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)

Glutamate-gated ion channels mediate most excitatory synaptic transmission in the central nervous system and play crucial roles in synaptic plasticity, neuronal development and some neuropathological conditions. These ionotropic glutamate receptors have been classified according to their preferred agonists as NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) and KA (kainate) receptors. On the basis of sequence similarity and pharmacological properties, the recently cloned glutamate receptor subunits have been assigned as components of NMDA (NMDAR1, 2A-D), AMPA (GluR1-4) and KA (GluR5-7, KA1, KA2) receptors. Protein phosphorylation of glutamate receptors by protein kinase C and cyclic AMP-dependent protein kinase (PKA) has been suggested to regulate their function, possibly playing a prominent role in certain forms of synaptic plasticity such as long-term potentiation and long-term depression. Here we report that the GluR6 glutamate receptor, transiently expressed in mammalian cells, is directly phosphorylated by PKA, and that intracellularly applied PKA increases the amplitude of the glutamate response. Site-specific mutagenesis of the serine residue (Ser 684) representing a PKA consensus site completely eliminates PKA-mediated phosphorylation of this site as well as the potentiation of the glutamate response. These results provide evidence that direct phosphorylation of glutamate receptors modulates their function.
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PMID:Phosphorylation and modulation of recombinant GluR6 glutamate receptors by cAMP-dependent protein kinase. 809 92

Spinal cords were maintained in vitro and suction electrodes used to record activity in lumbar 4 or 5 ventral roots. Stimulation of the latero-ventral aspect of the thoracic cord elicited fast and slow responses on the same and on the opposite side of the cord. There were 5 distinct responses: ipsilaterally a short latency (d ISL), a polysynaptic and a slow response, and contralaterally a fast (d CON FAST) and a slow response. The largest amplitude component, d ISL, may arise from stimulation of propriospinal neurones; the other responses may arise from stimulation of descending pathways. The slow responses had half decay times of 13-15 s and required a high intensity stimulus to elicit a maximal response. All 5 responses were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione suggesting that kainate/AMPA receptors were involved in their generation. In addition, NMDA receptors were involved in generation of the slow responses. Potentiation of certain responses by the 5-HT2 antagonists, ketanserin, ritanserin and Lilly 53837, indicated that endogenous 5-HT was exerting a modulatory depression of these responses. In addition to eliciting the 5 responses, thoracic cord stimulation caused an inhibition of segmental reflexes evoked from the lumbar dorsal root. Exogenous 5-HT, 8-hydroxy-2-(di-n-propylamino) tetralin, 5-carboxamidotryptamine, dipropyl-5-carboxamido-tryptamine and methysergide depressed all or some of the descending responses. Blockade of adrenoceptors using yohimbine, idazoxan, prazosin or propranolol had no unequivocal effect suggesting that the release of endogenous catecholamines was minimal. Clonidine was a potent depressant of the slow responses.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The pharmacology of descending responses evoked by thoracic stimulation in the neonatal rat spinal cord in vitro. 810 94

Synaptic transmission between dorsal root afferents and neurons in the superficial laminae of the spinal dorsal horn (laminae I-III) was examined by intracellular recording in a transverse slice preparation of rat spinal cord. Brief high-frequency electrical stimulation (300 pulses at 100 Hz) of primary afferent fibers produced a long-term potentiation (LTP) or a long-term depression (LTD) of fast (monosynaptic and polysynaptic) EPSPs in a high proportion of dorsal horn neurons. Both the AMPA and the NMDA receptor-mediated components of synaptic transmission at the primary afferent synapses with neurons in the dorsal horn can exhibit LTP and LTD of the synaptic responses. In normal and neonatally capsaicin-treated rats, the induction of LTP requires the activation of NMDA receptor-gated conductances. The induction of LTP or LTD, however, was not abolished in the presence of bicuculline, a GABAA receptor antagonist. The results demonstrate that distinct and long-lasting modulation in synaptic efficiency can be induced at primary afferent synapses with neurons in the superficial laminae of spinal dorsal horn by high-frequency stimulation of dorsal root afferents and that these changes may be physiologically relevant for transmission and integration of sensory information, including pain.
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PMID:Long-term potentiation and long-term depression of primary afferent neurotransmission in the rat spinal cord. 825 70

Cerebellar long-term depression is a persistent, input-specific attenuation of the parallel fiber-Purkinje neuron synapse induced by co-activation of parallel fibers and climbing fibers. This phenomenon endows the Purkinje neuron with a powerful associative computational ability. Recent investigations have provided strong evidence that two mechanisms, Ca2+ influx via voltage-gated channels, and stimulation of protein kinase C via metabotropic receptor activation, are required for induction of long-term depression. In addition, two other mechanisms, Na+ influx via AMPA receptors, and stimulation of a nitric oxide/cGMP cascade may also be involved in this process.
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PMID:Cellular mechanisms of long-term depression in the cerebellum. 836 30

