Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Maintenance of cerebral perfusion pressure is a prerequisite for the prevention of cerebral ischemia. Physiological fluctuations in systemic perfusion pressure are compensated by cerebrovascular autoregulation. Cerebral hypoperfusion could result from (1) systemic hemodynamic failure (eg, distal to severe arterial stenosis), overcharging the vasoregulatory capacity; (2) dysfunction and exhaustion of cerebrovascular autoregulation; or (3) both. Ultrasound offers an excellent temporal resolution, is noninvasive, and is easily applicable for follow-up investigations. Despite its poor spatial resolution, transcranial Doppler sonography has been used for determination of cerebral perfusion reserve studies measuring cerebral blood flow velocity (CBFV) during hypercapnia or application of vasoactive agents (eg, acetazolamide). This approach evaluates vasomotor regulation in patients with hemodynamic compromise distal to severe stenosis or occlusion of the brain supplying arteries. Monitoring CBFV during tilt table examinations directly measures cerebral autoregulation. In patients with systemic orthostatic hypotension, maintainance or failure of cerebrovascular compensation and, even more importantly, cerebrovascular dysautoregulation, despite normal systemic blood pressure regulation, may be demonstrated. Vasoneuronal coupling is reflected by CBFV variations during appropriate neuronal stimulation. Neuronal dysfunction is associated with CBFV abnormalities as exemplified by preconditions of focal cerebral dysfunction in the posterior cerebral artery (PCA) in migraineurs with aura, where massive alteration of vasoneuronal coupling and ischemia is threatening during spreading depression. A highly significant asymmetric gain of vasoneuronal coupling in the interictal state may act as a trigger mechanism in these patients. Testing for vasoneuronal coupling within the middle cerebral artery (MCA) territory is more difficult due to the poor spatial resolution with various neuronal stimuli (eg, motorsensory or cognitive paradigms), only eliciting local neuronal areas underrepresented in the MCA CBFV global changes. However, motor stimulation evoked CBFV may be used to indicate dysintegration of vasoneuronal coupling in the course of acute cerebral ischemia with sensorimotor hemiparesis and, moreover, seems to be of prognostic value regarding the motor deficit.
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PMID:Cerebrovascular regulation and vasoneuronal coupling. 769

Recent studies from this laboratory have shown that neurons in this hypothalamic region are stimulated by hypoxia in vivo and in vitro. In addition, GABAergic activity is depressed in the posterior hypothalamus of the spontaneously hypertensive rat compared to the normotensive rat. The major purposes of the present study were to: a) evaluate if posterior hypothalamic neurons respond differently to GABA in the hypertensive rat compared to the normotensive rat; and b) examine the possibility that hypothalamic neurons from spontaneously hypertensive rats respond differently to hypoxia than those from normotensive rats. In addition, the effects of GABA on hypoxia-sensitive neurons was recorded. Extracellular single unit recordings of hypothalamic neurons were performed in a rat brain slice preparation. Neuronal responses to hypoxia (10% O2/5% CO2/85% N2) and to GABA were recorded from slices taken from both Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Administration of three different concentrations of GABA evoked a dose-related decrease in discharge rate in similar percentages of neurons from both SHR and WKY rats. The magnitude of the depression elicited by GABA did not differ significantly between the neurons from SHR and WKY rats. Hypoxia increased the firing rate of 75% and 69% of the SHR and WKY neurons, respectively; no differences (p > 0.05) were noted in the magnitude of the response or in the percentage of neurons responding to hypoxia between the two strains of rats. The discharge rate of most of these neurons fell to below control level following removal of the hypoxic stimulus. A significant percentage of SHR (75%) and WKY (75%) neurons that were stimulated by hypoxia were inhibited by exogenously applied GABA. These results indicate that a) an altered sensitivity of hypothalamic neurons to GABA does not contribute to hypertension in the SHR and b) the depressed respiratory response to hypoxia in the SHR is not due to a decreased responsiveness of hypothalamic neurons to hypoxia.
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PMID:In vitro effects of GABA and hypoxia on posterior hypothalamic neurons from spontaneously hypertensive and Wistar-Kyoto rats. 771 8

