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)

omega-Conotoxin GVIA and omega-agatoxin IVA are specific peptide blockers of N- and P/Q-type calcium channel, respectively. Effects of their intracerebroventricular injection (1-3 pmol/mouse) on psychostimulant-induced hyperactivity were investigated in mice. omega-Conotoxin GVIA antagonized methylphenidate-, methamphetamine- and phencyclidine-induced hyperactivity in a dose-dependent manner. omega-Agatoxin IVA blocked methylphenidate-induced but not methamphetamine- or phencyclidine-induced hyperactivity. Neither peptides showed any effect on apomorphine-induced hyperactivity or spontaneous activity, suggesting that the inhibitory effects on psychostimulant-induced hyperactivity are not due to dopamine receptor blockage or nonspecific behavioral depression. Antagonism of calcium channels, particularly N-type, may ameliorate activation of the dopaminergic system induced by increased dopamine release.
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PMID:Peptide N- and P/Q-type Ca2+ blockers inhibit stimulant-induced hyperactivity in mice. 970 Jul 49

Mice were injected for 30 days with plasma from three patients with Lambert-Eaton Myasthenic Syndrome (LEMS). Recordings were made from the perineurial sheath of motor axon terminals of triangularis sterni muscle preparations. The objective was to characterize pharmacologically the identity of kinetically distinct, defined potential changes associated with motor nerve terminal Ca2+ currents (ICa) that were affected by LEMS autoantibodies. ICa elicited at 0.01 Hz were significantly reduced in amplitude by approximately 35% of control in LEMS-treated nerve terminals. During 10-Hz stimulation, ICa amplitude was unchanged in LEMS-treated motor nerve terminals, but was depressed in control. During 20- or 100-Hz trains, facilitation of ICa occurred in LEMS-treated nerve terminals whereas in control, no facilitation occurred during the trains at 20 Hz and marked depression occurred at 100 Hz. Saturation for amplitude and duration of ICa in control terminals occurred at 2 and 4-6 mM extracellular Ca2+, respectively; in LEMS-treated terminals, the extracellular Ca2+ concentration had to increase by two to three times of control to cause saturation. Amplitude of the two components of ICa observed when the preparation was exposed to 50 microM 3,4-diaminopyridine and 1 mM tetraethylammonium were both reduced by LEMS plasma treatment. The fast component (ICa,s) was reduced by 35%, whereas the slow component (ICa, s) was reduced by 37%. omega-Agatoxin IVA (omega-Aga-IVA; 0.15 microM) and omega-conotoxin-MVIIC (omega-CTx-MVIIC; 5 microM) completely blocked ICa in control motor nerve terminals. The same concentrations of toxins were 20-30% less effective in blocking ICa in LEMS-treated terminals. The residual ICa remaining after treatment with omega-Aga-IVA or omega-CTx-MVIIC was blocked by 10 microM nifedipine and 10 microM Cd2+. Thus LEMS plasma appears to downregulate omega-Aga-IVA-sensitive (P-type) and/or omega-CTx-MVIIC-sensitive (Q-type) Ca2+ channels in murine motor nerve terminals, whereas dihydropyridine (DHP)-sensitive (L-type) Ca2+ channels are unmasked in these terminals. Acute exposure (90 min) of rat forebrain synaptosomes to LEMS immunoglobulins (Igs; 4 mg/ml) did not alter the binding of [3H]-nitrendipine or [125I]-omega-conotoxin-GVIA (-omega-CgTx GVIA) when compared with synaptosomes incubated with an equivalent concentration of control Igs. Conversely, LEMS Igs significantly decreased the Bmax for [3H]-verapamil to approximately 45% of control. The apparent affinity of verapamil (KD) for the remaining receptors was not significantly altered. Thus acute exposure of isolated central nerve terminals to LEMS Igs does not increase DHP sensitivity, whereas it reduces the number of binding sites for verapamil but not for nitrendipine or omega-CgTx-GVIA. These results suggest that chronic but not acute exposure to LEMS Igs either upregulates or unmasks DHP-sensitive Ca2+ channels in motor nerve endings.
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PMID:Passive transfer of Lambert-Eaton myasthenic syndrome induces dihydropyridine sensitivity of ICa in mouse motor nerve terminals. 974 21