Most reported actions of kainate are mediated by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) receptors. Here we report that, unlike AMPA which stimulates, kainate elicits a dose-dependent decrease in L-glutamate release from rat hippocampal synaptosomes and also depresses glutamatergic synaptic transmission. Brief exposure to kainate inhibited Ca(2+)-dependent [3H]L-glutamate release by up to 80%. Inhibition was reversed by kainate antagonists but not by the AMPA-selective non-competitive antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466). A corresponding reversible kainate-evoked depression of NMDA (N-methyl-D-aspartate) receptor-mediated excitatory postsynaptic currents (e.p.s.cs) was observed when AMPA receptors were blocked by GYKI 52466. The synaptic depression was preceded by a brief period of enhanced release and a small inward current was also observed. The effects of kainate were unaffected by metabotropic glutamate (mGlu), GABAA, GABAB, glycine and adenosine receptor antagonists. These results indicate that glutamate release can be modulated directly by kainate autoreceptors.
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PMID:Regulation of glutamate release by presynaptic kainate receptors in the hippocampus. 853 45

Theta burst stimulation (TBS) produces an extremely stable form of long-term potentiation (LTP). In contrast, a brief episode of single-pulse stimulation at theta frequency [theta pulse stimulation (TPS)] has been demonstrated to reverse LTP in area CA1 of slices and freely moving animals without causing depression when administered to nonpotentiated pathways. The present in vitro studies confirm these results and establish that the susceptibility of LTP to reversal and the degree of depotentiation are time-dependent. Specifically, a 1 min train of TPS delivered 30 sec after LTP induction produced an almost complete and lasting depotentiation but had increasingly less impact at longer delays and virtually no effect at 30 min. Increasing the duration of TPS did not cause more depotentiation. However, pharmacological facilitation of AMPA receptor-mediated currents significantly enhanced the strength of the reversal process and allowed TPS to produce robust depotentiation up to 30 min after LTP induction. The reversal effect was selective to potentiated synapses receiving TPS, was reversible, and was not blocked by NMDA receptor antagonism. Additional experiments indicated that AMPA receptor facilitation promotes depotentiation by enhancing an active process triggered by TPS that reverses expression without extending the time course of consolidation. These results suggest that the mechanisms responsible for LTP reversal are linked to the amplitude and/or duration of fast excitatory currents mediated by synaptic AMPA receptors and are effective up to the completion of LTP stabilization.
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PMID:Factors regulating the reversibility of long-term potentiation. 855 65

GYKI 52466, a non-competitive AMPA/kainate glutamate receptor antagonist, administered in graded doses (0.5-8 mg/kg, i.v.) at 10 min intervals, decreased the amplitude and duration of reflex bladder contractions (maximal inhibition = 63%), the intercontraction interval (maximal inhibition = 83%) and external urethral sphincter activity (maximal inhibition = 91%) in urethane-anesthetized (1.2 g/kg, s.c.) intact rats during continuous transurethral cystometrograms. On the other hand, in unanesthetized decerebrate rats, the drug did not alter reflex bladder activity but did produce a significant depression of sphincter activity (maximal inhibition = 59%). The depressant effects of single doses of GYKI 52466 (4 mg/kg, i.v.) on external urethral sphincter EMG activity occurred with similar time courses in both urethane-anesthetized (1.2 g/kg, s.c.) intact and unanesthetized decerebrate rats during continuous transurethral cystometrograms. In urethane-treated (0.6 g/kg, i.p.) decerebrate rats, GYKI 52466 (0.5-4 mg/kg, i.v.) depressed bladder contraction amplitude and sphincter EMG activity, similar to the effects in urethane-anesthetized (1.2 g/kg, s.c.) intact rats. CNQX (0.01-1 mg/kg, i.v.), a competitive AMPA/kainate receptor antagonist, administered to urethane-anesthetized (1.2 g/kg, s.c.) intact or unanesthetized decerebrate rats did not alter the bladder or the external urethral sphincter activity during continuous transurethral cystometrograms, possibly due to the inability of the drug to readily cross the blood-brain barrier. The present results indicate that glutamatergic excitatory transmission mediated by AMPA/kainate receptors is essential for the activation of external urethral sphincter activity during micturition in anesthetized and unanesthetized preparation. However, the depressant effect of GYKI 52466 on reflex bladder activity is only unmasked by urethane anesthesia, raising the possibility that urethane interacts with AMPA/kainate glutamate receptors in the spinobulbospinal micturition reflex pathway.
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PMID:Effects of GYKI 52466 and CNQX, AMPA/kainate receptor antagonists, on the micturition reflex in the rat. 859 52

