Biomedical subjects

H L Haas

Publications and source records attributed to H L Haas.

At least 37 records · Page 2Linked to original sources

PubMed2001

Glycine receptor mediated responses in rat histaminergic neurons.

Patch-clamp whole-cell recordings were made in the hypothalamic tuberomammillary (TM) nucleus from isolated histaminergic neurons, identified by their expression of histidine decarboxylase. We compared strychnine-sensitive glycine-mediated currents with maximal currents activated by gamma-Aminobutyric acid (GABA, 0.5 mM) which were blocked by gabazine. The maximal glycine response (1 mM) in histaminergic cells with larger somata (25 microm) was about half of the maximal GABA response whereas in the cells with a smaller soma size (19.5 microm) the glycine response was absent or very small. We conclude that histaminergic cells are heterogeneous with respect to their sensitivity to glycine and this correlates with their size.

Animals↗

PubMed2001

Histamine H(3) receptors depress synaptic transmission in the corticostriatal pathway.

The effect of histamine on the main input to the striatum - the corticostriatal pathway - was studied using electrophysiological techniques in brain slices from rats and mice. Field potentials (FPs) were recorded in the striatum following stimulation at the border of the striatum and the cortex. Bath application of histamine caused a pronounced and long-lasting depression of FPs in rat slices with an IC(50) of 1.6 microM and a maximal depression of around 40%. In mouse slices histamine also depressed FPs, but to a lesser extent and more transiently. Further experiments in rat slices showed that histamine H(3) receptors were responsible for this depression since the selective H(3) receptor agonist R-alpha-methylhistamine (1 microM) mimicked the action of histamine whilst the selective H(3) receptor antagonist, thioperamide (10 microM) blocked the depression caused by histamine application. The histaminergic depression was probably not mediated indirectly through interneurons since blockade of GABA(A), GABA(B), nicotinic and muscarinic receptors or nitric oxide synthase did not prevent the histamine effect. Intracellular recordings from medium spiny neurons in the striatum revealed that histamine did not affect postsynaptic membrane properties but increased paired-pulse facilitation of excitatory synaptic responses indicating a presynaptic locus of action.

Animals↗

PubMed2001

Serotonin excites tuberomammillary neurons by activation of Na(+)/Ca(2+)-exchange.

We have studied the effects of serotonin on the histaminergic neurons in the hypothalamic tuberomammillary nucleus. Intracellular recordings of the membrane potential were made with sharp electrodes from superfused rat hypothalamic slices. We found that serotonin increased the firing rate of the neurons to 224% of the control rate and depolarized them dose-dependently. Insensitivity to tetrodotoxin indicated a postsynaptic effect, which was unrelated to any conductance change. The involved receptor appeared to be a 5-HT2C receptor. The depolarization was strongly dependent on temperature and replacement of extracellular Na(+) with Li(+) or with N-methyl-D-glucamine suppressed the depolarization. Pretreatment with Ni(2+), 2',4'-dichlorobenzamil or KB-R7943 strongly attenuated the effect. These features indicate that the depolarization is the result of activation of an electrogenic Na(+)/Ca(2+)-exchanger which leads to an net inward current. These results support the view that the Na(+)/Ca(2+)-exchanger can play a role in determining the excitability of neurons. The results also provide a functional connection between two transmitter systems, the histaminergic and serotonergic, which modulate many physiological functions in the brain.

Amiloride↗

PubMed2001

Orexin A excites serotonergic neurons in the dorsal raphe nucleus of the rat.

Orexin A (10-300 nM) strongly excited dorsal raphe serotonergic neurons maintained in vitro. The depolarization persisted in the presence of tetrodotoxin (TTX, 0.5 microM) and was associated with an increase in input resistance. These results have relevance in the context of food intake regulation and the disease, narcolepsy.

Action Potentials↗

PubMed2001

The physiology of brain histamine.

