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)

Several neurotransmitters, including GABA acting at presynaptic GABA(B) receptors, modulate glutamate release at synapses between hippocampal mossy fibers and CA3 pyramidal neurons. This phenomenon gates excitation of the hippocampus and may therefore prevent limbic seizure propagation. Here we report that status epilepticus, triggered by either perforant path stimulation or pilocarpine administration, was followed 24 hr later by a loss of GABA(B) receptor-mediated heterosynaptic depression among populations of mossy fibers. This was accompanied by a decrease in the sensitivity of mossy fiber transmission to the exogenous GABA(B) receptor agonist baclofen. Autoradiography revealed a reduction in GABA(B) receptor binding in the stratum lucidum after status epilepticus. Failure of GABA(B) receptor-mediated modulation of mossy fiber transmission at mossy fibers may contribute to the development of spontaneous seizures after status epilepticus.
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PMID:Plasticity of GABA(B) receptor-mediated heterosynaptic interactions at mossy fibers after status epilepticus. 1467 2

The peptide cholecystokinin (CCK) is abundant in the rat nucleus accumbens (NAc). Although it is colocalized with dopamine (DA) in afferent terminals in this region, neurochemical and behavioural reports are equally divided as to whether CCK enhances or diminishes DA's actions in this nucleus. To better understand the role of this peptide in the physiology of the NAc, we examined the effects of CCK on excitatory synaptic transmission and tested whether these are dependent on DA and/or other neuromodulators. Using whole-cell recording in rat forebrain slices containing the NAc, we show that sulphated CCK octapeptide (CCK-8S), the endogenously active neuropeptide, consistently depolarized cells and depressed evoked excitatory postsynaptic currents (EPSCs) in the rostral NAc. It caused a reversible, dose-dependent decrease in evoked EPSC amplitude that was accompanied by an increase in the decay constant of the EPSC but with no apparent change in paired pulse ratio. It was mimicked by unsulphated CCK-8 (CCK-8US), a CCK(B) receptor-selective agonist, and blocked by LY225910, a CCK(B) receptor-selective antagonist. Both CCK-8S and CCK-8US induced an inward current with a reversal potential around -90 mV that was accompanied by an increase in input resistance and action potential firing. The CCK-8S-induced EPSC depression was slightly reduced in the presence of SCH23390 but not in the presence of sulpiride or 8-cyclopentyltheophylline. By contrast, it was completely blocked by CGP55845, a potent GABA(B) receptor-selective antagonist. These results indicate that CCK excites NAc cells directly while depressing evoked EPSCs indirectly, mainly through the release of GABA.
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PMID:Cholecystokinin activates CCKB receptors to excite cells and depress EPSCs in the rat rostral nucleus accumbens in vitro. 1467 85

Although there is much evidence for a role of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the pathophysiology of anxiety and depression, the role of GABA(B) receptors in behavioral processes related to these disorders has not yet been fully established. GABA(B) receptors are G-protein-coupled receptors, which act as functional heterodimers made up of GABA(B(1)) and GABA(B(2)) subunits. Using recently generated GABA(B(1)) -/- mice, which lack functional GABA(B) receptors, and pharmacological tools we assessed the role of GABA(B) receptors in anxiety- and antidepressant-related behaviors. In the light-dark box, GABA(B(1)) -/- mice were more anxious than their wild-type littermates (less time spent in the light; reduced number of transitions). GABA(B(1)) -/- mice were also more anxious in the staircase test. Conversely, acute and chronic treatment with GS39783, a novel GABA(B) receptor positive modulator, decreased anxiety in the light-dark box and elevated zero maze tests for anxiety. On the other hand, GABA(B(1)) -/- mice had decreased immobility (antidepressant-like behavior) in the forced swim test (FST). These behavioral effects are unrelated to alterations in locomotor activity. In confirmation of the genetic data, acute and chronic treatment with CGP56433A, a selective GABA(B) receptor antagonist, also decreased immobility in the FST, whereas GS39783 did not alter this behavior. Taken together, these data suggest that positive modulation of the GABA(B) receptor may serve as a novel therapeutic strategy for the development of anxiolytics, whereas GABA(B) receptor antagonism may serve as a basis for the generation of novel antidepressants.
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PMID:Genetic and pharmacological evidence of a role for GABA(B) receptors in the modulation of anxiety- and antidepressant-like behavior. 1503 62

GABA(B) agonists inhibit excitatory transmission to hippocampal CA3 neurons during low frequency stimulation. We examined whether GABA(B) receptor activation can also enhance synaptic efficacy, when investigated at an input with high initial release probability. Short-term depression of field excitatory postsynaptic potential (EPSP) amplitude was observed during trains of stimuli applied to associational/commissural inputs (10-50 Hz; 22 degrees C). Baclofen (10 microM) reduced the amplitude of initial EPSPs in a train, and also reduced the degree of short-term depression. EPSPs recorded late in a train were significantly larger in baclofen than those recorded in control solution. These dual effects were mimicked by another selective GABA(B) agonist (SKF 97541, 10 microM), and abolished by a GABA(B)-selective antagonist (SCH 50911, 20 microM). The effects of baclofen were similar at a higher recording temperature (32 degrees C), where short-term depression was observed at higher stimulation frequencies. These results are consistent with the idea that a reduction of transmitter release probability could increase the fidelity of high-frequency transmission at this input, an effect that could help account for excitatory effects of GABA(B) agonists in some seizure models.
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PMID:GABA(B)-receptor modulation of short-term synaptic depression at an excitatory input to murine hippocampal CA3 pyramidal neurons. 1523 71