1. Paired recordings from monosynaptically connected CA3 interneurons and pyramidal cells of rat hippocampal slice cultures were used to compare the modulation of GABA release at synapses from distinct interneurons. 2. The group II metabotropic glutamate receptor (mGluR) agonist (2S,2'R,3'R)-2-(2',3'-dicarboxylcyclopropyl) glycine (DCG-IV, 5 muM) reduced the amplitude of IPSPs originating from stratum radiatum but not stratum oriens interneurons. In contrast, the GABAB receptor agonist (-)baclofen (10 muM) reduced the amplitude of unitary IPSPs elicited by all interneurons. 3. IPSPs mediated by stratum oriens interneurons were unaffected by the N-type calcium channel blocker omega-conotoxin MVIIA (1 muM) but were suppressed by the P/Q-type blocker omega-agatoxin IVA (200 nM). In contrast, IPSPs mediated by stratum radiatum interneurons were abolished by omega-conotoxin MVIIA. 4. Transmission dynamics were different at synapses from the two groups of interneurons. IPSPs mediated by stratum oriens interneurons showed marked paired-pulse depression (PPD) at intervals of 50 400 ms. IPSPs mediated by stratum radiatum interneurons showed paired-pulse facilitation (PPF) at 50 ms and PPD at longer intervals. 5. The amplitude of unitary IPSPs from all interneurons was unaffected by the GABAB receptor antagonist CGP52432 (2 muM) as was PPD at both 50 and 400 ms intervals. However, CGP52432 did reduce PPD of extracellularly evoked IPSPs. 6. Our results show that two groups of inhibitory synapses impinging onto CA3 pyramidal cells can be distinguished according to their dynamic and modulatory properties.
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PMID:Differential control of GABA release at synapses from distinct interneurons in rat hippocampus. 1101 11

High pressure induces CNS hyperexcitability while markedly depressing synaptic transmitter release. We studied the effect of pressure (up to 10.1 MPa) on the parallel fibre (PF) synaptic response in biplanar cerebellar slices of adult guinea pigs. Pressure mildly reduced the PF volley amplitude and to a greater extent depressed the excitatory field postsynaptic potential (fPSP). The depression of the PF volley was noted even at supramaximal stimulus intensities, indicating an effect of pressure on the amplitude of the action potential in each axon. Low concentrations of TTX mimicked the effects of pressure on the PF volley without affecting the fPSP. Application omega-conotoxin GVIA (omega-CgTx) reduced the synaptic efficacy by 34.3+/-2.7%. However, in the presence of omega-CgTx the synaptic depression at pressure was significantly reduced. Reduced Ca2+ entry by application of Cd2+ or low [Ca2+]o did not have a similar influence on the effects of pressure. Application of omega-AGA IVA, omega-AGA TK and Funnel-web spider toxin did not affect the synaptic response in concentrations that usually block P-type Ca2+ channels, whilst the N/P/Q-type blocker omega-conotoxin MVIIC reduced the response to 52.7+/-5.0% indicating the involvement of Q-type channels and R-type channels in the non-N-type fraction of Ca2+ entry. The results demonstrate that N-type Ca2+ channels play a crucial role in the induction of PF synaptic depression at pressure. This finding suggests a coherent mechanism for the induction of CNS hyperexcitability at pressure.
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PMID:Pressure-induced depression of synaptic transmission in the cerebellar parallel fibre synapse involves suppression of presynaptic N-type Ca2+ channels. 1106 97

This study investigated the involvement of N- and P/Q-type Ca(2+) channels in sensorimotor transmission and synaptic depression in the in vitro neonatal rat spinal cord preparation. Postsynaptic potentials were intracellularly recorded from spinal motoneurones during stimulation of the dorsal roots. We found that omega-agatoxin-IVA (P/Q-type Ca(2+) channels blocker), omega-conotoxin-GVIA (N-type Ca(2+) channel blocker) and omega-conotoxin-MVIIC (N-, P/Q-type Ca(2+) channel blocker) markedly decreased both poly- and monosynaptic potentials. We also found that the frequency-dependent depression which occurred in the monosynaptic response, for stimulus intervals shorter than 30 s, persisted in the presence of the various Ca(2+) channels blockers. Hyperpolarizing the motoneurons significantly reduced depression, suggesting contribution from some additional postsynaptic mechanisms. We conclude that at birth, as in adult central nervous system (CNS) synapses, several types of voltage dependent calcium channels mediate sensorimotor neurotransmission and that synaptic depression, which is characteristic of neonatal sensorimotor transmission, does not involve these Ca(2+) channels.
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PMID:N- and P/Q-type Ca(2+) channels are involved in neurotransmitter release but not in synaptic depression in the spinal cord of the neonatal rat. 1107 29