Histamine-releasing neurons are located exclusively in the TM of the hypothalamus, from where they project to practically all brain regions, with ventral areas (hypothalamus, basal forebrain, amygdala) receiving a particularly strong innervation. The intrinsic electrophysiological properties of TM neurons (slow spontaneous firing, broad action potentials, deep after hyperpolarisations, etc.) are extremely similar to other aminergic neurons. Their firing rate varies across the sleep-wake cycle, being highest during waking and lowest during rapid-eye movement sleep. In contrast to other aminergic neurons somatodendritic autoreceptors (H3) do not activate an inwardly rectifying potassium channel but instead control firing by inhibiting voltage-dependent calcium channels. Histamine release is enhanced under extreme conditions such as dehydration or hypoglycemia or by a variety of stressors. Histamine activates four types of receptors. H1 receptors are mainly postsynaptically located and are coupled positively to phospholipase C. High densities are found especially in the hypothalamus and other limbic regions. Activation of these receptors causes large depolarisations via blockade of a leak potassium conductance, activation of a non-specific cation channel or activation of a sodium-calcium exchanger. H2 receptors are also mainly postsynaptically located and are coupled positively to adenylyl cyclase. High densities are found in hippocampus, amygdala and basal ganglia. Activation of these receptors also leads to mainly excitatory effects through blockade of calcium-dependent potassium channels and modulation of the hyperpolarisation-activated cation channel. H3 receptors are exclusively presynaptically located and are negatively coupled to adenylyl cyclase. High densities are found in the basal ganglia. These receptors mediated presynaptic inhibition of histamine release and the release of other neurotransmitters, most likely via inhibition of presynaptic calcium channels. Finally, histamine modulates the glutamate NMDA receptor via an action at the polyamine binding site. The central histamine system is involved in many central nervous system functions: arousal; anxiety; activation of the sympathetic nervous system; the stress-related release of hormones from the pituitary and of central aminergic neurotransmitters; antinociception; water retention and suppression of eating. A role for the neuronal histamine system as a danger response system is proposed.

Animals↗

PubMed2001

Expression and function of glycine receptors in striatal cholinergic interneurons from rat and mouse.

Although glycine receptors are widely expressed in the forebrain their function is obscure. We studied their activation by two possible endogenous ligands, glycine and taurine, and demonstrate a different expression pattern of glycine receptors in neostriatal cholinergic interneurons from two rodent species. Single-cell-reverse transcription-polymerase chain reaction analysis of glycine receptor-subunit expression was combined with whole-cell recordings from acutely isolated cholinergic interneurons. All cells expressed the alpha2-glycine receptor subunit, the majority (72%) in mice but none in young and aged rats expressed the alpha3-subunit. The beta-subunit expression was associated with both a higher efficacy and a higher potency of the partial agonist taurine. Cells expressing the alpha3-subunit displayed a slower desensitization of taurine responses than of glycine responses, in contrast to cells expressing the alpha2-, beta-subunits where desensitization time constants were similar. Glycine responses were reduced by preapplication of taurine; this effect was more pronounced in cells lacking the alpha3-subunit. We demonstrate interspecies differences and heterogeneity in expression and function of glycine receptors within the same neuronal population in the neostriatum.

Acetylcholine↗

PubMed2000

Functions of neuronal adenosine receptors.

Endogenous adenosine in nervous tissue, a central link between energy metabolism and neuronal activity, varies according to behavioral state and (patho)physiological conditions, it may be the major sleep propensity substance. The functional consequences of activation of the four known adenosine receptors, A1, A2A, A2B and A3, are considered here. The mechanisms and electrophysiological actions, mainly those of the A1-receptor, have been extensively studied using in vitro brain-slice preparations. A1-receptor activation inhibits many neurons postsynaptically by inducing or modulating ionic currents and presynaptically by reducing transmitter release. A1-receptors are almost ubiquitous in the brain and affect various K+ (Ileak, IAHP), mixed cationic (Ih), or Ca2+ currents, through activation of Gi/o-proteins (coupled to ion channels, adenylyl cyclase or phospholipases). A2A-receptors are much more localized, their functional role in the striatum is only just emerging. A2B- and A3-receptors may be affected in pathophysiological events, their function is not yet clear. The cAMP-PKA signal cascade plays a central role in the regulation of both neural activity and energy metabolism. Under conditions of increased demand and decreased availability of energy (such as hypoxia, hypoglycemia and/or excessive neuronal activity), adenosine provides a powerful protective feedback mechanism. Interaction with adenosine metabolism is a promising target for therapeutic intervention in neurological and psychiatric diseases such as epilepsy, sleep, movement (parkinsonism or Huntington's disease) or psychiatric disorders (Alzheimer's disease, depression, schizophrenia or addiction).

