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)

GABAergic, somatostatin-containing bitufted interneurons in layer 2/3 of rat neocortex are excited via glutamatergic excitatory postsynaptic potentials (EPSPs) by pyramidal neurons located in the same cortical layer. Pair recordings showed that short bursts of backpropagating dendritic action potentials (APs) reduced the amplitude of unitary EPSPs. EPSP depression was dependent on a rise in dendritic [Ca2+]. The effect was blocked by the GABA(B) receptor (GABA(B)-R) antagonist CGP55845A and was mimicked by the GABA(B)-R agonist baclofen. As presynaptic GABA(B)-Rs were activated neither by somatostatin nor by GABA released from axon collaterals of the bitufted cell, we conclude that GABA(B)-Rs were activated by a retrograde messenger, most likely GABA, released from the dendrite. Because synaptic depression was prevented by loading bitufted neurons with GDP-beta-S, it is likely to be caused by exocytotic GABA release from dendrites.
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PMID:Dendritic GABA release depresses excitatory transmission between layer 2/3 pyramidal and bitufted neurons in rat neocortex. 1062 60

G-protein inhibition of voltage-gated calcium channels can be transiently relieved by repetitive physiological stimuli. Here, we provide evidence that such relief of inhibition contributes to short-term synaptic plasticity in microisland-cultured hippocampal neurons. With G-protein inhibition induced by the GABA(B) receptor agonist baclofen or the adenosine A1 receptor agonist 2-chloroadenosine, short-term synaptic facilitation emerged during action potential trains. The facilitation decayed with a time constant of approximately 100 msec. However, addition of the calcium channel inhibitor Cd(2+) at 2-3 microM had no such effect and did not alter baseline synaptic depression. As expected of facilitation from relief of channel inhibition, analysis of miniature EPSCs implicated presynaptic modulation, and elevating presynaptic Ca(2+) entry blunted the facilitation. Most telling was the near occlusion of synaptic facilitation after selective blockade of P/Q- but not N-type calcium channels. This was as predicted from experiments using recombinant calcium channels expressed in human embryonic kidney (HEK) 293 cells; we found significantly stronger relief of G-protein inhibition in recombinant P/Q- versus N-type channels during action potential trains. G-protein inhibition in HEK 293 cells was induced via recombinant M2 muscarinic acetylcholine receptors activated by carbachol, an acetylcholine analog. Thus, relief of G-protein inhibition appears to produce a novel form of short-term synaptic facilitation in cultured neurons. Similar short-term synaptic plasticity may be present at a wide variety of synapses, as it could occur during autoreceptor inhibition by glutamate or GABA, heterosynaptic inhibition by GABA, tonic adenosine inhibition, and in many other instances.
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PMID:Relief of G-protein inhibition of calcium channels and short-term synaptic facilitation in cultured hippocampal neurons. 1064 93

The antiepileptic drug, gamma-vinyl GABA (GVG, vigabatrin), is an irreversible inhibitor of GABA-transaminase, the enzyme responsible for the breakdown of GABA. In hippocampal slices prepared from rats pretreated with either an anticonvulsant dose of GVG (1500 mg/kg) or saline, electrophysiological recordings were performed in order to examine the effects of GVG pretreatment on GABAergic neurotransmission. Although GVG had no effect on the effectiveness of GABA-mediated inhibition when elicited by a single stimulus, it reversed the activity-dependent depression of inhibition which is typically observed when inhibitory pathways are activated repetitively by a train of stimuli delivered at low frequency. Similarly, GVG pretreatment prevented the progressive decline in the amplitude of monosynaptic inhibitory postsynaptic potentials (IPSPs) during low-frequency stimulation of inhibitory interneurons. Thus, in slices from GVG pretreated rats, the amplitudes of both the fast and slow components of the last of a series of IPSPs evoked by a 5 Hz, 4 s train were maintained at 91.5 +/- 6.6% and 87.7 +/- 6.5%, respectively, compared to 61.1 +/- 3.9% and 57.1 +/- 5.0% in control slices. Finally, in slices from GVG pretreated rats, we observed a reduction in the ability of the GABA(B) receptor agonist, baclofen, to decrease the amplitude of monosynaptic inhibitory postsynaptic currents. These results suggest that GVG may produce its frequency-dependent actions by reducing the function of release regulating presynaptic GABA(B) autoreceptors. The frequency-dependent reinforcement of inhibition by GVG may importantly contribute to the anticonvulsant effectiveness of this compound.
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PMID:Reversal of the activity-dependent suppression of GABA-mediated inhibition in hippocampal slices from gamma-vinyl GABA (vigabatrin)-pretreated rats. 1066 20