The granule cell population response to perforant path stimulation decreased significantly within seconds following release of endogenous dynorphin from dentate granule cells. The depression was blocked by the opioid receptor antagonists naloxone and norbinaltorphimine, suggesting that the effect was mediated by dynorphin activation of kappa 1 type opioid receptors. Pharmacological application of dynorphin B in the molecular layer was effective at reducing excitatory synaptic transmission from the perforant path, but application in the hilus had no significant effect. These results suggest that endogenous dynorphin peptides may be released from a local source within the dentate molecular layer. By light microscopy, dynorphin-like immunoreactivity (dynorphin-LI) was primarily found in granule cell axons in the hilus and stratum lucidum with only a few scattered fibers evident in the molecular layer. At the extreme ventral pole of the hippocampus, a diffuse band of varicose processes was also seen in the molecular layer, but this band was not present in more dorsal sections similar to those used for the electrophysiological studies. Electron microscopic analysis of the molecular layer midway along the septotemporal axis revealed that dynorphin-LI was present in dense-core vesicles in both spiny dendrites and unmyelinated axons with the majority (74%) of the dynorphin-LI-containing dense-core vesicles found in dendrites. Neuronal processes containing dynorphin-LI were observed throughout the molecular layer. The results suggest that dynorphin release from granule cell processes in the molecular layer regulates excitatory inputs entering the hippocampus from cerebral cortex, thus potentially counteracting such excitation-induced phenomena as epileptogenesis or long-term potentiation.
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PMID:Dynorphin opioids present in dentate granule cells may function as retrograde inhibitory neurotransmitters. 791 18

Neuronal injury following focal cerebral ischemia is widely attributed to the excitotoxic effects of glutamate. However, critical analysis of published data on glutamate toxicity in vitro and the comparison of these data with in vivo release of glutamate and the therapeutic effect of glutamate antagonists raises doubts about a neurotoxic mechanism. An alternative explanation for glutamate-mediated injury is hypoxia due to peri-infarct spreading depression-like depolarizations. These depolarizations are triggered in the core of the ischemic infarct and spread at irregular intervals into the peri-infarct surrounding. In ischemically uncompromised tissue, the metabolic workload associated with spreading depression is coupled to an increase in blood flow and oxygen supply, assuring maintenance of oxidative respiration. In the penumbra region of focal ischemia, the hemodynamic constraints of collateral blood circulation prevail the adequate adjustment of oxygen delivery, leading to transient episodes of relative tissue hypoxia. The hypoxic episodes cause a suppression of protein synthesis, a gradual deterioration of energy metabolism and a progression of irreversibly damaged tissue into the penumbra zone. The generation of peri-infarct spreading depressions and the associated metabolic workload can be suppressed by NMDA and non-NMDA antagonists. As a result, the penumbral inhibition of protein synthesis and the progressing energy failure is also prevented, and the volume of ischemic infarct decreases. Interventions to improve ischemic resistance should therefore aim at improving the oxygen supply or reducing the metabolic workload in the penumbra region.
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PMID:Glutamate-mediated injury in focal cerebral ischemia: the excitotoxin hypothesis revised. 791 80

1. Neuronal systems activated by stimulation in the region of the locus coeruleus/subcoeruleus (LC/SC) and raphe nuclei have previously been shown to depress transmission from group II muscle afferents in regions of the midlumbar spinal segments in which premotor interneurones are located. The aim of the present investigation was to determine the extent to which such depression is paralleled by depression of the reflex actions of group II afferents on motoneurones. 2. The effects of short trains of conditioning electrical stimuli applied within the LC/SC and raphe nuclei were examined on postsynaptic potentials (PSPs) evoked by group I and group II muscle afferents in hindlimb motoneurones. The effects were examined over a wide range of conditioning-test intervals but particular emphasis was placed on the effects produced at long intervals (> 100 ms) since such effects are more likely to be mediated by the descending noradrenergic and serotonergic neurones of the LC/SC and raphe nuclei which are of slow conduction velocity. In addition, conditioning stimuli alone evoked PSPs in motoneurones (with latencies of 7-15 ms and a duration of 50-80 ms) and effects evoked at short conditioning-test intervals might therefore have been secondary to changes in motoneurone membrane properties. 3. At conditioning-test intervals between 100 and 350 ms synaptic actions of group II origin were strongly and consistently depressed. Both EPSPs and IPSPs were affected, two-thirds of those tested being reduced in amplitude by 50% or more. A similar depression was exerted on PSPs evoked from the quadriceps and deep peroneal nerves mediated predominantly by interneurones located in the midlumbar segments and on PSPs evoked from the hamstring and triceps surae nerves mediated by interneurones located in more caudal segments. It is thus concluded that neuronal systems activated by stimuli applied in the LC/SC and raphe nuclei are capable of gating transmission in all those interneuronal pathways which mediate the reflex actions of group II afferents on motoneurones in anaesthetized animals.
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PMID:Gating of transmission to motoneurones by stimuli applied in the locus coeruleus and raphe nuclei of the cat. 839 30

