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)

The nucleus accumbens (NAc) of the ventral striatum is involved in attention, motivation, movement, learning, reward, and addiction. GABAergic medium spiny projection neurons that make up approximately 90% of the neuronal population are commonly driven by convergent bursts of afferent excitation. We monitored spiny projection neurons in mouse striatal slices while applying stimulus trains to mimic bursts of excitation. A stimulus train evoked a simple, short-lived postsynaptic response from CA1 hippocampal pyramidal neurons, but the train evoked a complex series of excitatory postsynaptic potentials (EPSPs) or currents (EPSCs) from the NAc spiny projection neurons. As is commonly seen with projection neurons, the EPSC amplitudes initially displayed facilitation followed by depression, and that pattern was sensitive to the extracellular calcium concentration. In addition, there were two other novel observations. The spiny projection neurons responded to the stimulus train with a prolonged depolarization that was accompanied by a posttrain increase of spontaneous glutamatergic synaptic activity. Blocking AMPA/kainate glutamate receptors strongly inhibited the evoked EPSP/EPSCs, the posttrain spontaneous synaptic activity, and the prolonged depolarization. A potassium channel inhibitor increased and extended the prolonged postsynaptic depolarization, causing a long-lasting depolarized plateau potential. Our results indicate that burst-like activity along ventral striatal afferents is extended in time by additional spontaneous glutamate release that is integrated by the postsynaptic spiny projection neurons into a prolonged depolarization. The results suggest that the posttrain quantal glutamate release helps to blend and maintain multiple afferent inputs. That convergent excitation is further integrated by the postsynaptic neuron into a prolonged depolarization that may contribute to the depolarized "up state" observed in vivo.
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PMID:Complex response to afferent excitatory bursts by nucleus accumbens medium spiny projection neurons. 1533 41

The present studies were designed to test the hypothesis that neuronal-specific protein kinase Cgamma (PKCgamma) plays a critical role in acute ethanol withdrawal hyper-responsiveness in spinal cord. Patch-clamp studies were carried out in motor neurons in neonatal rat spinal cord slices. Postsynaptic currents were evoked by brief pulses of 2 mM N-methyl-D-aspartic acid (NMDA) in the presence of bicuculline methiodide 10 microM; strychnine 5 microM and tetrodotoxin 0.5 microM. Both ethanol depression and withdrawal hyper-responsiveness of NMDA-evoked currents are dependent on increases in intracellular Ca(2+). Blocking intracellular increase in Ca(2+) by 30 mM 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA) not only decreased the ethanol-induced depression of NMDA-evoked currents (33+/-5% in control vs 20+/-3% in BAPTA, P<0.05) but also eliminated acute ethanol withdrawal hyper-responsiveness. Immunohistochemistry studies revealed that neonatal spinal cord motor neurons contain an abundance of nuclear PKCgamma. Exposure to ethanol (100 mM) induced PKCgamma translocation from the nucleus to cytoplasm in motor neurons. Pretreatment with the gamma-isozyme-specific peptide PKC inhibitor, gammaV5-3, blocked ethanol-induced translocation and also blocked withdrawal hyper-responsiveness. The results show that PKCgamma mediates ethanol withdrawal hyper-responsiveness in spinal motor neurons; the results may be relevant to some symptoms of ethanol withdrawal in vivo.
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PMID:Protein kinase Cgamma mediates ethanol withdrawal hyper-responsiveness of NMDA receptor currents in spinal cord motor neurons. 1565 32