Adenosine↗

PubMed2000

Opposite modulation of histaminergic neurons by nociceptin and morphine.

We have studied the effects of nociceptin/orphanin FQ on the histaminergic neurons in the tuberomammillary (TM) nucleus and compared them with the actions of opioid agonists. Intracellular recordings of the membrane potential were made with sharp electrodes from superfused rat hypothalamic slices. Nociceptin strongly inhibited the firing of the TM neurons. In the concentration range 10-300 nM, nociceptin hyperpolarized the neurons in a dose-dependent and reversible manner. Insensitivity to tetrodotoxin indicated a postsynaptic effect which was associated with decreased input resistance. Voltage-current plots suggested the involvement of a potassium conductance which was highly sensitive to Ba(2+) and decreased by Cs(+), in keeping with the activation of an inwardly rectifying potassium channel. Morphine (20-100 microM) depolarized the TM neurons and increased their firing, and this effect was blocked by tetrodotoxin. Dynorphin A(1-13) at 100-300 nM did not affect the TM neurons. Nociceptin and morphine modulate the activity of the TM neurons, and most likely histamine release, in opposite ways. Histamine has an antinociceptive effect in the brain and may be involved in opioid-induced analgesia. Nociceptin might therefore influence pain transmission by inhibiting opioid-induced histamine release from the TM nucleus and also modulate other physiological mechanisms which have been ascribed to the histaminergic system.

Analgesics, Opioid↗

PubMed2000

Interaction between copper and zinc at GABA(A) receptors in acutely isolated cerebellar Purkinje cells of the rat.

Nanomolar concentrations of Cu(2+) induce a slowly reversible block of GABA(A) receptor-mediated currents which can be removed by chelating substances. The possible interaction of Cu(2+) with the Zn(2+) binding site on the GABA(A) receptor complex was studied in acutely isolated Purkinje cells using whole-cell recording and a fast drug application system. When Zn(2+) was applied together with 2 microM GABA, the Zn(2+)-induced block of GABA-mediated currents was not additive to the Cu(2+)-induced block. In the presence of 0.1 microM Cu(2+) in the bath solution the degree of inhibition of GABA-mediated responses by Zn(2+) was strongly attenuated. Preapplication of 100 microM Zn(2+) during 10 s, terminated 1 s before exposure to 2 microM GABA did not affect the GABA current in Cu(2+)-free solution, but relieved its block by 0.1 microM Cu(2+). This effect of Zn(2+) was concentration-dependent with an EC(50) of 72 microM. When the Cu(2+)-induced block was removed by histidine, preapplication of Zn(2+) did not increase the GABA current, indicating that the relief of Cu(2+) block by Zn(2+) is the result of its ability to actively remove Cu(2+) from the GABA receptor complex. It is proposed that the inhibitory effects of Zn(2+) and Cu(2+) on GABA-induced currents result from an action of these metal ions at distinct, but conformationally linked sites on the GABA(A) receptor protein. Under physiological conditions Zn(2+) would liberate Cu(2+) from the GABA(A) receptor, thus facilitating Cu(2+) turnover and its binding by other endogenous chelating molecules.

Animals↗

PubMed2000

Differential modulation of AMPA receptors by cyclothiazide in two types of striatal neurons.

The modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA) receptor-mediated currents by cyclothiazide was investigated in acutely isolated cells from rat striatum with whole-cell patch-clamp recording. Single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) was used to identify medium spiny and giant aspiny neurons and to determine their AMPA receptor subunit composition mostly in separate experiments. After pretreatment with cyclothiazide, kainate-induced AMPA responses were more strongly potentiated in medium spiny than in giant aspiny neurons; cyclothiazide induced a ninefold leftward shift in the kainate concentration-response curve for medium spiny neurons (not giant aspiny neurons). The EC50s for the cyclothiazide potentiation did not differ substantially between medium spiny neurons and giant aspiny neurons. The recovery of kainate-activated currents from modulation by cyclothiazide was slower for medium spiny neurons than for giant aspiny neurons. Medium spiny neurons expressed GluR-A, GluR-B and GluR-C, but not GluR-D subunits in both flip and flop splice variants. All giant aspiny neurons expressed GluR-A and GluR-D, exclusively in the flop form, half of them also expressed GluR-B and GluR-C. This is in keeping with slow and fast desensitization kinetics in medium spiny neurons and giant aspiny neurons, respectively, and differences in cyclothiazide modulation. The rate of cyclothiazide dissociation from the AMPA receptor, activated by glutamate, was approximately 90 times slower in medium spiny neurons than in giant aspiny neurons. In giant aspiny neurons (not medium spiny neurons) this rate was strongly dependent on the presence of an agonist; 1 mM glutamate increased it 30-fold. Thus, two major cell groups in the striatum display distinct AMPA receptor compositions carrying specific properties of glutamate responses. Excitatory transmission will thus be differentially affected by cyclothiazide-type compounds.

Alternative Splicing↗

PubMed1999

Long-term suppression of synaptic transmission by tetanization of a single pyramidal cell in the mouse hippocampus in vitro.

1. The consequences of stimulating a single pyramidal cell in the CA1 area of the hippocampus for synaptic transmission in the stratum radiatum were investigated. 2. Tetanic activation of single pyramids caused by depolarizing current injection, but not an equal number of distributed action potentials, reduced excitatory transmission by 20 %, with a delayed onset, for more than 1 h. 3. EPSPs in the tetanized pyramidal cells were increased for equally long periods but this was not the cause of the field EPSP reduction. Spontaneous somatic IPSPs were not affected; evoked IPSPs were decreased in the tetanized cell. 4. Paired pulse facilitation of the field EPSPs was unchanged. 5. The field EPSP reduction was markedly diminished by a knife cut along the base of pyramidal cells in CA1. 6. The addition of antagonists of GABA, NMDA and metabotropic glutamate receptors blocked or diminished the field EPSP slope reduction evoked by intracellular stimulation. 7. Simultaneous recordings revealed long-lasting excitations of interneurons located in the outer oriens layer as a result of single pyramid tetanization. 8. Intense firing of small numbers of pyramidal cells can thus persistently inhibit mass transmission through the hippocampus. This effect involves activation of interneurons by glutamate receptors.

2-Amino-5-phosphonovalerate↗

PubMed1999

On the mechanism of histaminergic inhibition of glutamate release in the rat dentate gyrus.

1. Histaminergic depression of excitatory synaptic transmission in the rat dentate gyrus was investigated using extracellular and whole-cell patch-clamp recording techniques in vitro. 2. Application of histamine (10 microM, 5 min) depressed synaptic transmission in the dentate gyrus for 1 h. This depression was blocked by the selective antagonist of histamine H3 receptors, thioperamide (10 microM). 3. The magnitude of the depression caused by histamine was inversely related to the extracellular Ca2+ concentration. Application of the N-type calcium channel blocker omega-conotoxin (0. 5 or 1 microM) or the P/Q-type calcium channel blocker omega-agatoxin (800 nM) did not prevent depression of synaptic transmission by histamine. 4. The potassium channel blocker 4-aminopyridine (4-AP, 100 microM) enhanced synaptic transmission and reduced the depressant effect of histamine (10 microM). 4-AP reduced the effect of histamine more in 2 mM extracellular calcium than in 4 mM extracellular calcium. 5. Histamine (10 microM) did not affect the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and had only a small effect on their frequency. 6. Histaminergic depression was not blocked by an inhibitor of serine/threonine protein kinases, H7 (100 microM), or by an inhibitor of tyrosine kinases, Lavendustin A (10 microM). 7. Application of adenosine (20 microM) or the adenosine A1 agonist N6-cyclopentyladenosine (CPA, 0.3 microM) completely occluded the effect of histamine (10 microM). 8. We conclude that histamine, acting on histamine H3 receptors, inhibits glutamate release by inhibiting presynaptic calcium entry, via a direct G-protein-mediated inhibition of multiple calcium channels. Histamine H3 receptors and adenosine A1 receptors act upon a common final effector to cause presynaptic inhibition.