Lamprey spinal cord neurons possess N-, L-, and P/Q-type high-voltage-activated (HVA) calcium channels. We have analyzed the role of the different HVA calcium channels subtypes in the overall functioning of the spinal locomotor network by monitoring the influence of their specific agonists and antagonists on synaptic transmission and on N-methyl-D-aspartate (NMDA)-elicited fictive locomotion. The N-type calcium channel blocker omega-conotoxin GVIA (omega-CgTx) depressed synaptic transmission from excitatory and inhibitory interneurons. Blocking L-type and P/Q-type calcium channels with nimodipine and omega-agatoxin, respectively, did not affect synaptic transmission. Application of omega-CgTx initially decreased the frequency of the locomotor rhythm, increased the burst duration, and subsequently increased the coefficient of variation and disrupted the motor pattern. These effects were accompanied by a depression of the synaptic drive between neurons in the locomotor network. Blockade of L-type channels by nimodipine also decreased the frequency and increased the duration of the locomotor bursts. Conversely, potentiation of L-type channels increased the frequency of the locomotor activity and decreased the duration of the ventral root bursts. In contrast to blockade of N-type channels, blockade or potentiation of L-type calcium channels had no effect on the stability of the locomotor pattern. The P/Q-type calcium channel blocker omega-agatoxin IVA had little effect on the locomotor frequency or burst duration. The results indicate that rhythm generation in the spinal locomotor network of the lamprey relies on calcium influx through L-type and N-type calcium channels.
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PMID:Roles of high-voltage-activated calcium channel subtypes in a vertebrate spinal locomotor network. 1111 Aug 6

The nucleus accumbens (NAc) is an important cerebral area involved in reward and spatial memory (Pennartz et al., 1994), but little is known about synaptic plasticity in this region. Here, electron microscopy revealed that, in the NAc, metabotropic glutamate receptors 2/3 (mGlu2/3) immunostaining was essentially associated with axonal terminals and glial processes, whereas postsynaptic dendrites and neuronal cell bodies were unstained. Electrophysiological techniques in the NAc slice preparation demonstrated that activation of mGlu2/3 with synaptically released glutamate or specific exogenous agonist, such as LY354740 (200 nm, 10 min), induced long-term depression of excitatory synaptic transmission (mGlu2/3-LTD). Tetanic-LTD and pharmacological mGlu2/3-LTD occluded each other, suggesting common mechanisms. The mGlu2/3-LTD did not require synaptic activity but depended on the cAMP-protein kinase A cascade. Selective inhibition of P/Q-type Ca(2+) channels with omega-agatoxin-IVA occluded the expression of mGlu2/3-LTD, and, conversely, the inhibitory effects of omega-agatoxin-IVA were abolished during mGlu2/3-LTD. Thus, mGlu2/3 play an important role in the control of use-dependent synaptic plasticity at prelimbic cortex-NAc synapses: their activation causes a form of LTD mediated by the long-lasting reduction of P/Q-type Ca(2+)channels contribution to transmitter release.
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PMID:Role of p/q-Ca2+ channels in metabotropic glutamate receptor 2/3-dependent presynaptic long-term depression at nucleus accumbens synapses. 1204 40

Neurotrophic factors yield neuroprotection by mechanisms that may be related to their effects as inhibitors of apoptosis as well as their effects on ion channels. The effect of ciliary neurotrophic factor (CNTF) on high-threshold voltage-activated Ca channels in cultured fetal mouse brain cortical neurones was investigated. Addition of CNTF into serum-free growth medium resulted in delayed reduction of the Ca2+ currents. The currents decreased to 50% after 4 h and stabilized at this level during incubation with CNTF for 48 h. Following removal of CNTF the inhibition was completely reversed after 18 h. CNTF reduced the current of all pharmacological subtypes of Ca channels as shown by use of selective blockers of L, N, and P/Q type Ca channels (nifedipine, omega-conotoxin MVIIA, omega-agatoxin IVA). The Ca channel depression was mediated via the CNTF receptor, because enzymatic cleavage of the alpha-subunit glycerophosphatidylinositol anchor of the receptor eliminated the response. The CNTF effect was not elicited through pertussis toxin-sensitive G proteins. Other neurotrophic factors like neurotrophin-3 and insulin-like growth factor-I had no effect on the Ca2+ currents. These results may have important implications for the possible functions of CNTF in the nervous system, such as altered synaptic activity, neuronal excitability and susceptibility to brain ischaemia.
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PMID:CNTF inhibits high voltage activated Ca2+ currents in fetal mouse cortical neurones. 1215 74

