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Biomedical subjects

M Segal

Publications and source records attributed to M Segal.

At least 199 records · Page 11Linked to original sources
PubMed1989

Raphe cells grafted into the hippocampus can ameliorate spatial memory deficits in rats with combined serotonergic/cholinergic deficiencies.

The ability of embryonic raphe cells grafted into the hippocampus to restore spatial learning ability was tested in rats with combined serotonergic/cholinergic deficits. Embryonic raphe cells (E14) were transplanted into the hippocampus of serotonin-depleted rats. Two to 3 months after transplantation, control, lesioned and grafted rats were tested in a spatial memory task (a water maze) with and without the addition of atropine. All 3 groups could negotiate the water maze equally well, in non-drug conditions. The injection of atropine caused a severe disruption of performance only in the serotonin depleted rats. The presence of an active serotonergic graft was examined in the intact rat hippocampus using the serotonin releasing drug fenfluramine (FFA). A pronounced depression of hippocampal EEG was observed in control and grafted but not in lesioned rats 15 min after the injection of FFA. These results suggest the involvement of serotonin in cognitive functions in the rat. Furthermore, it is suggested that an interaction between serotonergic and cholinergic neurotransmission occurs in the hippocampus.

Animals↗
PubMed1989

Spatial performance is severely impaired in rats with combined reduction of serotonergic and cholinergic transmission.

A possible interaction between serotonergic and cholinergic neurotransmission was examined in relation to the performance of a spatial memory task. Blockade of cholinergic transmission with a high dose of atropine was sufficient to impair performance of a water maze task. A partial reduction of cholinergic transmission using a low dose of atropine had no effect on this performance. Reducing serotonin synthesis, using a specific inhibitor of tryptophane hydroxylase p-chlorophenylalanine (PCPA) also had no effect on performance of such a task. However, a combined treatment with a low dose of atropine and PCPA severely impaired the performance of rats in the water maze. The rats were impaired in both acquisition of the initial spatial task and in reacquisition of a new spatial position (= working memory). These findings suggest an interaction between cholinergic and serotonergic transmission in acquisition and retention of spatial information. Furthermore they propose that deficits in cognitive abilities, observed in aging or Alzheimer's disease, may result from the combined reduction in cholinergic and serotonergic transmission.

Acetylcholine↗
PubMed1989

Presynaptic cholinergic inhibition in hippocampal cultures.

Activity of hippocampal neurons was recorded in a dissociated culture under patch-clamp conditions. Excitatory and inhibitory postsynaptic currents (PSCs) were evoked in response to short pulse application of glutamate to other neurons in the culture dish. These PSCs were suppressed by topical application of acetylcholine (ACh) near the recorded neuron. The dose-dependent effect of the muscarinic antagonist pirenzepine indicates that the effect of ACh is mediated by an M2 receptor. ACh did not affect inward current responses to direct application of glutamate onto postsynaptic neurons. This indicates that ACh may interfere with the release process and not with the postsynaptic response to the neurotransmitter. In some cells, ACh reduced inward Ca currents recorded in the presence of Na and K channel blockers. This effect was atropine sensitive and may underly the reduced PSCs. It is suggested that ACh modulates release of neurotransmitters by reducing presynaptic Ica and thereby reducing evoked PSCs.

Acetylcholine↗
PubMed1989

Presynaptic cholinergic action in the hippocampus.

The hippocampus is among the regions in the brain richest in M1 cholinergic receptors. Topical application of acetylcholine (ACh) onto hippocampal slices produces a characteristic complex response consisting of a depolarization, an increase in input resistance especially upon depolarization and a blockade of a slow afterhyperpolarization (AHP). The first two of these responses can be recorded also in non-cholinergic septal neurons in an area which contains about 8% of the M1 muscarinic receptors found in the hippocampus. The responses of hippocampal but not septal neurons to ACh involve an increase in the spontaneous synaptic activity and a decrease in evoked responses to afferent stimulation. The dissociated hippocampal culture was used to study these presynaptic effects. The neurons in culture possess muscarinic receptors which develop gradually over a period of several weeks after plating. ACh rarely depolarizes hippocampal neurons in culture. Instead, it causes an increase in spontaneous discharge of small postsynaptic currents (PSC's) and a marked decrease of large, evoked PSC's. In some cultured hippocampal cells ACh reduced ICa without affecting any of several outward K currents studied. It is suggested that ACh reduces evoked activity by reducing Ca currents at presynaptic terminals.

Acetylcholine↗
PubMed1988

Serotonin releasers modulate reactivity of the rat hippocampus to afferent stimulation.

Electrical stimulation of the perforant path produces a characteristic population EPSP and population spike in the dentate gyrus of the anesthetized rat. Parenteral administration of a serotonin releasing drug D-fenfluramine (FFA) caused a marked (30-100%) and highly significant increase in dentate gyrus population spike response to perforant path stimulation without affecting the slope of the population excitatory postsynaptic potential (EPSP). This indicates that FFA modifies granular cell excitability to afferent stimulation. The facilitatory effect of FFA was not present in rats depleted of serotonin following treatment with the synthesis inhibitor p-chlorophenylalanine (PCPA) but was restored after restoration of serotonin synthesis with the precursor 5-hydroxytryptophan indicating that presence of serotonin in terminals is required for the action of FFA.

