Quantitative chiral analysis of salsolinol in different brain regions of rats genetically predisposed to alcoholism

A method to determine the catecholamine content in putamen (CPU) and midbrain (MB) regions of the brain of alcohol-preferring rats (P) is presented with a focus on the low-level detection of S,R-salsolinol, a metabolite of dopamine and a putative alcoholism marker. The developed strategy allows both quantitative profiling of related catecholamines and the enantiomeric separation and quantification of the S- and R-salsolinol isomers and their ratios. The described LC/MS strategy simplifies the current methodology that typically employs GC-MS by eliminating the need for derivatization. The data also suggest an increase in the non-enzymatic formation of salsolinol as a consequence of ethanol exposure.     

Morpho-chemical characteristics of the brain of rats genetically predisposed to catalepsy

Cell organization of the cerebral cortex and striatum has been studied by+light optics and enzymatic activity of neuromediators catabolism--histochemically. In layers III and V of the sensomotor cortex and in the nucleus caudatus the number of neurons per unit area is increased, and their size is decreased. Volume of cytoplasm and nuclei of neurons in both layers is decreased, the latter--to less extent. The total amount of the perineuronal glia in the nucleus caudatus is also decreased at the expense of astroglia. In the cerebral cortex it is equal, but the ratio between astro-++- and oligodendroglia is changed. Acetylcholinesterase activity in the layers III and V of the sensomotor cortex is lower than in the control, while monoamine oxidase activity is kept at the control level. The genetically determined anomalies++ of growth and development of the cerebral cells is supposed to be considered as a structural base of the cataleptic state.     

Stress facilitates body weight gain in genetically predisposed rats on medium-fat diet

To assess the interaction between stress and energy homeostasis, we immobilized male Sprague-Dawley rats prone to diet-induced obesity (DIO) or diet resistance (DR) once for 20 min and then fed them either low-fat (4.5%) chow or a medium-fat (31%), high-energy (HE) diet for 9 days. Stressed, chow-fed DIO rats gained less, while stressed DIO rats on HE diet gained more body weight and had higher feed efficiency and plasma leptin levels than unstressed controls. Neither stress nor diet affected DR body weight gain. While stress-induced plasma corticosterone levels did not differ between phenotypes, DIO rats were initially more active in an open field and had higher hippocampal dentate gyrus and CA1 glucocorticoid receptor (GR) mRNA than DR rats, regardless of prior stress or diet. HE diet intake was associated with raised dentate gyrus and CA1 GR and amygdalar central nucleus (CeA) corticotropin-releasing hormone (CRH) mRNA expression, while stress was associated with reduced hypothalamic dorsomedial nucleus Ob-R mRNA and CeA CRH specifically in DIO rats fed HE diet. Thus a single stress triggers a complex interaction among weight gain phenotype, diet, and stress responsivity, which determines the body weight and adiposity of a given individual.     

Hemispheric asymmetry of the nigrostriatal system of the brain in rats genetically predisposed to catalepsy]

Hemispheric asymmetry of nigro-striate system in a strain of rats GC bred from Wistar for a predisposition to cataleptic reaction was studied by means of biochemical and morphological methods. Hemispheric asymmetry was found in GC and Wistar rats with respect to aminopeptidase activity in neurons of caudate nucleus, with a more pronounced left-side increase in GC rats, the asymmetry index being 13.7%. Acetylcholine esterase activity in subcellular particles of caudate nucleus showed an inversion of asymmetry with higher activity in the left hemisphere of Wistar and right hemisphere of GC rats, and asymmetry index of 15.5%. With respect to the number of astroglia cells in S. nigra, and astroglia and oligodendroglia in N. accumbens there was also an inversion of asymmetry in GC rats who had more cells in the structures of the left hemisphere, whereas Wistar rats had more in the right hemisphere. The asymmetry index was high and equal to 29.8% for astroglia in S. nigra, and 17% for astroglia and 21.4% for oligodendroglia in N. accumbens. However, in S. nigra the number of neurons and oligodendroglia cells was equally increased in the right hemisphere in GC and Wistar rats. The data suggest that the mechanism of hereditary pathology of brain nigro-striate system involves both enhancement and inversion of the hemispheric asymmetry.     