Spreading acidification and depression (SAD) is a form of propagated activity in the cerebellar cortex characterized by acidification and a transient depression in excitability. This study investigated the role of Kv1 potassium channels in SAD using neutral red, flavoprotein autofluorescence, and voltage-sensitive dye optical imaging in the mouse cerebellar cortex, in vivo. The probability of evoking SAD was greatly increased by blocking Kv1.1 as well as Kv1.2 potassium channels by their specific blockers dendrotoxin K (DTX-K) and tityustoxin (TsTX), respectively. DTX-K not only greatly lowered the threshold for evoking SAD but also resulted in multiple cycles of spread and spontaneous SAD. The occurrence of spontaneous SAD originating from spontaneous parallel fiber-like beams of activity suggests that blocking Kv1 channels increased parallel fiber excitability. This was confirmed by the generation of parallel fiber-like beams with the microinjection of glutamate into the upper molecular layer in the presence of DTX-K. The dramatic effects of DTX-K suggest a possible connection between SAD and episodic ataxia type 1 (EA1), a Kv1.1 potassium channelopathy. The threshold for evoking SAD was significantly lowered in the Kv1.1 heterozygous knockout mouse compared with wild-type littermates. Carbamazepine and acetazolamide, both effective in the treatment of EA1, significantly decreased the likelihood of evoking SAD. Blocking GABAergic neurotransmission did not alter the effectiveness of DTX-K. The cyclin D2 null mouse, which lacks cerebellar stellate cells, also exhibited SAD. Therefore blocking Kv1 potassium channels establishes the conditions needed to generate SAD. Furthermore, the results are consistent with the hypothesis that SAD may underlie the transient attacks of ataxia characterizing EA1.
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PMID:Involvement of kv1 potassium channels in spreading acidification and depression in the cerebellar cortex. 1584 81

Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC50=18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID50: 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 microM) and intrastriatal glycine-induced rotations in mice (MED: 1 mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB1 receptors): it reversed the decrease in electrically evoked [3H]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.
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PMID:Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic. 1595 94

N-methyl-D-aspartate (NMDA)-type glutamate receptors perform critical functions during the development of the nervous system and in the initiation of synaptic plasticity. An important mechanism in setting the gain of NMDA receptors involves the stimulation of G-protein-coupled receptors (GPCRs), which through activation of protein tyrosine kinases leads to an upregulation of NMDA receptors. In contrast, little is known about how NMDA receptors are downregulated. In the present study, we characterized a signaling pathway that mediates the depression of NMDA receptor function in response to stimulation of muscarinic acetylcholine receptors. Whole-cell patch-clamp recordings obtained from CA3 pyramidal cells in organotypic slice cultures revealed that under conditions of low intracellular calcium buffering application of muscarine-depressed NMDA receptor current. The sensitivity of this response to pirenzipine indicated that the M1 acetylcholine receptor is mediating this depression. The muscarine-induced depression of NMDA current was prevented by blocking G-protein function or after depleting intracellular Ca2+ stores with cyclopiazonic acid. Inhibitors of calmodulin prevented the depression whereas blocking calcineurin enhanced the depression of NMDA currents. Blocking tyrosine phosphatase activity with pervanandate converted the muscarine-induced depression into a potentiation of NMDA currents, whereas blocking protein kinase A (H-89), Src kinase (PP2, SU6656), or PKC (GF 109203X) failed to prevent the depression of NMDA currents. As Src tyrosine kinase is known to phosphorylate and upregulate NMDA receptors, we propose that a protein tyrosine phosphatase(s) counteracting the action of Src is the final target in the mAChR-dependent inhibitory signaling cascade. Our data are consistent with a transduction cascade comprising an M1 acetylcholine receptor-->G-protein-->Ca2+ release-->calmodulin-->tyrosine phosphatase.
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PMID:Muscarinic receptor stimulation reduces NMDA responses in CA3 hippocampal pyramidal cells via Ca2+-dependent activation of tyrosine phosphatase. 1599 5

