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

The modulation of Ca2+ currents by the excitatory neurotransmitter glutamate and its analogs was investigated in hippocampal neurons in culture. In the presence of glutamate receptor-gated ion channel antagonists, all of the analogs tested caused either a small reversible depression or had no effect on the Ca2+ current. However, in neurons dialyzed with GTP gamma S, quisqualate and glutamate but not NMDA, kainate, AMPA, or L-APB caused marked and irreversible depressions of the Ca2+ current. This inhibition was only observed if Ca2+ was present in either the internal or external medium. Intracellular H-7, staurosporine, IP3, cAMP, cGMP, or calmodulin inhibitors failed to prevent the quisqualate-induced Ca2+ current inhibition. These observations are consistent with an interaction between a G protein-coupled glutamate receptor and Ca2+ channels.
 ...
PMID:Quisqualate receptor-mediated depression of calcium currents in hippocampal neurons. 197 15

The binding of DL-[3,4-3H] 2-amino-4-phosphonobutyric acid DL[3H]-APB to rat whole brain synaptic membranes was investigated. Binding was linear with membrane protein concentration, and optimal at physiological pH and temperature. The association rate was rapid, achieving equilibrium within 10 min. Prolonged incubations (greater than 20 min) revealed additional sites, which apparently possessed identical binding characteristics to those detected with 10 min incubations. Binding of DL-[3H]-APB was enriched in synaptic membrane fractions, and assessment of the regional distribution, indicated greatest binding in those areas with a rich glutamatergic innervation. The binding of DL-[3H]-APB in HEPES-KOH buffer exhibited an absolute requirement for Cl-. The addition of Ca2+ resulted in a further enhancement of binding. Saturation analysis revealed the presence of specific glutamate-sensitive DL-[3H]-APB binding sites, with a KD = 1.26 microM and Bmax = 12.08 pmol mg-1 protein. A Hill plot revealed a slope slightly greater than unity, which could possibly be a reflection of a contribution to binding of a further site which is relatively insensitive to glutamate. Analysis of 60 min incubation data indicated an approximately 3 fold increase in the capacity of the system, but a relatively unchanged KD. Examination of the pharmacological specificity of binding, showed that for both agonist and antagonist molecules, the L-enantiomers were invariably more active than the D-forms. For example, the L-(+)-2-amino-4-phosphonobutyrate isomer was 15 times more active than the D-(-)-form in inhibiting the binding of DL-[3H]-APB. This is in close agreement with the ability of these compounds to produce depression of synaptic transmission. The most potent inhibitor of binding was quisqualate. It is suggested that APB may interact with a quisqualate-preferring class of excitatory amino acid receptors, possibly localised predominantly on presynaptic terminals.
 ...
PMID:Characterization of the binding of DL-[3H]-2-amino-4-phosphonobutyrate to L-glutamate-sensitive sites on rat brain synaptic membranes. 614 60

Previous studies have clearly shown that motor imagery modulates corticospinal excitability. However, there is no clear evidence for the modulation of intracortical inhibition (ICI) during imagined task performance. The aim of this study was to use transcranial magnetic stimulation (TMS) to assess changes in corticospinal excitability and ICI during the imagined performance of two types of task. In Experiment 1, eight subjects performed phasic depression of a computer mouse button using the dominant index finger in time with a 1 Hz auditory metronome. Single and paired pulse magnetic stimuli were delivered at rest, and during the 'on' and 'off' phases of actual and imagined task performance. Motor evoked potentials (MEPs) were recorded from FDI and APB. In Experiment 2, eight subjects performed phasic isometric abduction of the dominant thumb in time with a 1 Hz auditory metronome. As before, single and paired pulse magnetic stimuli were delivered at rest, and during the 'on' and 'off' phases of actual and imagined task performance. In both experiments, the conditioning stimulus intensity was set to produce 50% inhibition at rest, to enable both increases and decreases in ICI during task performance to be detected. No significant temporal or spatial modulation of MEP amplitude or ICI was observed in Experiment 1. In contrast, MEP amplitude was significantly greater, and ICI significantly lower during the 'on' phase of imagined task performance in Experiment 2. These results are most likely related to the higher levels of target muscle activation required during actual task performance and the greater anatomical distance between target and control muscles in Experiment 2. These task characteristics may influence the observed degree of corticospinal excitability and ICI modulation.
 ...
PMID:Modulation of corticospinal excitability and intracortical inhibition during motor imagery is task-dependent. 1499 59