Spectral and coherence EEG analysis of rats differing in the level of seizure readiness

The resting EEGs of several brain structures (motor and visual cortex, caudate nucleus and intralaminar thalamic nuclei) were submitted to spectral and coherence computer analyses in two rat strains. Genetically predisposed to convulsive state KM rats were shown to differ from nonpredisposed Wistar rats in EEG spectral properties. KM rats EEG pattern was characterized by increase of low frequencies (1-2 Hz) power and decrease of faster activity (5-12 Hz) power in cortical spectrograms as well as by decrease of caudate nucleus EEG absolute power. The coherence value between cortical or subcortical structures at below 4 Hz was intensified in KM rats. Reinforcement of cortical auto-oscillating properties manifested by ECoG synchronization in cortical-thalamic resonance interaction as well as weakening of striatal inhibitory system may constitute neurophysiological mechanisms of enhanced convulsive readiness. The probable role of mediator imbalance in these mechanisms is discussed.     

Oncogenic potential in fibroblasts from individuals genetically predisposed to cancer

There is now considerable evidence to suggest that genetic factors can influence the incidence of cancer. Although expression of this susceptibility to cancer appears to be tissue-specific, the normal skin fibroblasts from individuals predisposed to cancer (predisposed fibroblasts) have also been shown to express the risk of the target cell in the development of cancer. In the context of the 2-stage theory of chemical carcinogenesis predisposed fibroblasts may, therefore, exist in a pre-neoplastic or initiated state. The purpose of the present study was to determine whether predisposed fibroblasts would be oncogenically transformed in vitro by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) alone. TPA treatment induced similar changes in cellular morphology, cytoskeleton, and epidermal growth-factor binding, in predisposed and normal cells. None of these cell lines acquired anchorage-independent growth or an unlimited growth potential in culture after chronic application of TPA. Fluorescent microscopy with an F-actin probe, in the absence of TPA, showed a disorganization of the microfilament and intermediate filament network in skin fibroblasts from individuals with familial polyposis coli, hereditary and sporadic retinoblastoma, basal cell nevus syndrome, and Gardner's syndrome, as compared to normal skin fibroblasts. Single and 2-dimensional electrophoresis also indicated that the incorporation of 35S-methionine into actin in predisposed fibroblasts was 2-fold greater than in normal fibroblasts, and the turnover rate of actin in predisposed fibroblasts was less than 5 h, compared to 48 h in normal fibroblasts. These observations clearly suggest that predisposed fibroblasts may not exist in a pre-neoplastic or initiated state, and that the mechanism of genetic susceptibility to cancer may be different from that of chemical carcinogenesis. In contrast, the results of this study indicate that genetic susceptibility to a variety of cancers may be associated with a rapid turnover of actin and a disorganization of the microfilament and intermediate filament networks.     

Anticataleptic effect of delta sleep-inducing peptide and its action on brain monoamine oxidase in rats genetically predisposed to catalepsy

Rats with genetic susceptibility to catalepsy (GC strain) were compared with Wistar rats (W). After an intraperitoneal administration of 120 micrograms/100 g delta sleep-inducing peptide (DSIP) in GC rats the duration of cataleptic freezing was shortened (13.8 +/- 9.5 sec against 27.2 +/- 7.5 sec in control). MAO-B activity decreased due to DSIP administration both in GC and W rats. It is hypothesized that the DSIP effect MAO-B in GC rats may correct the lost MAO-A function in deamination of dopamine, a common MAO-A and MAO-B substrate, and the dopaminergic neurotransmission in catalepsy.     