GABA(B) receptor (GABA(B)R)-mediated presynaptic inhibition regulates neurotransmitter release from synaptic terminals. In the neonatal hippocampus, GABA(B)R activation reduces GABA release and terminates spontaneous network discharges called giant depolarizing potentials (GDPs). Blocking GABA(B)Rs transforms GDPs into longer epileptiform discharges. Thus, GABA(B)R-mediated presynaptic inhibition of GABA release (GABA auto-inhibition) controls both spontaneous network activity and excitability in the developing hippocampus. Here we show that extensive release of endogenous GABA during epileptiform activity impairs GABA auto-inhibition, but not GABA(B)R-mediated inhibition of glutamate release, leading to hyperexcitability of the neonatal hippocampal network. Paired-pulse depression of GABA release (PPD) and heterosynaptic depression of glutamate release were used to monitor the efficacy of presynaptic GABA(B)R-mediated inhibition in slices. PPD, but not heterosynaptic depression, was dramatically reduced after potassium (K+)-induced ictal-like discharges (ILDs), suggesting a selective impairment of GABA(B)R-dependent presynaptic inhibition of GABAergic terminals. Impairing GABA auto-inhibition induced a 44% increase in GDP width and the appearance of pathological network discharges. Preventing GABA-induced activation of GABA(B)Rs during ILDs avoided PPD loss and most modifications of the network activity. In contrast, a partial block of GABA(B)Rs induced network discharges strikingly similar to those observed after K+-driven ILDs. Finally, neither loss of GABA auto-inhibition nor network hyperexcitability could be observed following synchronous release of endogenous GABA in physiological conditions (during GDPs at 1 Hz). Thus, epileptiform activity was instrumental to impair GABA(B)R-dependent presynaptic inhibition of GABAergic terminals. In conclusion, our results indicate that endogenous GABA released during epileptiform activity can reduce GABA auto-inhibition and trigger pathological network discharges in the newborn rat hippocampus. Such functional impairment may play a role in acute post-seizure plasticity.
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PMID:Epileptiform activity triggers long-term plasticity of GABA(B) receptor signalling in the developing rat hippocampus. 1609 37

Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system (CNS) and the periphery. Three subtypes of SK channels have so far been identified in different parts of the brain. Activation of the SK channels by a rise in intracellular calcium leads to the hyperpolarisation of the membrane, reducing cell excitability. Blocking the SK channels might be beneficial in the treatment of depression, Parkinson's disease and cognitive disorders. However, few blockers of SK channels have been characterized. In this study, a pharmacophoric model of SK channels blockers is presented. It is based on a series of nonpeptidic compounds and apamin, a peptidic blocker. To create the pharmacophore model, the conformational space of nonpeptidic blockers was investigated to generate a series of distance constraints applied to a simulated annealing study of apamin. The resulting conformation was superimposed with the nonpeptidic blockers to give a pharmacophore.
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PMID:Identification of a pharmacophore of SKCa channel blockers. 1640 87

Ventilation of the lungs is mediated by neurons of the respiratory network in the lower brainstem. The activity of rhythmogenic respiratory network neurons seems to depend greatly on cellular levels of the second messenger cAMP. Accordingly, depression of breathing in (preterm) infants associated with clinical administration of opioids and prostaglandins results likely from a fall of cAMP in these cells caused by G(i/o) proteins that are activated via mu-opiate or EP(3) prostanoid receptors, respectively. Typically, such drug-induced depression of infant breathing is treated with high doses of methylxanthines that have notable adverse effects. It was the aim of our study to investigate whether clinically applicable blockers of cAMP-hydrolyzing phosphodiesterase-4 counteract the inhibition of the respiratory network associated with a drug-induced fall of cAMP. For this purpose, inspiratory-related cervical nerve activity was measured in isolated brainstem-spinal cord preparations from newborn rats. Respiratory frequency was depressed by >80% (from >5 bursts/min to <1 burst/min) with nociceptin (1 microM) which decreases cAMP via a G(i/o) protein-coupled opioid-like receptor. The nociceptin-induced respiratory depression was reversed by the activator of adenylyl cyclase, forskolin (5-25 microM) and the phosphodiesterase-4 blockers rolipram (0.1-1 microM) and RO-201724 (1-5 microM). Blocking phosphodiesterases 3 and 5 with milrinone (25-100 microM) and zaprinast (25-100 microM), respectively, was not effective. The results indicate that phosphodiesterase-4 blockers are strong stimulants of the respiratory network. We hypothesize that these or related agents may be potent tools for a treatment of drug-induced disturbances of breathing in (preterm) infants.
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PMID:Reversal by phosphodiesterase-4 blockers of in vitro apnea in the isolated brainstem-spinal cord preparation from newborn rats. 1658 Nov 83

