Helix neurons invovled in control of rhythmic movement in the pneumostome

Three neurons capable of generating coordinated bursting activity or synchronized slow-wave fluctuations in membrane potential (MP) were identified in the left parietal ganglion ofHelix pomatia. The function of these units contributes to regulating rhythmic opening and closing movements in the pneumostome. Both bursting activity and slow-wave neuronal MP synchronize with rhythmic movements of the pneumostome. Onset of bursting activity and fluctuations in MP on the one hand or suppression of these effects due to different influences on the cells on the other leads to initiation or extinction of pneumostome movements respectively. These neurons do not exhibit endogenous bursting activity but do produce a fairly high rate of firing activity without bursting pattern and without slow-waves in MP in isolation. Bursting activity occurs in these neurons in the intact central nervous system (CNS) as a result of gigantic synchronized IPSP in some cases and due to the aforementioned slow waves in MP and in others. No direct chemically- or electrically-operated synaptic connections exist between the three cells. Serotonin triggers both waves in MP and bursting activity in all three neurons in the intact CNS and exerts a pronounced hyperpolarizing action on each of these factors in isolation.N. K. Kol'tsov Institute of Developmental Biology, Academy of Sciences of the USSR. Moscow. Balaton Limnological Research Institute of the Hungarian Academy of Sciences, Tihany. Translated from Neirofiziologiya, Vol. 20, No. 4, pp. 509–517, July–August, 1988.     

Epileptiform seizures in domestic fowl. V. The anticonvulsant activity of delta9-tetrahydrocannabinol.

The anticonvulsant activity of delta9-tetrahydrocannabinol (delta9-THC) has been determined against seizures induced in epileptic chickens by intermittent photic stimulation (IPS) and in epileptic and nonepileptic chickens by Metrazol. Intravenous administration of the drug reduced both the severity and incidence of seizures evoked by IPS in epileptic chickens. This anticonvulsant action was accompanied by a reduction in frequency of inter-ictal slow-wave high-voltage electroencephalographic activity and by the absence of spiking during IPS. delta9-THC did not affect the incidence of Metrazol-induced seizures in epileptic or nonepileptic chickens.     

Mechanism of action of cyproheptadine (peritol) on the hypothalamo-pituitary-adrenal axis

The present paper is concerned with the mechanism of action of the blocker of serotonin receptors, cyproheptadine (peritol) on the hypothalamohypophyseal-adrenal system activity. It has been established in male rats that the inhibitory, antiserotonin action of peritol on the indicated system activity depends on the rate and rhythmicity of the drug administration, and, to a less degree, on its dosage. Peritol exerts a specific antiserotonin action via the CNS and by acting on some regulatory mechanism in peripheral tissues (adenylate cyclase system, corticosterone secretion).     

Central nervous system drug design

A model which suggests that there is a common structural basis for the action of many different classes of CNS drugs is described. It is shown that this general model is consistent with specific models for opioid analgesic and antidepressant activity. The significance of these models is not only that they define specific spatial relationships between the structural requirements in different CNS drug classes, but also that they allow the formulation of three very simple drug design techniques which will be referred to as pruning, splicing and grafting. When combined with available structure-activity information, these techniques may provide a rational approach to the design of drugs with specified CNS activity.     

Dissection and reduction of a modeled bursting neuron

An 11-variable Hodgkin-Huxley type model of a bursting neuron was investigated using numerical bifurcation analysis and computer simulations. The results were applied to develop a reduced model of the underlying subthreshold oscillations (slow-wave) in membrane potential. Two different low-order models were developed: one 3-variable model, which mimicked the slow-wave of the full model in the absence of action potentials and a second 4-variable model, which included expressions accounting for the perturbational effects of action potentials on the slow-wave. The 4-variable model predicted more accurately the activity mode (bursting, beating, or silence) in response to application of extrinsic stimulus current or modulatory agents. The 4-variable model also possessed a phase-response curve that was very similar to that of the original 11-variable model. The results suggest that low-order models of bursting cells that do not consider the effects of action potentials may erroneously predict modes of activity and transient responses of the full model on which the reductions are based. These results also show that it is possible to develop low-order models that retain many of the characteristics of the activity of the higher-order system.     