Spectral analysis and mathematical modeling of electrical cerebral activity in rats with genetically determined predisposition to seizure and in controls

Spectral signs of genetically determined predisposition to seizure characteristic of Krushinskii-Molodkina (KM) strain rats were found when studying summated cerebral potentials, namely increased power of low (1–3 Hz) frequencies in spectra of motor and visual cortex potentials together with an abrupt increase and a reduction respectively in the power of hippocampal and caudate nucleus potentials. Comparative spectra of summated electrical activity within neuronal networks [10] and those of experimentally obtained potentials as determined by modeled parameters simulating neuronal networks were found (an inverse problem of modeling). It was found that spectral signs of predisposition to seizure could reflect changes in the physiological properties of neuronal networks belonging to the rat brain structures investigated. It might be suggested on the basis of the calculations performed that genetic predisposition to seizure in KM strain rats is determined by attenuation of the inhibitory function of the caudate nucleus and by heightened excitability (reactivity) in neurons of the paleo- and neocortex.Institute of Higher Nervous Activity and Neurophysiology, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 22, No. 2, pp. 184–193, March–April, 1990.     

Spatial organization of EEG in rats with genetically determined emotionality

In order to study the possibility of EEG discrimination of genetically determined emotionality (increased propensity to emotional and stress reactions and anxiety) brain electrical activity was recorded in rats of two strains: Maudsley Reactive and Maudsley Nonreactive (24 derivations from the convexital skull surface were used). The program package "Synchro-EEG" was used for EEG processing. It was demonstrated that the two rat strains were significantly different in 120 EEG parameters of 840 ones analyzed. On the basis of 37 parameters, each rat was correctly recognized as belonging to the respective group with the error of 4.89%. The analysis of the detected signs allowed their classification to be performed in accordance with the peculiarities of the emotional and cognitive processes and the level of nonspecific activation. Specific forms of interaction between these components in the system of emotional reactions were revealed.     

Cardiac myosin induces myocarditis in genetically predisposed mice

After infection with coxsackie virus B3 (CB3), H-2 congenic mice on an A- background develop immunologically mediated myocarditis associated with an increased titer of myosin autoantibody, part of which is specific for the cardiac myosin isoform. The present study demonstrates that cardiac myosin itself induces severe myocarditis and high titers of myosin autoantibodies in A/J, A.SW/SnJ, and A.CA/SnJ mice. As in CB3-induced myocarditis, one population of these autoantibodies was specific for cardiac myosin. A.BY/SnJ and B10.A/SgSnJ mice also developed the disease after immunization, but the prevalence and the myosin autoantibody titers were lower. In contrast, C57BL/6J and C57BL/10J mice were resistant to myocarditis induced by cardiac myosin and did not develop increased myosin autoantibodies or cardiac myosin-specific autoantibodies. Immunization with skeletal muscle myosin had no effect compared with controls injected with complete Freund's adjuvant, thereby suggesting that the immunogenic epitopes are unique to the cardiac myosin isoform. Furthermore, we found that susceptibility to myocarditis induced by cardiac myosin is influenced by the major histocompatibility complex and by genes not closely linked to the major histocompatibility complex. Because there are parallels between myocarditis induced by cardiac myosin and that induced by CB3, this new animal model can be used to analyze the pathologic mechanisms in autoimmune heart disease.     

Spectral analysis of the human EEG while listening to music

EEG was recorded from 16 electrodes (International 10-20 System) in 14 healthy volunteers aged from 18 to 45 in the state of rest and during listening to music (popular classical symphonic pieces). The EEG spectral analysis was carried out. Presentation of musical pieces increased the EEG spectral power in the alpha-range in the parietal and occipital areas of both hemispheres. During repeated listening of the same musical fragment there was a tendency for attenuation of these changes. A significant decrease in the peak frequency of the alpha-band was found in the process of listening. The spectral values did not significantly differ between the left and right hemispheres. The findings suggest a decrease in the level of CNS activation under the influence of music.     