4-Aminopyridine↗

PubMed1999

Mice deficient in endothelial nitric oxide synthase exhibit a selective deficit in hippocampal long-term potentiation.

Long-term potentiation, a persistent increase in synaptic efficacy, may require a retrograde signal originating in the postsynaptic cell that induces an increase in presynaptic neurotransmitter release. We have constructed a mouse homozygous for a targeted null mutation in the endothelial isoform of nitric oxide synthase and report that long-term potentiation in the CA1 region of these mice is entirely absent under weak stimulation conditions. Application of a membrane-permeant guanosine-3',5'-cyclic monophosphate analogue during tetanus fails to compensate for this deficit, suggesting that nitric oxide produced by endothelial nitric oxide synthase may affect long-term potentiation through a cascade that does not include guanylyl cyclase. We also report that strong tetanic stimulation can induce robust long-term potentiation in these mice which is not blocked by pharmacological inhibitors of nitric oxide synthase. Furthermore, mice lacking endothelial nitric oxide synthase show no shift in the frequency-response curve for the induction of long-term potentiation. Basal synaptic transmission, paired-pulse facilitation and the electrical properties of CA1 cells in these mice were similar to controls. These results support a selective role for endothelial nitric oxide synthase in long-term potentiation, but also demonstrate that nitric oxide synthase is not involved in this process under all conditions.

Animals↗

PubMed1999

GABAB-receptor-mediated control of GABAergic inhibition in rat histaminergic neurons in vitro.

The onset of slow wave sleep may require an inhibition of histaminergic neurons by GABAergic afferents from the ventrolateral preoptic area. We have utilized electrophysiological methods in an in vitro brain slice preparation to examine the role of GABAB receptor activation in GABAergic synaptic inhibition in histaminergic neurons of the tuberomammillary nucleus. Tetrodotoxin blocked evoked GABAergic IPSPs but not miniature IPSPs or IPSCs. Evoked IPSPs varied in amplitude and exhibited failures of transmission. Baclofen reduced the amplitude of evoked IPSPs in all experiments and often caused an increase in failures of transmission. Responses elicited by application of exogenous GABA were insensitive to baclofen treatment. The action of baclofen was blocked by CGP-35348 (100 microm), a GABAB receptor antagonist, which also enhanced the amplitude of evoked IPSPs. The frequency of spontaneous and miniature IPSPs and IPSCs was reduced by baclofen. However, the amplitude distribution of mIPSCs was not altered. We conclude that GABA release onto TM neurons is under presynaptic control via GABAB receptors. This presynaptic control of transmission to tuberomammillary neurons may reduce inhibition, increasing histamine release and enhancing wakefulness.

Animals↗

PubMed1999

Impairment of neocortical long-term potentiation in mice deficient of endothelial nitric oxide synthase.