Psychopharmacological profile of Chamomile (Matricaria recutita L.) essential oil in mice

In this study, the effect of Matricaria recutita L. essential oil (MEO) on the central nervous system (CNS) of mice was investigated using some behavioral methods. Chemical profiling both by GC and GC-MS analyses of the hydrodistilled essential oil of M. recutita revealed α-bisabolol oxide A (28%), α-bisabolol oxide B (17.1%), (Z)-β-Farnesene (15.9%) and α-bisabolol (6.8%) as the main components. Changes induced by MEO (25, 50 and 100 mg/kg) and reference drug caffeine (25 mg/kg) in spontaneous locomotor activities and motor coordinations of mice were investigated by activity cage measurements and Rota-Rod tests, respectively. Open field, social interaction and elevated plus-maze tests were applied to assess the emotional state of the animals. Further, tail-suspension test was performed for evaluating the effect of MEO on depression levels of mice. As a result, at 50 and 100 mg/kg, MEO significantly increased the numbers of spontaneous locomotor activities, exhibited anxiogenic effect in the open field, elevated plus-maze and social interaction tests and decreased the immobility times of animals in tail suspension tests. The falling latencies in Rota-Rod tests did not change. This activity profile of MEO was similar to the typical psychostimulant caffeine. The exact mechanism of action underlying this stimulant-like effect should be clarified with further detailed studies.     

CNS Drug Design Based on Principles of Blood-Brain Barrier Transport

Abstract: Lipid-soluble small molecules with a molecular mass under a 400–600-Da threshold are transported readily through the blood-brain barrier in vivo owing to lipid-mediated transport. However, other small molecules lacking these particular molecular properties, antisense drugs, and peptide-based pharmaceuticals generally undergo negligible transport through the blood-brain barrier in pharmacologically significant amounts. Therefore, if present day CNS drug discovery programs are to avoid termination caused by negligible blood-brain barrier transport, it is important to merge CNS drug discovery and CNS drug delivery as early as possible in the overall CNS drug development process. Strategies for special formulation that enable drug transport through the blood-brain barrier arise from knowledge of the molecular and cellular biology of blood-brain barrier transport processes.     

New aspects of the neurophysiological mechanism of the action of nootropic preparations

The influence of nootropic drugs on EEG spectral power of the cortex and hippocamp was studied in resting rats. All these drugs had a specific action on EEG spectral power, causing an increase and stabilization of maximum basic distribution peak of the EEG spectral power. Such action may be attributed to better organization of rhythmic activity in theta-range. The drugs also decreased interhemispheric asymmetry of the cortical and hippocampal EEG. The authors suggest that the increase and improvement of the basic rhythmic activity in the brain and an increased level of distant (spatial) synchronization form the basis for the nootropic drug effect.     

Effect of sidnocarb on learning and memory

It has been established that in well-trained rats sydnocarb (mesocarb) does not exert a considerable effect on the generation of conditioned reflex of passive avoidance (CRPA). On the contrary, in poorly-trained animals sydnocarb significantly improves CRPA indexes at all three stages of its generation. Sydnocarb proved most effective, when injected before training (on day I). The absence of sydnocarb-induced pain threshold decrease in response to electrical pain stimulation suggests a direct drug effect on memory processes.     

Simulation of human sleep: ultradian dynamics of electroencephalographic slow-wave activity

The typical declining trend of electroencephalographic (EEG) slow-wave activity (SWA) within a sleep period is represented in the two-process model of sleep regulation by an exponentially decaying process (Process S). The model has been further elaborated to simulate not only the global changes of SWA, but also the dynamics within non-rapid-eye-movement (non-REM) sleep episodes. In this new model, the initial intraepisodic buildup of SWA is determined by the combined action of an exponentially increasing process and a saturation process, whereas its fall at the end of an episode is due to an exponentially decreasing process. The global declining trend of SWA over consecutive episodes results from the monotonic decay of the intraepisodic saturation level. In contrast to Process S in the two-process model, this decay is not represented by an exponential function, but is proportional to the momentary level of SWA. REM sleep episodes are triggered by an external function. The model allows one to simulate the ultradian pattern of SWA for baseline nights as well as changes induced by a prolonged waking period, a daytime nap, a partial slow-wave sleep deprivation, or an antidepressant drug.     

Protein 70 kDa in the control of sleep and thermoregulation

Studies of expression of molecular chaperones of the family of Heat Shock Proteins 70 kDa (HSP70) in the mouse and rat brain during sleep deprivation do not answer the question whether the HSP70 produce somnogenic effect. In the present work there are studied effects of exogenous Hsp70 that is known to be able to penetrate into living cells in vitro and to acquire properties of endogenous chaperone. Hsp70 was microinjected into the third brain ventricle of rats and pigeons at the beginning of the non-active 24-h phase when under natural conditions the sleep duration increases and the somato-visceral parameters decrease. Hsp70 has been established to enhance this natural process and to produce an additional increase of the total time of slow-wave sleep, a more pronounced inhibition of the muscle contractive activity, and a deeper decrease of the brain temperature. A similarity in effects of Hsp70 in rats and pigeons has been revealed. In both species the somnogenic Hsp70 action is realized by activation of mechanisms of maintenance of the longer episodes of the slow-wave sleep. The hypothermic Hsp70 effect seems to be associated with a decrease of the muscle contractive activity level, rather than with an enhancement of peripheral vasodilation and with an increase of heat loss. A hypothesis is put forward that the hyposedative/neuroleptic-like Hsp70 action that includes the somnogenic, myorelaxing, and hypothermic effects is mediated by activation of GABA_A receptors of the main inhibitory brain system.     