In adult pentobarbital-anesthetized and unanesthetized decerebrate cats, the D(1)R agonists (6-chloro-APB, SKF-38393, dihydrexidine) given intravenously restored phrenic nerve and vagus nerve respiratory discharges and firing of bulbar post-inspiratory neurons after the discharges were abolished by the micro-opioid receptor agonist fentanyl given intravenously. Reversal of opioid-mediated discharge depression was prevented by the D(1)R antagonist SCH23390. Iontophoresis of the micro-opioid receptor agonist DAMGO depressed firing of medullary bulbospinal inspiratory neurons. Co-iontophoresis of SKF-38393 did not restore firing and had no effect on bulbospinal inspiratory neuron discharges when applied alone. The D(1)R agonists given intravenously prolonged and intensified phrenic nerve and bulbospinal inspiratory neuron discharges. They also increased reactivity to CO(2) by lowering the phrenic nerve apnea threshold and shifting the phrenic nerve-CO(2) response curve to lower et(CO(2)) levels. Intravenous fentanyl on the other hand decreased CO(2) reactivity by shifting the phrenic nerve apnea threshold and the response curve to higher et(CO(2)) levels. Fentanyl effects on reactivity were partially reversed by D(1)R agonists.
 ...
PMID:Dopamine1 receptor agonists reverse opioid respiratory network depression, increase CO2 reactivity. 1512 91

Opioids depress respiration and decrease chest wall compliance. A previous study in this laboratory showed that dopamine-D(1) receptor (D(1)R) agonists restored phrenic nerve activity after arrest by fentanyl in immobilized, mechanically ventilated cats. The reinstated phrenic nerve rhythm was slower than control, so it was not known whether D(1)R agonists can restore spontaneous breathing to levels that provide favorable alveolar gas exchange and blood oxygenation. It was also not known whether the agonists counteract opioid analgesia. In the present study, anesthetized, spontaneously breathing cats were given intravenous doses of fentanyl (18.0 +/- 3.4 microg/kg) that severely depressed depth and rate of respiration, lowered arterial hemoglobin oxygenation (HbO(2)), elevated end-tidal carbon dioxide (ETCO(2)), and abolished the nociceptive hind limb crossed-extensor reflex. Fentanyl (30 microg/kg) also evoked tonic discharges of caudal medullary expiratory neurons in paralyzed mechanically ventilated cats, which might explain decreased chest compliance. The selective D(1)R agonists 6-chloro APB (3 mg/kg) or dihydrexidine (DHD, 1 mg/kg) increased depth and rate of spontaneous breathing after opioid depression and returned HbO(2) and ETCO(2) to control levels. Opioid arrest of the nociceptive reflex remained intact. Pretreatment with DHD prevented significant depression of spontaneous breathing by fentanyl (17.5 +/- 4.3 microg/kg). Tonic firing evoked by fentanyl in expiratory neurons was converted to rhythmic respiratory discharges by DHD (1 mg/kg). The results suggest that D(1)R agonists might be therapeutically useful for the treatment of opioid disturbances of breathing without impeding analgesia.
 ...
PMID:D1-dopamine receptor agonists prevent and reverse opiate depression of breathing but not antinociception in the cat. 1570

The role of inositol 1, 4, 5-trisphosphate receptors (IP3Rs) in long-term potentiation (LTP) and long-term depression (LTD) was studied in CA1 neurons in guinea pig hippocampal slices. In standard solution, short tetanic stimulation consisting of 15 pulses at 100 Hz induced LTP, while three short trains of low-frequency stimulation (LFS; 200 pulses at 1 Hz) at 18-min intervals or one long train of LFS (1000 pulses at 1 Hz) induced stable LTD in both the slope of the field EPSP (S-EPSP) and the amplitude of the population spike (A-PS). Bath application of 2-aminoethoxydiphenyl borate (2-APB), an IP3R antagonist, or of alpha-methyl-4-carboxyphenylglycine (MCPG), a wide-spectrum metabotropic glutamate receptor antagonist, during weak tetanic stimulation significantly increased the magnitude of the LTP in both the S-EPSP and A-PS. Three short trains of LFS or one long train of LFS delivered in the presence of 2-APB or MCPG did not induce LTD, but elicited LTP. Based on these results, we conclude that, in hippocampal CA1 neurons, IP3Rs play an important role in synaptic plasticity by attenuating LTP and facilitating LTD.
 ...
PMID:Involvement of IP3 receptors in LTP and LTD induction in guinea pig hippocampal CA1 neurons. 1628 18

The spinal synaptic plasticity is associated with a central sensitization of nociceptive input, which accounts for the generation of hyperalgesia in chronic pain. However, how group I metabotropic glutamate receptors (mGluRs) may operate spinal plasticity remains essentially unexplored. Here, we have identified spike-timing dependent synaptic plasticity in substantia gelatinosa (SG) neurons, using perforated patch-clamp recordings of SG neuron in a spinal cord slice preparation. In the presence of bicuculline and strychnine, long-term potentiation (LTP) was blocked by AP-5 and Ca2+ chelator BAPTA-AM. The group I mGluR antagonist AIDA, PLC inhibitor U-73122, and IP3 receptor blocker 2-APB shifted LTP to long-term depression (LTD) without affecting acute synaptic transmission. These findings provide a link between postsynaptic group I mGluR/PLC/IP3-gated Ca2+ store regulating the polarity of synaptic plasticity and spinal central sensitization.
 ...
PMID:Group I mGluR regulates the polarity of spike-timing dependent plasticity in substantia gelatinosa neurons. 1683 78