Afferent Pathways↗
PubMed1988

Enantiomeric cannabinoids: stereospecificity of psychotropic activity.

The 1,1-dimethylheptyl homolog of (-)-(3R,4R)-7-hydroxy-delta-6- tetrahydrocannabinol (compound II) is highly psychotropic in mice, rats and pigeons. The (+)-(3S,4S) enantiomer (III) was found to be psychotropically inactive at doses up to several thousand times those of the ED50 of (II).

Animals↗
PubMed1988

A correlation between regional acetylcholinesterase activity in rat brain and performance in a spatial task.

The acquisition and retention of a water maze task was examined in 12 intact, young Wistar rats. Acetylcholinesterase activity in 43 discrete brain regions was then measured in the same rats by quantitative histochemistry. Individual learning and retention indices were found to be significantly correlated with acetylcholinesterase (AChE) levels in specific regions, e.g. cholinergic nuclei; the ventral pallidum and nucleus basalis; and in the dentate gyrus of the hippocampus. High levels of AChE in these regions predicted poor performance in the water maze. Thus cholinergic activity in selected regions of the rat brain might be involved in the performance of spatial memory tasks.

Acetylcholinesterase↗
PubMed1988

Synaptic activation of a cholinergic receptor in rat hippocampus.

Tetanic stimulation of the basal dendritic field (stratum oriens) of Ca1 area of rat hippocampal slice can produce a slow depolarization associated with an increase in input resistance, decrease in accommodating properties of the cell to a depolarizing drive and an increase in synaptic activity. These effects are enhanced by an acetylcholinesterase inhibitor, eserine, and blocked by the muscarinic antagonists, pirenzepine and atropine. The accommodating property of the cell is more sensitive to the stimulation than the membrane potential or input resistance. The effects of oriens stimulation can be obtained also in fornix-fimbria transected hippocampal slice indicating that it may activate a local cholinergic or non-cholinergic pathway. The stimulation causes a heterosynaptic enhancement of reactivity of neurons to afferent stimulation indicating that acetylcholine may cause an enhanced excitability of hippocampal neurons.

Action Potentials↗
PubMed1988

The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins.

Two glucose-regulated proteins, GRP78 and GRP94, are major constituents of the endoplasmic reticulum (ER) of mammalian cells. These proteins are synthesized constitutively in detectable amounts under normal growth conditions; they can also be induced under a variety of conditions of stress including glucose starvation and treatment with drugs that inhibit cellular glycosylation, with calcium ionophores or with amino-acid analogues. Unlike the closely-related heat shock protein (HSP) family, the GRPs are not induced significantly by high temperature. Recently, GRP78 has been identified as the immunoglobulin heavy chain binding protein (BiP) (ref. 5 and Y.K. et al., in preparation) which binds transiently to a variety of nascent, wild-type secretory and transmembrane proteins and permanently to malfolded proteins that accumulate within the ER. We have tested the hypothesis that the presence of malfolded proteins may be the primary signal for induction of GRPs by expressing wild-type and mutant forms of influenza virus haemagglutinin (HA) in simian cells. Only malfolded HAs, whose transport from the ER is blocked, induced the synthesis of GRPs 78 and 94. Additional evidence is presented that malfolding per se, rather than abnormal glycosylation, is the proximal inducer of this family of stress proteins.

Animals↗
PubMed1988

Effects of a lidocaine derivative QX-572 on CA1 neuronal responses to electrical and chemical stimuli in a hippocampal slice.

Activity of CA1 neurons was recorded in rat hippocampal slices with a lidocaine-derived QX-572-filled micropipette. The QX compound abolished Na action potentials as reported earlier. In addition it reduced markedly the burst slow afterhyperpolarization seen in these neurons in response to a depolarizing current pulse. It also modified responses to neurotransmitter substances associated with changes in K currents, acetylcholine and serotonin. QX-filled micropipettes can therefore provide some insight into mechanisms of action of certain neurotransmitters in the brain but they cannot be used as selective blockers of Na currents.

Acetylcholine↗
PubMed1988

Aging and brain cholinergic muscarinic receptors: an autoradiographic study in the rat.

Cholinergic muscarinic receptors in aged and young rat brains were studied by quantitative autoradiography of tritiated quinuclidinyl benzilate. A selective pattern of decreased binding density was observed in the aged rat. A large number of regions showed no effect of aging; these include subdivisions of the hippocampal formation and most thalamic and hypothalamic nuclei. Small but significant decreases were found in cortical regions and in the striatum. The largest effects were seen in ventral forebrain cholinergic nuclei, where 40-60% depletions were found in the diagonal band, nucleus basalis magnocellularis, ventral pallidum, and substantia innominata.