Wakefulness-sleep cycle and hypothalamo-pituitary system of young rat pups on the background of photostimulation

Effects of multiple photostimulations (PS) on behavioral reactions of the 30-day old rats were studied in the “open field” test, on the dynamics of the time EEG parameters of the wakefulness-sleep cycle, and on morpho-functional characteristics of the hypothalamo-pituitary neuroendocrine system. It has been revealed that PS promotes the gradual inhibition of the locomotor activity and exploratory behavior (p < 0.05) and an enhancement of autonomic reactions (p < 0.05) as well as an initial increase of intensity of orientation reactions with a subsequent decrease of their number (in connection with adaptation to a light stimulus), A comparative analysis of time parameters of the wakefulness-sleep cycle (WSC) shows a decrease of the part of wakefulness, the slow-wave and rapid-wave sleep phases with a simultaneous increase of the cataleptic stage and the sleep stage transient to the rapid-wave stage, as well as of the number of microactivations appearing on the sleep background at once after the several first PS. By the 4–5th photostimulations the CWS parameters on the whole are restored, except for the cataleptic stage, whose value remains statistically significantly high. The obtained data indicate the initial total CNS excitation and a decrease of the CWS stability. This conclusion is confirmed by the data of analysis of spectral characteristics of electrograms of cortical, hippocampal, hypothalamic brain parts and of caudate nucleus, which revealed only a brief small increase of δ-waves in the slow-wave sleep phase, but a statistically significant long decrease of power of the EEG δ-and ?-oscillations with a simultaneous power increase of α-components in the rapid-wave sleep. The quantitative parameters of changes of the morpho-functional state of neurosecretory cells of the hypothalamus supraoptic and paraventricular nuclei indicate the stress effect of this performed stimulation. The aspects of interaction of the hypothalamic-cortical and thalamo-cortical levels of the CWS integration on the background of chronic stress are discussed.     

Immunocorrection of the physiologic status of white rats by sidnofen conjugates with bovine serum albumin

The effect of immunisation by covalent conjugates of known psychostimulant and antidepressant sydnophen with bovine serum albumin (BSA) on behaviour, formation of conditioned reflex reactions and alcoholization of white rats has been studied. The immunization of sydnophen with BSA by conjugates permits to obtain a long-term alteration of the emotional status: suppression of behavioral activity, learning and alcohol attraction of rats similar in some elements to the action of neuroleptic drugs. The direction of these alterations is opposite to ones caused by the action of sydnophen. It gives possibility to consider fruitful the conception on the ways of long-term immunocorrection of the physiological status of organism.     

Biochemical properties and kinetic parameters of dihydroxyphenylalanine--5-hydroxytryptophan decarboxylase in brain, liver, and adrenals of cat.

Biochemical properties and kinetic parameters of nonpurified dihydroxyphenylalanine-5-hydroxytryptophan decarboxylase extracted from brain and two peripheral organs, liver and adrenals, were studied in the cat. This study shows that decarboxylase activity in brain is lower than in peripheral organs and that 5-hydroxytryptophan can be decarboxylated without exogenous addition of pyridoxal-5'-phosphate (PLP). However, the addition of PLP substantially increases the enzyme activity. Excess of coenzyme (greater than 60 muM) induces inhibition in adrenals and liver but not in the central nervous system (CNS). The observed inhibition might be related to the presence of a tetrahydroisoquinoline derivative formed in the medium. Differentiation between mechanisms of action of decarboxylase in the CNS and peripheral organs is suggested.     

SELECTIVE INCREASE OF BRAIN DOPAMINE SYNTHESIS BY SULPIRIDE

—Sulpiride (5–200 mg/kg) increases brain HVA and DOPAC levels, causes no change in dopamine concentration, does not interfere with the outflow of HVA from the CNS and enhances the disappearance of brain dopamine after inhibition of tyrosine hydroxylase. The compound influences neither 5-HT nor NE metabolism. The central action of sulpiride differs from that of classic neuroleptics in that this drug stimulates dopamine turnover without producing catalepsy.     

Spectral analysis of the effects of nomifensine on bioelectric activity of the rat brain]

The influence of nomifensine on bioelectrical activity of sensorimotor cortex, dorsal hippocamp and lateral hypothalamus in conscious rats in free behavior was studied. The pharmacological and EEG analysis of nomifensine action on EEG power spectra by Fourier technique was measured. It was established that nomifensine evoked an increase and stabilization of the dominant peak in EEG spectra in the left and right cortex and in the left hippocamp, while in the other ranges of frequency a decrease was observed. The effects on hypothalamus was opposite--EEG power spectra decreased in all the ranges. The authors conclude that nomifensine evokes higher level of wakefulness, vigilance of the animals. This is likely to underlie neurophysiological mechanisms of optimal behavior due to stimulants of CNS, including nomifensine.     