Metaplasticity refers to the activity-dependent modification of the ability of synapses to undergo subsequent potentiation or depression, and is thought to maintain homeostasis of cortical excitability. Continuous magnetic theta-burst stimulation (cTBS; 50 Hz-bursts of 3 subthreshold magnetic stimuli repeated at 5 Hz) is a novel repetitive magnetic stimulation protocol used to model changes of synaptic efficacy in human motor cortex. Here we examined the influence of prior activity on the effects induced by cTBS. Without prior voluntary motor activation, application of cTBS for a duration of 20 s (cTBS300) facilitated subsequently evoked motor potentials (MEP) recorded from APB muscle. In contrast, MEP-size was depressed, when cTBS300 was preceded by voluntary activity of sufficient duration. Remarkably, even without prior voluntary activation, depression of MEP-size was induced when cTBS was extended over 40 s. These findings provide in vivo evidence for extremely rapid metaplasticity reversing potentiation of corticospinal excitability to depression. Polarity-reversing metaplasticity adds considerable complexity to the brain's response toward new experiences. Conditional dependence of cTBS-induced depression of corticospinal excitability on prior neuronal activation suggests that the TBS-model of synaptic plasticity may be closer to synaptic mechanisms than previously thought.
 ...
PMID:Depression of human corticospinal excitability induced by magnetic theta-burst stimulation: evidence of rapid polarity-reversing metaplasticity. 1816 82

It is now accepted that dopamine plays an important neuromodulatory role in the central nervous control of respiration. D1, D2, and D4 subtypes of the receptor seem to be important players, but the assignment of various respiratory tasks to specific subtypes of the dopamine receptor is a work in progress. In the present investigation, dihydrexidine (DHD), a full dopamine receptor agonist with affinity for both D1- and D2-subtypes of receptor, was tested for its effects on inspiratory neurons and motor output and on membrane potential properties of medullary bulbospinal expiratory augmenting expiratory neurons in the pentobarbital anesthetized adult cat. The effects of DHD were compared with those of the highly selective D1-dopamine receptor (D1R) agonists SKF-38393 and 6-chloro-APB. DHD increased the intensity and duration of inspiratory motor output. Phrenic nerve discharge intensity was increased and prolonged, contributing to elevated inspiratory effort and duration when spontaneous breathing was monitored with tracheal pressure measurements. Intracellular recording from rostral medullary inspiratory neurons revealed that DHD, like SKF-38393, increases and prolongs inspiratory phase membrane depolarization, resulting in a longer and more intense discharge of action potentials. Remarkably, DHD had opposite effects on Aug-E neurons. Membrane potential was hyperpolarized, and action potential discharges were suppressed or abolished. In association with reduction of discharge intensity, action potential half width was reduced and after-hyperpolarization increased. The stimulatory action of DHD on inspiratory motor output is attributed to D1R effects, while the depression of Aug-E neurons seems to be linked to D2R actions on the postsynaptic membrane.
 ...
PMID:D1/D2-dopamine receptor agonist dihydrexidine stimulates inspiratory motor output and depresses medullary expiratory neurons. 1927 96

Paired associative transcranial magnetic stimulation (PAS) has been shown to induce long-term potentiation (LTP)-like or long-term depression (LTD)-like change in excitability of human primary motor cortex (M1), as probed by motor evoked potential (MEP) amplitude. In contrast, little is known about PAS effects on volitional motor cortical activity. In 10 healthy subjects, movement related cortical potentials (MRCP) were recorded to index volitional motor cortical activity during preparation of simple thumb abduction (prime mover: abductor pollicis brevis, APB) or wrist extension movements (prime mover: extensor carpi radialis, ECR). PAS(LTP) increased, PAS(LTD) decreased, and PAS(control) did not change MEP(APB), while MEP(ECR), not targeted by PAS, remained unchanged in all PAS conditions. PAS(LTP) decreased MRCP negativity during the late Bereitschaftspotential (-500 to 0 ms before movement onset), only in the APB task, and predominantly over central scalp electrodes contralateral to the thumb movements. This effect correlated negatively with the PAS(LTP) induced increase in MEP(APB). PAS(LTD) and PAS(control) did not affect MRCP amplitude. Findings indicate a specific interference of PAS with preparatory volitional motor cortical activity, suggestive of a net result caused by increased M1 excitability and disrupted effective connectivity between premotor areas and M1.
 ...
PMID:Modulation of preparatory volitional motor cortical activity by paired associative transcranial magnetic stimulation. 1938 89


1 2 Next >>