The effects of the selective 5-HT1A receptor agonist (R)-8-hydroxy-2(di-n-propylamino)tetralin [(R)-8-OH-DPAT] and the novel 5-HT1A antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-301] were studied with regard to the firing pattern of single mesencephalic dopamine (DA) neurons with extracellular recording techniques in chloral hydrate anesthetized male rats. Neuronal activity was studied with respect to firing rate, burst firing and regularity of firing. In the ventral tegmental area (VTA) low doses of (R)-8-OH-DPAT (2-32 micrograms/kg i.v.) caused an increase in all three parameters. The effect on firing rate of DA neurons was more pronounced in the parabrachial pigmentosus nucleus than in the paranigral nucleus, the two major subdivisions of VTA. In the substantia nigra zona compacta (SN-ZC), (R)-8-OH-DPAT (2-256 micrograms/kg i.v.) had no effect on firing rate and regularity of firing and only slightly increased burst firing. High doses of (R)-8-OH-DPAT (512-1024 micrograms/kg i.v.) decreased the activity of DA cells in both areas, an effect that was prevented by pretreatment with the selective DA D2 receptor antagonist raclopride. (S)-UH-301 (100-800 micrograms/kg i.v.) decreased both firing rate and burst firing without affecting regularity of DA neurons in the VTA. In the SN-ZC, (S)-UH-301 decreased the firing rate but failed to affect burst firing and regularity of firing. These effects of (S)-UH-301 were blocked by raclopride pretreatment. Local application by pneumatic ejection of 8-OH-DPAT excited the DA cells in both the VTA and the SN-ZC, whereas (S)-UH-301 inhibited these cells when given locally. These results show that 5-HT1A receptor related compounds differentially affect the electrophysiological activity of central DA neurons. The DA receptor agonistic properties of these compound appear to contribute to the inhibitory effects of high doses of (R)-8-OH-DPAT and (S)-UH-301 on DA neuronal activity. Given the potential use of 5-HT1A receptor selective compounds in the treatment of anxiety and depression their effects on central DA systems involved in mood regulation and reward related processes are of considerable importance.
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PMID:The 5-HT1A receptor selective ligands, (R)-8-OH-DPAT and (S)-UH-301, differentially affect the activity of midbrain dopamine neurons. 851 Jul 63

Research on a wide variety of vertebrates, from fish to mammals, reveals that corticosteroid hormones and vasotocin-like neuropeptides can potently modulate reproductive behaviors. But, it is not clear how the behavioral effects of these chemical messengers relate to functional properties of behavior-controlling neurons. This problem was investigated in the roughskin newt, Taricha granulosa, an amphibian in which the administration of arginine vasotocin (AVT) facilitates and corticosterone (CORT) inhibits courtship clasping of females by males. In waking, immobilized male newts, neurophysiological effects of AVT and CORT were studied in neurons in the rostral medulla due to the probable role of these neurons in the control of clasping. Topical medullary application of a clasp-facilitating dose of AVT produced a rapid increase in neuronal responsiveness to pressure on the cloaca, a trigger stimulus for clasping responses. Neuronal responses to noncloacal somatic stimuli and to moving visual stimuli were also enhanced. Systemic CORT administration, which has previously been shown to depress newt medullary neuronal sensory responsiveness, reversed the action of AVT such that the peptide depressed sensory responsiveness when applied 30 min after CORT. When AVT application preceded CORT injection by 10-17 min, however, the usual suppressive CORT effect was reversed and this treatment resulted in a rapidly appearing potentiation of neuronal activity and enhanced somatic sensory responsiveness. If the interval between AVT and CORT was increased to 30 min, the steroid caused a rapid depression of firing and a diminished somatic sensory responsiveness in most neurons, similar to what occurs in newts treated with CORT alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neurophysiological effects of vasotocin and corticosterone on medullary neurons: implications for hormonal control of amphibian courtship behavior. 854 54