Long-term depression (LTD) at the parallel fiber-Purkinje cell synapse in the cerebellum is a well-known example of synaptic plasticity. Although LTD is thought to reflect an enduring loss of postsynaptic AMPA receptor sensitivity, the underlying mechanisms are unclear. Protein-tyrosine kinases (PTKs) are able to modulate ionotropic receptor function and are enriched in Purkinje cells. Using intracellular recording from Purkinje cells, it is shown that two structurally and mechanistically distinct PTK inhibitors, lavendustin A and herbimycin A, block LTD induced by pairing parallel fiber stimulation with postsynaptic Ca2+ spiking. Intracellular application of the protein kinase C (PKC) activator, (-)-indolactam V, consistently depressed parallel fiber-Purkinje cells EPSPs and occluded pairing-induced LTD. Herbimycin A nullified the run-down produced by (-)-indolactam V. These data suggest that PTKs are necessary for LTD at the parallel fiber-Purkinje cell synapse and that PKC-induced synaptic depression requires PTK activity.
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PMID:Tyrosine kinase is required for long-term depression in the cerebellum. 860 98

The effects of a benzoyl-piperidine drug (BDP) that facilitates AMPA receptor-mediated synaptic responses were tested on the acquisition and retention of long-term memory at dosages that had no detectable effects on a variety of performance measures. BDP-12 produced a dose-dependent suppression of exploratory activity in rats with statistically reliable effects occurring at 50 mg/kg (i.p.). The drug had no effects on balance beam performance at 30 mg/kg but at 45 mg/kg reduced the number of crossings made within a session; it did not, however, affect the time required to perform a traversal. The performance of well-trained rats presented with a familiar pair of odors (correct and incorrect) was not not detectably altered by BDP-12 at 30 mg/kg; however, the number of correct responses made in a five-trial test was reduced at 45 mg/kg. These results indicate that the AMPA receptor modulator at 30 mg/kg has little influence on arousal, motivation, sensori-motor processing, and attention; higher dosages cause a depression of learned and unlearned prepotent responses. The effects of the lower concentration were tested on two-odor discrimination learning in rats that had extensive training on the task. The animals (n = 20) were given three or five acquisition trials with novel odor pairs immediately after an injection of drug or vehicle and then tested 1-3 d later for retention in five unrewarded probe trials. Retention performance was not significantly better than chance 52.6 +/- 4.5% correct) for odors learned on vehicle injection days but was well above chance for odors learned on drug injection days (70.6 +/- 4.2% correct). Within-subject comparisons confirmed the memory enhancing effect of BDP-12 (p < 0.01). Analyses of performance during five training trials indicated that the rats made more correct responses on days on which they were given the drug than on days on which they were injected with vehicle (p < 0.02). Within-subject differences in acquisition were correlated with differences in retention (r = 0.70). There were no evident effects of the drug on response latencies during acquisition. These results suggest that AMPA receptor modulators reduce the amount of training needed for the formation of long-term memory and do so at dosages which have little effect on variables that secondarily influence acquisition. Possible reasons for this selectivity are discussed.
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PMID:Facilitation of olfactory learning by a modulator of AMPA receptors. 861 39

To understand how the cerebellum adaptively times the classically conditioned nictitating membrane response (NMR), a model of the metabotropic glutamate receptor (mGluR) second messenger system in cerebellar Purkinje cells is constructed. In the model, slow responses, generated postsynaptically by mGluR-mediated phosphoinositide hydrolysis and calcium release from intracellular stores, bridge the interstimulus interval (ISI) between the onset of parallel fiber activity associated with the conditioned stimulus (CS) and climbing fiber activity associated with unconditioned stimulus (US) onset. Temporal correlation of metabotropic responses and climbing fiber signals produces persistent phosphorylation of both AMPA receptors and Ca(2+)-dependent K+ channels. This is responsible for long-term depression (LTD) of AMPA receptors. The phosphorylation of Ca(2+)-dependent K+ channels leads to a reduction in baseline membrane potential and a reduction of Purkinje cell population firing during the CS-US interval. The Purkinje cell firing decrease disinhibits cerebellar nuclear cells, which then produce an excitatory response corresponding to the learned movement. Purkinje cell learning times the response, whereas nuclear cell learning can calibrate it. The model reproduces key features of the conditioned rabbit NMR: Purkinje cell population response is timed properly; delay conditioning occurs for ISIs of up to 4 sec, whereas trace conditioning occurs only at shorter ISIs; mixed training at two different ISIs produces a double-peaked response; and ISIs of 200-400 msec produce maximal responding. Biochemical similarities between timed cerebellar learning and photoreceptor transduction, and circuit similarities between the timed cerebellar circuit and a timed dentate-CA3 hippocampal circuit, are noted.
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PMID:Metabotropic glutamate receptor activation in cerebellar Purkinje cells as substrate for adaptive timing of the classically conditioned eye-blink response. 864 19


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