Oxygen withdrawal blocks mitochondrial respiration. In rat hippocampal slices, this triggers a massive depolarization of CA1 neurons and a negative shift of the extracellular DC potential, the characteristic sign of hypoxia-induced spreading depression (HSD). To unveil the contribution of mitochondria to the sensing of hypoxia and the ignition of HSD, we modified mitochondrial function. Mitochondrial uncoupling by carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP, 1 microM) prior to hypoxia hastened the onset and shortened the duration of HSD. Blocking mitochondrial ATP synthesis by oligomycin (10 microg/ml) was without effect. Inhibition of mitochondrial respiration by rotenone (20 microM), diphenyleneiodonium (25 microM), or antimycin A (20 microM) also hastened HSD onset and shortened HSD duration. 3-nitropropionic acid (1 mM) increased HSD duration. Cyanide (100 microM) hastened HSD onset and increased HSD duration. At higher concentrations, cyanide (1 mM), azide (2 mM), and FCCP (10 microM) triggered SD episodes on their own. Compared with control HSD, the spatial extent of the intrinsic optical signals of cyanide- and azide-induced SDs was more pronounced. Monitoring NADH (nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide) autofluorescence and mitochondrial membrane potential verified the mitochondrial targeting by the drugs used. Except 1 mM cyanide, no treatment reduced cellular ATP levels severely and no correlation was found between ATP, NADH, or FAD levels and the time to HSD onset. Therefore ATP depletion or a cytosolic reducing shift due to NADH/FADH2 accumulation cannot serve as a general explanation for the hastening of HSD onset on mitochondrial inhibition. Additional redox couples (glutathione) or events downstream of the mitochondrial depolarization need to be considered.
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PMID:Mitochondrial inhibition prior to oxygen-withdrawal facilitates the occurrence of hypoxia-induced spreading depression in rat hippocampal slices. 1661 42

The aim of this study was to investigate the contribution of proprioceptive feedback to the amplitude modulation of the soleus muscle activity during human walking. We have previously shown that slow-velocity, small-amplitude ankle dorsiflexion enhancements and reductions applied during the stance phase of the step cycle generate, respectively, increments and decrements on the ongoing soleus activity. We have also shown that the increments in soleus activity are at least partially mediated by feedback from group Ia fibres. In the present study, we further investigated the afferent-mediated contribution from muscle group II afferents, cutaneous and proprioceptive afferents from the foot, and load-sensitive afferents to the soleus EMG. Slow-velocity, small-amplitude ankle trajectory modifications were combined with the pharmaceutical depression of group II polysynaptic pathways with tizanidine hydrochloride, anaesthetic blocking of sensory information from the foot with injections of lidocaine hydrochloride, and modulation of load feedback by increasing and decreasing the body load. The depression of the group II afferents significantly reduced the soleus response to the ankle trajectory modifications. Blocking sensory feedback from the foot did not have an effect on the soleus muscle activity. Changes in body load affected the ongoing soleus activity level; however, it did not affect the amplitude of the soleus EMG responses to the ankle trajectory modifications. These results suggest that the feedback from group II afferents, and possibly from load-sensitive afferents, contribute to the amplitude modulation of the soleus muscle activity during the stance phase of the step cycle. However, feedback from cutaneous afferents and instrinsic proprioceptive afferents from the foot does not seem to contribute to this muscle activation.
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PMID:Afferent-mediated modulation of the soleus muscle activity during the stance phase of human walking. 1663 1


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