Activation of adrenoreceptors modulates synaptic transmission in the basolateral amygdala. Here, we investigated the effects of alpha2-adrenoreceptor activation on long-term depression and long-term potentiation in an in vitro slice preparation of the mouse basolateral amygdala. Field potentials and excitatory postsynaptic currents were evoked in the basolateral amygdala by stimulating the lateral amygdala. Norepinephrine (20 micro m) reduced synaptic transmission and completely blocked the induction of long-term potentiation and long-term depression. The alpha2-adrenoreceptor antagonist yohimbine (2 micro m) reversed this effect. The alpha2-adrenoreceptor agonist clonidine (10 micro m) mimicked the effects of norepinephrine. The Gi/o-protein inhibitor pertussis toxin (5 micro g/mL) reversed the effect of clonidine. Long-term depression was blocked in the presence of omega-conotoxin GVIA, but not omega-agatoxin IVA. Clonidine inhibited voltage-activated Ca2+ currents mediated via N- or P/Q-type Ca2+-channels. The inhibitory action of clonidine on long-term depression was reversed when inwardly rectifying K+-channels were blocked by Ba2+ (300 micro m). The present data suggest that alpha2-adrenoreceptor activation impairs the induction of long-term depression in the basolateral amygdala by a Gi/o-protein-mediated inhibition of presynaptic N-type Ca2+-channels and activation of inwardly-rectifying K+-channels.
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PMID:Alpha2-adrenoreceptor activation inhibits LTP and LTD in the basolateral amygdala: involvement of Gi/o-protein-mediated modulation of Ca2+-channels and inwardly rectifying K+-channels in LTD. 1271 44

Ca2+ channels and pyramidal cell Ca2+ are involved in hippocampal spreading depression (SD), but their roles remain elusive. Accordingly, we characterized Ca2+ changes during SD in CA3 pyramidal neurons and determined whether Ca2+ channel antagonists could prevent SD. SD was induced in hippocampal organotypic cultures (HOTCs), in which experimental conditions can be rigorously controlled. SD was triggered by transient exposure to sodium acetate (NaAc)-based Ringer's coupled to an electrical pulse in the dentate gyrus and its occurrence confirmed with interstitial DC recordings. Pyramidal cell Ca2+ was measured with fura-2 filled cells and was quantified at the soma, proximal and more distal apical dendrites. Regional Ca2+ changes began simultaneously with the triggering pulse of SD and reached three distinct peaks before returning to baseline concomitant with the interstitial DC potential of SD. The first peak occurred within 5 s of the triggering pulse, was smallest, and heralded the onset of SD. The second Ca2+ change was the greatest and reached a peak 6 s later, during the early phase of SD. The third was intermediate in size and occurred 18 s later, as SD reached its maximum interstitial DC change. SD was prevented by nonselective Ca2+ blockade (Ni2+ and Cd2+) but not by either L-Ca2+ channel (nifedipine) or N-Ca2+ channel inhibition (omega-conotoxin GVIA). Importantly, SD was blocked by P/Q Ca2+ channel antagonism (omega-agatoxin-IVA), which also prompted a significant reduction in pyramidal cell Ca2+ change and hyperexcitability. These results show that the spatiotemporal pattern of pyramidal cell Ca2+ change with SD is multiphasic; they provide further evidence that these changes begin before electrophysiologic evidence of SD. Furthermore, they show that P/Q Ca2+ channel antagonism can prevent SD in HOTCs and it appears to do so by preventing the NaAc-induced increased pyramidal cell excitability from NaAc exposure, which may involve altered GABAergic transmission.
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PMID:P/Q Ca2+ channel blockade stops spreading depression and related pyramidal neuronal Ca2+ rise in hippocampal organ culture. 1513 35


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