The role of the possible retrograde messenger nitric oxide (NO) in the induction of long-term potentiation (LTP) was studied in supragranular layers of somatosensory cortical slices obtained from adult mice. High-frequency stimulation produced a slowly rising, long-lasting (50 min) and significant (P < 0.001) increase in the extracellular synaptic response by 23%. The induction of LTP was independent from activation of N-methyl-D-aspartate (NMDA) receptors, but prevented by bath application of NG-nitro-L-arginine methyl ester (L-NAME), indicating that one or several of the different NO synthases (NOS) produced NO within the postsynaptic neuron. No LTP could be induced in knockout mice lacking the endothelial NOS (eNOS) isoform. These data suggest that eNOS is involved in an NMDA receptor-independent form of LTP in the rodent cerebral cortex.

2-Amino-5-phosphonovalerate↗

PubMed1998

Histamine increases the bursting activity of pyramidal cells in the CA3 region of mouse hippocampus.

An excitatory action of histamine was investigated by intracellular recording in the CA3 region of hippocampal slices. Bath application of histamine or impromidine, a H2 receptor agonist, had the following effects: (1) a depolarisation in 60% and no changes in membrane potential in 40% of the CA3 pyramids; (2) single cell firing and burst activity were evoked or more than doubled when spontaneously present; (3) the bursts were prolonged and often followed by afterdischarges instead of the normal afterhyperpolarisations (AHPs); (4) synaptic stimulation evoked large bursts instead of excitatory synaptic potentials (EPSPs) and primary burst responses became prolonged. CA3 bursts may play a decisive role in memory trace formation, their facilitation and potentiation is in keeping with a positive role of the histaminergic system in attention and learning.

Action Potentials↗

PubMed1998

Differential modulation of hippocampal signal transfer by tuberomammillary nucleus stimulation in freely moving rats dependent on behavioral state.

Tuberomammillary histamine neurons (TM) in the posterior hypothalamus project to extensive parts of the brain, including the hippocampal formation. The purpose of the present experiments was to investigate whether activation of the TM modulates signal transfer from the perforant pathway (PP) or ventral hippocampal commissure (VHC) to the dentate gyrus (DG) in freely moving rats. Paired pulses of electrical stimulation were delivered to PP or VHC, and evoked field potentials (fEPSPs and pop spikes) were recorded in the DG. Before activating PP or VHC, the TM was triggered by electrical stimulation. Experimentation was performed during four behavioral conditions: exploration, grooming, awake immobility, and slow-wave sleep. Electrical activation of the TM was found to modify dentate fEPSPs evoked by PP or VHC stimulation without generating a field potential by itself. Train stimulation of the TM (100 Hz, 500 ms) preceding paired pulses on the hippocampus by 50 ms decreased dentate fEPSPs in dependence of the ongoing behavior and the pathway stimulated. During exploration but not consummatory behavior, the PP signal was reduced when preceded by TM stimulation; during consummatory behavior but not exploration, the VHC signal was reduced. In contrast to other hippocampal afferents which increase pop spikes but leave fEPSPs unchanged, TM stimulation decreased dentate fEPSPs without affecting pop-spike activity. Thus, the TM-histaminergic system seems to modulate signal processing in the dentate gyrus in a specific way, exerting an inhibitory action on the entorhinal input only during learning-related exploratory behavior.

Animals↗

PubMed1998

Facilitation of learning after lesions of the tuberomammillary nucleus region in adult and aged rats.

The tuberomammillary nucleus (TM) located in the posterior part of the hypothalamus is the main source of neuronal histamine in the central nervous system. Recent work from our laboratories has indicated an involvement of the TM region in neuronal plasticity and reinforcement processes. In the present study, we investigated the effects of TM lesions on the performance of adult and aged Wistar rats in a set of learning tasks, which differed in terms of complexity and reward contingencies (habituation learning, inhibitory avoidance, discrimination learning, Morris water maze). An improvement was found in every test applied, indicating that TM lesions seem to generally enhance learning and memory capacities independent of the special demands of a given task. Age-related learning deficits were strongly diminished. Immunohistochemistry revealed that the excitotoxic lesions used to destroy the TM region led to a marked decrease in the number of histamine-positive neurons in the vicinity of the injection site, indicating an involvement of the brain histaminergic system in the observed behavioral changes.

Aging↗