We have previously reported that, depending on the dose, nitric oxide (NO)-generating agents exert a dual facilitatory and inhibitory action on glutamatergic transmission on the rostral ventrolateral medulla (RVLM) neurons. The molecular mechanisms underlying the NO-mediated synaptic inhibition have not yet been defined. Here we show that the amplitude of excitatory postsynaptic currents (EPSCs) was reversibly reduced by the NO donors 3-morpholinylsydnoneimine (SIN-1) (1 mM) and spermine NONOate (1 mM). This effect was antagonized by an active peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride, G(i/o)-coupled receptor blockers, N-ethylmaleimide and pertussis toxin, A(1) adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, or adenosine deaminase. However, NO-sensitive guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, GABA(B) receptor antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911), or cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A) had no effect on the inhibitory action of SIN-1 on EPSCs. Perfusion of adenosine mimicked and subsequently occluded the action of SIN-1. Inhibition of EPSC amplitude by SIN-1 was associated with an increase in the paired-pulse ratio of EPSCs. Furthermore, SIN reduced the frequency of spontaneous EPSCs without altering their amplitude of distribution. Pretreatment with N-type Ca(2+)-channel blocker omega-conotoxin GVIA selectively blocked SIN-1-induced inhibition of EPSCs. These results suggest that a higher dose of SIN-1 acts presynaptically to elicit a synaptic depression on the RVLM neurons through an inhibition of presynaptic N-type Ca(2+)-channel activity, leading to reduced glutamate release. The presynaptic action of SIN-1 is mediated by the formation of peroxynitrite, which subsequently acts to release adenosine to activate A(1) adenosine receptors.
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PMID:3-Morpholinylsydnonimine inhibits glutamatergic transmission in rat rostral ventrolateral medulla via peroxynitrite formation and adenosine release. 1532 40

There is an emerging body of data purporting a role of gamma-aminobutyric acid (GABA) in the pathophysiology of mood disorders. However, the role of metabotropic GABA(B) receptors in depression is not well defined. The modified forced swim test has recently emerged as an excellent tool to assess behaviorally the role of monoamines in antidepressant action. To assess the role of GABA(B) receptors in antidepressant-related behavior, we examined a number of selective GABA(B) receptor ligands (novel positive modulators and antagonists) on behavior in the modified forced swim test. We demonstrate that the selective GABA(B) receptor antagonists CGP56433A [[3-{1-(S)-[{3-cyclohexylmethyl)hydroxy phosphinyl}-2-(S) hydroxy propyl]amino}ethyl]benzoic acid; 1-10 mg/kg] and [3-[[1-(S)-3-dichlorophenyl)ethyl]amino]-2-(S)-hydroxy-propyl]phenylmethyl-phosphinic acid hydrochloride; 3-10 mg/kg] had a similar profile to the selective serotonin reuptake inhibitor fluoxetine; they decreased immobility and increased swimming behavior. The tricyclic antidepressant desipramine decreased immobility but increased climbing behavior. In contrast, the novel GABA(B) receptor-positive modulator GS39783 (10-40 mg/kg) did not display antidepressant-like activity in the modified forced swim test. To further assess the possible interaction between GABA(B) receptor antagonism and serotonin, rats were pretreated with the tryptophan hydroxylase inhibitor para-chlorophenylalanine. 5-Hydroxytryptamine depletion (>90%) abolished the antidepressant-like behavior of CGP56433A (10 mg/kg) by attenuating the increase in swimming. Together, these data demonstrate that GABA(B) receptor antagonists via an interaction with the serotonergic system display antidepressant-like properties and therefore represent a novel approach for the treatment of depression.
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PMID:GABAB receptor antagonist-mediated antidepressant-like behavior is serotonin-dependent. 1533 77