CNS anti-depressant,anxiolytic and analgesic effects of Ganoderma applanatum (mushroom) along with ligand-receptor binding screening provide new insights: Multi-disciplinary approaches

This research was designed to evaluate the CNS depressant, anxiolytic, and analgesic action of aqueous and ethanol extract of Ganoderma applanatum, a valuable medicinal fungus used in multiple disorders belongs to Ganodermataceae family. Two extracts of G. applanatum were prepared using distilled water and ethanol as solvents and named AEGA and EEGA. Open field method, rotarod method, tail suspension method, and hole cross method were utilized for the CNS depressant action. In contrast, elevated plus-maze test and hole board method were utilized for the anxiolytic action. For determining the analgesic potential, acetic acid-induced writhing test, hot plate method, and tail immersion test were used. Besides, molecular docking has been implemented by using Discovery studio 2020, UCSF Chimera and PyRx autodock vina. At both doses (200 and 400 mg/kg) of AEGA and EEGA showed significant CNS depressant effect (p < 0.05 to 0.001) against all four tests used for CNS depressant activity. Both doses of AEGA and EEGA exhibited important anxiolytic activity effect (p < 0.05 to 0.001)against the EPM and hole board test. Both doses of AEGA and EEGA also exhibited a potential analgesic effect (p < 0.05 to 0.001) against all three tests used for analgesic action. In addition, in the molecular docking the compounds obtained the scores of ?5.2 to ?12.8 kcal/mol. Ganoapplanin, sphaeropsidin D and cytosporone C showed the best binding affinity to the selected recptors. It can be concluded that AEGA and EEGA have potential CNS depressant, anxiolytic, and analgesic action, which can be used as a natural antidepressant, anxiolytic, and analgesic source.     

Trafficking of dopamine transporters in psychostimulant actions

Brain dopamine (DA) plays a pivotal role in drug addiction. Since the plasma membrane DA transporter (DAT) is critical for terminating DA neurotransmission, it is important to understand how DATs are regulated and this regulation impacts drug addiction. The number of cell surface DATs is controlled by constitutive and regulated endocytic trafficking. Psychostimulants impact this trafficking. Amphetamines, DAT substrates, cause rapid up-regulation and slower down-regulation of DAT whereas cocaine, a DAT inhibitor, increases surface DATs. Recent reports have begun to elucidate the molecular mechanisms of these psychostimulant effects and link changes in DAT trafficking to psychostimulant-induced reward/reinforcement in animal models.     

Glycogen synthase kinase 3: a drug target for CNS therapies

Abstract Glycogen synthase kinase3 (GSK3) is emerging as a prominent drug target in the CNS. The most exciting of the possibilities of GSK3 lies within the treatment of Alzheimer's disease (AD) where abnormal increases in GSK3 levels and activity have been associated with neuronal death, paired helical filament tau formation and neurite retraction as well as a decline in cognitive performance. Abnormal activity of GSK3 is also implicated in stroke. Lithium, a widely used drug for affective disorders, inhibits GSK3 at therapeutically relevant concentrations. Thus while the rationale remains testable, pharmaceutical companies are investing in finding a selective inhibitor of GSK3. In the present review, we summarize the properties of GSK3, and discuss the potential for such a therapy in AD, and other CNS disorders.     

Topographical EEG Mapping in a Case of Recurrent Sleep Terrors

Sleep terrors are characterized by marked CNS arousal and typically occur during stage 3-4 sleep within the first NREM cycle. Studies of the EEG during sleep terrors suggest that delta power and synchrony in the EEG may be important physiological markers of sleep terror presence and intensity. An EEG mapping study was undertaken with a single participant who experienced three sleep terror episodes in the laboratory. A one-minute section of EEG was sampled immediately prior to the onset of each of the three sleep terrors. Similar EEG sections were taken from 10 healthy sex- and age-matched controls. The sleep tenors and control (normative) data were then compared topographically with z-scores (z-mapping). The z-maps indicated that all three sleep terrors contained more total and delta power in central and frontal areas than the control EEG sections. Moreover, relative delta power in these areas for the three sleep terrors was proportional to the subjective intensity of the episode. Although this pre-arousal EEG pattern may be related to ongoing slow-wave sleep mentation that may sometimes trigger sleep terror episodes, its functional significance remains an open question. The results demonstrate the utility of EEG mapping for the quantification of brain activation during sleep terror attacks and suggest that discrete activity profiles are identifiable for different types of dreaming-related arousal.