze, sugar preference test, and forced swim test. The levels of serotonin in the hippocampus and neuronal loss were estimated by HPLC and hematoxylin and eosin staining, respectively. The AT1 receptor antagonism delayed the onset of seizures and alleviated their frequency and duration during and after discontinuation of treatment. Losartan showed neuroprotection mostly in the CA3 area of the hippocampus and the septo-temporal hilus of the dentate gyrus in SHRs. However, the AT1 receptor antagonist did not exert a substantial influence on concomitant with epilepsy behavioral changes and decreased 5-HT levels in the hippocampus. Our results suggest that the antihypertensive therapy with an AT1 receptor blocker might be effective against seizure activity and neuronal damage in a co-morbid hypertension and epilepsy.