The hypothesis that plastic changes in the efficacy of excitatory neurotransmission occur in areas of chronic cortical injury was tested by assessing short-term plasticity of evoked excitatory synaptic currents (EPSCs) in neurons of partially isolated neocortical islands (undercut cortex). Whole cell recordings were obtained from layer V pyramidal neurons of sensorimotor cortical slices prepared from P36-P43 control and undercut rats. AMPA/kainate receptor-mediated EPSCs elicited by stimuli delivered at 40 to 66.7 Hz exhibited more paired-pulse depression (PPD) in undercut cortex than control, the time constant of depression evoked by trains of 20- to 66.7-Hz stimuli was faster, and the steady-state amplitude of EPSCs reached after five to seven EPSCs was lower. An antagonist of the glutamate autoreceptor, group II mGluR, increased the steady-state amplitude of EPSCs from undercut but not control cortex, suggesting that activation of presynaptic receptors by released glutamate is more prominent in undercut cortex. In contrast, the GABA(B) receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl)phosphinic acid had no effect. Increasing [Ca(2+)](o) from 2 to 4 mM increased PPD, with a smaller effect in neurons of the undercut. The I-V relationship of AMPA/kainate receptor-mediated EPSCs was close to linear in both control and undercut neurons, and spermine had no significant effect on the EPSCs, suggesting that decreases in postsynaptic glutamate receptors containing the GluR2 subunit were not involved in the alterations in short-term plasticity. Results are compatible with an increase in the probability of transmitter release at excitatory synapses in undercut cortex due to functional changes in presynaptic terminals.
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PMID:Cortical injury affects short-term plasticity of evoked excitatory synaptic currents. 1534 19

Laboratory and clinical studies suggest that depression is associated with changes in the hippocampus and that this brain region is a major target for antidepressant drugs. Given the data suggesting that GABA(B) receptor antagonists display antidepressant properties, the present study was undertaken to assess the effect of antidepressant administration on GABA(B) receptors in the rat hippocampus to determine whether changes in this regional receptor system may play a role in the response to these agents. Rats were administered (i.p.) the monoamine oxidase inhibitors tranylcypromine (10mg/kg) or phenelzine (10mg/kg), the tricyclic antidepressant desipramine (15 mg/kg), or fluoxetine (5mg/kg), a selective serotonin re-uptake inhibitor, once daily for seven consecutive days. Two hours following the last drug treatment the hippocampal tissue was prepared for defining the distribution and quantity of GABA(B) receptor subunits using in situ hybridization and for assessing GABA(B) receptor function by quantifying baclofen-stimulated [(35)S]-GTPgammaS binding. All of these antidepressants selectively increased the expression of the GABA(B(1a)) subunit in hippocampus, having no consistent effect on the expression of GABA(B(1b)) or GABA(B(2)). Moreover, except for fluoxetine, these treatments increased GABA(B) receptor function in this brain region. The results indicate that an enhancement in the production of hippocampal GABA(B(1a)) subunits may be a component of the response to antidepressants, supporting a possible role for this receptor in the symptoms of depression and the treatment of this condition.
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PMID:Effect of antidepressants on GABA(B) receptor function and subunit expression in rat hippocampus. 1545 91

GABA, the main inhibitory neurotransmitter in the brain, regulates many physiological and psychological processes. Thus, dysfunction of the GABA system is implicated in the pathophysiology of several neuropsychiatric disorders, including anxiety and depression. However, the role of GABA(B) receptors in behavioural processes related to these disorders has not been resolved. GABA(B) receptors are G-protein-coupled receptors that function as heterodimers of GABA(B(1)) and GABA(B(2)) subunits. In addition to highly selective agonists and antagonists, novel GABA(B) receptor tools have been developed recently to further assist elucidation of the role of GABA(B) receptors in CNS function. These include mice that lack functional GABA(B) receptors, and novel positive modulators of the GABA(B) receptor. In this review, we discuss evidence that points to a role of GABA(B) receptors in anxiety and depression.
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PMID:Don't worry 'B' happy!: a role for GABA(B) receptors in anxiety and depression. 1562 3

2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) is a recently reported positive allosteric modulator of gamma-aminobutyric acid (GABA)(B) receptors. In this study, we assessed the ability of CGP7930 to modulate the baclofen-induced depression of dopamine (DA) neuron activity via the activation of GABA(B) receptors in the ventral tegmental area in rat midbrain slices. The selective GABA(B) receptor agonist, baclofen, depressed the spontaneous firing rate of DA neurons in a concentration-dependent manner (EC50 = 0.27 microM, n = 11). CGP7930 (30 microM) significantly (P < 0.05) shifted the baclofen concentration-response curve to the left (EC50 = 0.15 microM, n = 5). The effects of baclofen alone or baclofen coapplied with CGP7930 were fully blocked by 1 microM (2S)-3-[[(1S)-1-(3,4-dichloropheny)ethyl]amino-2-hydroxypropyl] (phenylmethyl) phosphinic acid (CGP55845), a potent and selective GABA(B) receptor antagonist. In similar experiments, N-[3,3-diphenylpropyl]-alpha-methylbenzylamine (fendiline) (30 or 50 microM), a compound shown to potentiate GABA(B) receptor-mediated cortical hyperpolarisation, also significantly enhanced the inhibitory effect of baclofen. It is therefore concluded that the recently reported GABA(B) receptor modulators, CGP7930 and fendiline, can enhance GABA(B) receptor-mediated depression of DA neuronal activity. This finding suggests a therapeutic potential for GABA(B) potentiators for the treatment of diseases associated with a hyperfunctional mesocorticolimbic system.
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PMID:GABA(B) receptor modulators potentiate baclofen-induced depression of dopamine neuron activity in the rat ventral tegmental area. 1571 97


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