1. Within the hypothalamus, adenosine has been reported to influence temperature regulation, sleep homeostasis, and endocrine secretions. The effects of adenosine on hypothalamic neurons have not been studied at the cellular level. Adenosine (5 nM-30 microM) showed no influence on intracellular Ca2+ or electrical activity in the presence of glutamate receptor antagonists D-2-amino-5-phosphonovalerate and 6-cyano-7-nitroquinoxaline-2,3-dione; consequently, we examined the role of adenosine in modulating the activity of glutamate in cultured hypothalamic neurons (n > 1,700) with fura-2 Ca2+ digital imaging and whole cell patch-clamp electrophysiology in the absence of glutamate receptor block. 2. When glutamate receptors were not blocked, adenosine (1-30 microM) and the selective adenosine A1 receptor agonist N6-cyclopentyl adenosine (CPA; 5 nM-1 microM) caused a large reduction in intracellular Ca2+ and electrical activity, suggesting that glutamate neurotransmission was critical for an effect of adenosine to be detected. Neuronal Ca2+ levels were reversibly depressed by CPA (50 nM), with a maximum depression of 90%, and these effects were blocked by coadministration of the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). 3. Ca2+ levels in immature neurons before the time of synaptogenesis were not affected by adenosine. Adenosine A1 receptor activation suppressed glutamate-mediated Ca2+ activity in neurons in vitro 8 to 73 days. 4. Adenosine (1 or 10 microM) caused a hyperpolarization of membrane potential and a reduction of large postsynaptic potentials arising from endogenously released glutamate. The administration of low concentrations of CPA (5 nM) decreased the frequency of glutamate-mediated, neuronally synchronized Ca2+ transients and the frequency of postsynaptic potentials. 5. To compare the relative effects of adenosine on hypothalamic neurons with cells from other brain regions, we assayed the effects of CPA on glutamate-mediated Ca2+ in hippocampal and cortical cultures. CPA (50 nM) reversibly depressed glutamate-mediated Ca2+ rises in hypothalamic neurons by 35%, compared with 54% in hippocampal neurons and 46% in cortical neurons. 6. If it does play a functional role, adenosine should be released by hypothalamic cells. In some neurons the adenosine A1 receptor antagonists cyclopentyltheophylline or DPCPX caused an increase in intracellular Ca2+, suggesting that adenosine was secreted by hypothalamic cells, tonically depressing glutamate-enhanced neuronal Ca2+. 7. To determine whether adenosine could exert a postsynaptic effect, we coapplied it with glutamate agonists in the presence of tetrodotoxin. Within subpopulations of hypothalamic neurons, adenosine and CPA either inhibited (18% of total neurons) or potentiated (6% of total neurons) responses to glutamate, N-methyl-D-aspartate, and kainate by > or = 20%. 8. In contrast to the modest effects found in neurons, responses of hypothalamic astrocytes to the application of glutamate or the metabotropic glutamate receptor agonist (+/-)-trans-1-amino-1,3-cyclopentanedicarboxylic acid were strongly potentiated by adenosine (mean +225%) and CPA. 9. Together, these findings suggest that adenosine exerts a major presynaptic effect and a minor postsynaptic effect in the modulation of glutamate neurotransmission in the hypothalamus, where it can play a significant role in blocking a large part of the glutamate-induced Ca2+ rise. In the absence of glutamate transmission, adenosine has relatively little effect on either neuronal intracellular Ca2+ or electrical activity.
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PMID:Adenosine pre- and postsynaptic modulation of glutamate-dependent calcium activity in hypothalamic neurons. 859 3