Maternal obesity alters adiposity and monoamine function in genetically predisposed offspring

The impact of maternal obesity on brain monoamine function in adult offspring of dams selectively bred to express diet-induced obesity (DIO) or diet resistance (DR) was assessed by making dams obese or lean during gestation and lactation. After 12 wk on chow and 4 wk on a 31% fat diet, offspring hypothalamic nucleus size and [(3)H]nisoxetine binding to norepinephrine transporters (NET) and [(3)H]paroxetine binding to serotonin transporters (SET) were measured. Offspring of obese DIO dams became more obese than all other groups, but maternal obesity did not alter weight gain in DR offspring (25). Maternal obesity was associated with 10-17% enlargement of ventromedial nuclei (VMN) and dorsomedial nuclei in both DIO and DR offspring. Offspring of obese DIO dams had 25-88% lower NET binding in the paraventricular nuclei (PVN), arcuate nuclei, VMN, and the central amygdalar nuclei, while offspring of obese DR dams had 43-67% higher PVN and 90% lower VMN NET binding and a generalized increase in SET binding across all hypothalamic areas compared with other groups. Thus maternal obesity was associated with alterations in offspring brain monoamine metabolism, which varied as a function of genotype and the development of offspring obesity.     

Aggression and learning in a strain of rats predisposed to catalepsy

Noradrenaline content is lower in the diencephalon of rats with genetic predisposition to catalepsy as compared to control Wistar population. Besides, there is a statistically non significant tendency to a lower noradrenaline level in the striatum and hippocampus. Pain stimulus induces in cataleptic rats a smaller decrease in noradrenaline than in Wistar. The shock-induced aggression is higher in cataleptic rats than in Wistar. All these data point to a lower noradrenergic activity in rats with genetic predisposition to catalepsy. In cataleptic rats, both the development and extinction of the conditioned avoidance reaction is slower than in Wistar. The changes of noradrenergic activity and learning are similar to those described in chronic amphetamine intoxication. It is supposed that these changes in learning are caused by increased serotonergic (found earlier) and decreased noradrenergic activity.     

Comparative analysis of EEG spatial organization in the rats with different level of genetically determinated anxiety under ethanol

The pecularities of EEG changes in the rats with geneticaly different level of anxiety was studed after ethanol injection. The biopotentials spatial synchronization and entropy in the "high anxious" rats (strain MR) did not increase under low dose; on the contrary the above changes were characteristic for the rats without anxiety signs (strain MNRA). After injection of middle and high ethanol doses the "high anxious" rats as compared with "low anxious" ones had the "simplification" of reaction type--the increase of narrow frequency coherence (i.e. linear biopotentials relationship) and spectral power of theta-activity (5.75-7.25 Hz), which was combined with the decrease of nonlinear biopotential characteristics. This fact is interpreted as the predominance of subcortical mechanisms of the brain functional state regulation over cortical ones. The significant decrease of high frequency EEG components in "high anxious" rats takes place under more high ethanol doses, presumably reflecting the increase of the anxiolytic level of ethanol effect.     

Moderate body hypothermia alleviates behavioral and EEG manifestations of audiogenic seizures in metaphit-treated rats

We investigated the effects of hypothermia on the incidence and EEG signs of audiogenic seizures in rats treated with metaphit (1-[1(3isothiocyanatophenyl)-cyclohexyl] piperidine), an experimental model of generalized reflex epilepsy. After i.p. injection with metaphit (10 mg/kg) Wistar rats were exposed to audiogenic stimulation at hourly intervals during the time course of the experiment. After intermittent use of an ice pack 8 h after the metaphit treatment, when seizure was fully developed, the body temperature was reduced to 30 +/- 0.5 degrees C in one half of the rats, and maintained at 37 +/- 0.5 degrees C in the other half. Saline-injected rats served as a control group. In the hypothermia group, the incidence of audiogenic seizures induced by metaphit was completely suppressed during the 3 consecutive testing times, while no signs of epileptiform activity were noted in EEG tracings. The termination of hypothermic treatment resulted in the recovery of seizure susceptibility, and during audiogenic stimulation, bursts of spiking activity were recorded in the EEGs of metaphit-treated rats. These findings indicate that moderate body hypothermia is an effective anticonvulsant treatment for audiogenic seizures in metaphit-treated rats.