Aging↗
PubMed1988

A retrospective cohort study of lung cancer and diesel exhaust exposure in railroad workers.

The risk of lung cancer as a result of exposure to diesel exhaust from railroad locomotives was assessed in a cohort of 55,407 white male railroad workers 40 to 64 yr of age in 1959 who had started railroad service 10 to 20 years earlier. The cohort was traced until the end of 1980, and death certificates were obtained for 88% of 19,396 deaths; 1,694 lung cancer cases were identified. Yearly railroad job from 1959 to death or retirement was available from the Railroad Retirement Board, and served as an index of diesel exhaust exposure. Directly standardized rates and a proportional hazards model were used to calculate the relative risk of lung cancer based on work in a job with diesel exhaust exposure beginning in 1959. A relative risk of 1.45 (95% CI = 1.11, 1.89) for lung cancer was obtained in the group of workers 40 to 44 yr of age in 1959, the group with the longest possible duration of diesel exposure. The cohort was selected to minimize the effect of past railroad asbestos exposure, and analysis with workers with possible asbestos exposure excluded resulted in a similarly elevated risk. Workers with 20 yr or more elapsed since 1959, the effective start of diesel exposure for the cohort, had the highest relative risk. These results taken in conjunction with other reported results support the hypothesis that occupational exposure to diesel exhaust results in a small but significantly elevated risk for lung cancer.

Adult↗
PubMed1988

Effects of mu opioid receptor activation in rat hippocampal slice.

The effects of the mu opioid agonist DAGO were examined in the hippocampal slice preparation. The effects of the drug on active and passive properties of neurons in CA1 and CA2 were examined. Intracellular responses of these neurons to afferent stimulation were examined before and after DAGO application. As seen with other mu agonists, DAGO reduced IPSPs and enhanced the duration of EPSPs but not their rise time. In CA2 cells, DAGO also produced a transient hyperpolarization. Further experiments examined the interactions of the opioid peptides with other neurotransmitter systems in the hippocampus. The effects of DAGO were reduced by prior fornix transection. Some effects of DAGO on generation of a secondary afterdischarge are abolished by an NMDA receptor antagonist, 2-APV. The significance of these results to the understanding of functioning of the hippocampal circuit is discussed.

Animals↗
PubMed1988

Behavioral and physiological effects of trimethyltin in the rat hippocampus.

An injection of trimethyltin (TMT) into adult male Wistar rats produced a transient hyperirritability and aggressive behavior. When these effects of the drug subsided, the rats were still markedly impaired in performance of a spatial memory task examined in a watermaze. Activity of neurons in the hippocampus of these TMT-treated rats was studied in a slice preparation. A large (8 mg/kg) or double (7.5 and 3.5 mg/kg, two weeks apart) i.p. injection of TMT caused a loss of slow inhibitory postsynaptic potentials recorded in CA1 neurons in response to stimulation of stratum radiatum. A loss of accommodating properties of the neurons in response to a prolonged depolarizing current pulse was also seen in some of these cells. Other resting properties of the neurons were within the normal range. Topical application of acetylcholine (ACh) produces in normal hippocampal neurons a depolarizing response and a blockade of after-hyperpolarization. Only the latter response to ACh was seen in cells from TMT treated rats. No effect of the drug on reactivity to serotonin was detected. These effects of TMT were not seen when the drug was applied acutely while recording from cells in the slice indicating that it involves a degeneration process. These results suggest that the cognitive deficits in TMT treated rats might be associated with deficits in cholinergic functions.

Acetylcholine↗
PubMed1987

Repetitive inhibitory postsynaptic potentials evoked by 4-aminopyridine in hippocampal neurons in vitro.

The effects of topical application of microdrops containing 4-aminopyridine (4-AP) on properties of CA1 neurons were examined in the hippocampal slice preparation. 4-AP triggered repetitive large (4-10 mV) hyperpolarizing potentials (HPs) having a short rise time and slow (3-4 s) decay. There was a marked decrease in input resistance during the HPs. The HPs are likely to be caused by an increase in potassium conductance; their reversal potential was 15-20 mV negative to rest, the reversal potential shifted in the depolarizing direction when the slice was bathed in high potassium medium, and it was the same with KCl or potassium acetate recording electrodes. The HPs were not generated by release of neurotransmitter substances from terminals of extrinsic afferents since they were present in slices taken from deafferented hippocampus but they were blocked by tetrodotoxin (TTX) or Cd and Mn, indicating that they are synaptic potentials of local origin. HPs were still present when Ca-dependent K currents were blocked by acetylcholine and noradrenaline. Three of 56 cells recorded in the hippocampus could be classified as interneurons. They emitted high frequency trains of action potentials in response to 4-AP, at a rate corresponding to the HPs recorded in all other neurons. It is suggested that 4-AP excites a specific type of interneuron which in turn generates large K-mediated inhibitory postsynaptic potentials in the pyramidal neurons of CA1 region of the hippocampus.

1-Methyl-3-isobutylxanthine↗