1. Single-unit recording and iontophoresis were used in awake, unrestrained rats to assess the action of dopamine (DA) and glutamate (GLU) on the spontaneous activity of neurons in the neostriatum and nucleus accumbens. 2. A total of 88 neurons (40 neostriatal and 48 accumbal) was recorded from 7 rats during 13 recording sessions. During quiet rest, spontaneously active neurons discharged at a slow rate and irregular pattern of activity. Accumbal neurons had a significantly faster level of basal activity than neostriatal neurons (modal values of 10.3 vs. 2.1 imp/s, respectively). 3. Neuronal responses to separate applications of DA and GLU (5-80 nA; 15-30 s) were tested on 40 and 76 units (195 and 227 applications), respectively, during the quiet resting period. The effect of prolonged DA iontophoresis (5-80 nA; 2-3 min) on GLU-induced changes in impulse activity was tested on 38 units (72 applications). 4. GLU activated all cells in both structures. This response appeared with a latency of 0.5-4.0 s at different ejection currents (5-40 nA; mean threshold of 22.2 nA) and was highly variable (103-11,520% of basal activity). Response magnitude correlated strongly with the rate of basal activity (r = 0.822). 5. DA inhibited 75% of spontaneously active neostriatal and accumbal cells with a mean threshold of 20.4 nA. In contrast to the GLU excitation, the DA-induced inhibition was relatively weak in magnitude (10-90% of basal activity) and occurred with relatively longer on- and offset latencies than GLU (2-20 s). The inhibitory effect of DA was absent during phasic activations of neuronal activity associated with movement. Two neostriatal neurons responded to DA with a dose-dependent excitation. 6. Prolonged DA iontophoresis altered both basal impulse activity (causing a decrease in 36 of 72 applications and an increase in 4) and the magnitude of the GLU-induced activation (decreasing it in 27 of 72 applications and increasing it in 12). The net result was an overall enhancement of the GLU response relative to the DA-induced change in basal activity (74% of cases). This increase in the GLU response occurred at relatively low DA ejection currents (10-30 nA). It was stronger in the nucleus accumbens than in the neostriatum and was most evident on cells having both a moderate level of basal activity and a relatively small initial response to GLU. When DA was ejected at high currents (> 40 nA) and/or the magnitude of the preceding GLU-induced activation was high (> 800% of basal activity), DA tended to decrease the GLU response. 7. DA appears to exert a slight depression of striatal and accumbal activity, which has the effect of amplifying the phasic activation induced by GLU. Because forebrain DA release occurs in response to behaviorally important stimuli, the DA-induced modulation of the GLU response may play an important role in regulating goal-directed behavior.
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PMID:Dopaminergic modulation of glutamate-induced excitations of neurons in the neostriatum and nucleus accumbens of awake, unrestrained rats. 882 48

One major event taking place at the moment of traumatic brain injury in neuronal cells is the occurrence of massive ionic fluxes across the plasma membrane, which can be referred to as traumatic depolarization (TD). Unlike spreading depression, TD can occur over wide brain areas simultaneously. Furthermore, recovery from TD often takes far longer than recovery from ionic perturbation elicited by the passage of a single wave of spreading depression. Neuronal cell damage caused by ischemic brain injury is also initiated by massive ionic fluxes, termed anoxic depolarization. The occurrence of similar ionic events in these two forms of brain injury may account for the genesis of diffuse ischemia-like damage without actual episodes of hypoxia or ischemia in traumatic brain injury. We review the data indicating that excitatory amino acids (EAA) may play a vital role in producing TD, and that such EAA-mediated ionic perturbation is responsible for a number of posttraumatic events including subcellular metabolic dysfunction and cellular responses such as microglial activation and astrocytic transformation. TD may represent one of the most important mechanisms of diffuse neuronal cell dysfunction and damage associated with traumatic brain injury.
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PMID:Role of excitatory amino acid-mediated ionic fluxes in traumatic brain injury. 897 25


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