5-Hydroxytryptamine(1A) (5-HT(1A)) receptors, which activate inhibitory G-proteins, are implicated in psychiatric disorders including anxiety and depression. Studies suggest that chronic 5-HT(1A) receptor agonist administration alters 5-HT(1A) receptor function, but the effect of chronic treatment on 5-HT(1A) receptor-activated G-proteins is unclear. In this study, agonist-stimulated [35S]guanylyl-5'-O-(gamma-thio)-triphosphate (GTPgammaS) binding was examined following chronic administration of buspirone. Brains were processed for [35S]GTPgammaS autoradiography using R(+)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) for 5-HT(1A) receptors or baclofen for GABA(B) receptors. Net 8-OH-DPAT-stimulated [35S]GTPgammaS binding was decreased by 25-30% in the septum and dorsal raphe nucleus of buspirone-treated animals. No significant changes in 8-OH-DPAT-stimulated [35S]GTPgammaS binding were found in the prefrontal, entorhinal or cingulate cortices or hippocampus in buspirone-treated rats. GABA(B) receptor-stimulated [35S]GTPgammaS binding was increased by 25% in the hippocampus, with no significant changes in any other region examined. These results demonstrate region-specific alterations in 5-HT(1A) and GABA(B) receptor-activated G-proteins following chronic buspirone treatment, which may contribute to the clinical effects of this drug.
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PMID:Region-specific changes in 5-HT(1A) receptor-activated G-proteins in rat brain following chronic buspirone. 1068 78

Schizophrenia is considered to be associated with a hyperfunction of the dopaminergic system and with abnormalities in hippocampal information processing. To clarify whether an enhanced dopaminergic activity alters the hippocampal output, the effect of dopamine (DA) on inhibitory postsynaptic responses (IPSPs) in subicular neurons was examined. DA (200 microM) induced a small and inconsistent hyperpolarization that was accompanied by a reduction of membrane resistance. DA decreased polysynaptic IPSPs which was paralleled by a depression of isolated AMPA/kainate and NMDA receptor-mediated excitatory postsynaptic responses (EPSPs). In contrast, DA had no effect on isolated monosynaptic GABA(A) and GABA(B) receptor-mediated IPSP/Cs. We conclude that in addition to membrane effects, DA decreases polysynaptic IPSPs by attenuating the glutamatergic drive onto subicular interneurons.
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PMID:Dopamine depresses polysynaptic inhibition in rat subicular neurons. 1075 76

This study used whole cell patch clamp recordings in rat hypothalamic slice preparations to evaluate the effects of GABA(B) receptor activation on GABA(A)-mediated inhibitory postsynaptic currents (IPSCs) in paraventricular nucleus magnocellular neurons evoked by electrical stimulation in the suprachiasmatic nucleus (SCN). Baclofen induced a dose-dependent (1-10 microM) and reversible reduction in SCN-evoked IPSC amplitude (11/11 cells), blockable with 2-hydroxysaclofen (300 microM; 3/3 cells). IPSCs displayed paired-pulse depression (PPD), attenuated by both baclofen and 2-hydroxysaclofen, but neither altered resting membrane conductances or IPSC time constants of decay. Baclofen induced a significant dose-dependent (1-100 microM) reduction in frequency, but not amplitude, of spontaneous IPSCs and miniature IPSCs, reversible with 2-hydroxysaclofen pretreatment. Baclofen effects and PPD persisted in slices pretreated with pertussis toxin (PTX) and N-ethylmaleimide, implying that these GABA(B) receptors are coupled to PTX-insensitive G proteins. Responses were unaltered by barium (2 mM) or nimodipine, ruling out involvement of K(+) channels and L-type Ca(2+) channels. Thus pre- and postsynaptic GABA(B) and GABA(A) receptors participate in SCN entrainment of paraventricular neurosecretory neurons.
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PMID:GABA(B) presynaptically modulates suprachiasmatic input to hypothalamic paraventricular magnocellular neurons. 1080 Dec 89

In rat neocortical slices maintained in Mg2+-free Kreb's medium, the effects of Ca2+ concentration on repetitive spontaneous discharges and on GABA(B) receptor-mediated responses were investigated. Over a concentration range of 0.3-2.4 mM Ca2+, there was a reduction of discharge amplitude, with a 50 +/- 6.5% reduction in 0.3 mM Ca2+, whilst the burst frequency remained unaffected. Baclofen, the GABA(B) receptor agonist, produced a concentration-dependent depression of discharge frequency, reversibly antagonised by the antagonist (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid (Sch 50911). The EC50 value for baclofen in 2.4 mM Ca2+ was 11 microM, while the EC50 values in 0.3, 0.6, 1.2, and 1.8 mM Ca2+ were 1.3, 2.5, 3.6, and 10 microM, respectively, resulting in 8.5, 4.4, 3.1, and 1.1-fold leftward shifts. This enhanced action of baclofen in low extracellular Ca2+ concentrations in the neocortex may be the result of a lower concentration gradient which reinforces the action of baclofen.
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PMID:Effects of Ca2+ concentration on GABA(B) receptor function in rat neocortical slices. 1091 41

We have previously provided functional evidence that glycine and GABA are contained in the same synaptic vesicles and coreleased at the same synapses in lamina I of the rat spinal dorsal horn. However, whereas both glycine receptors (GlyRs) and GABA(A) receptors (GABA(A)Rs) are expressed on the postsynaptic target, under certain conditions inhibitory events appeared to be mediated by GlyRs only. We therefore wanted to test whether GABA(B) receptors could be activated in conditions where GABA released was insufficient to activate GABA(A)Rs. Focal stimulation in the vicinity of visually identified lamina I neurons elicited monosynaptic IPSCs in the presence of ionotropic glutamate receptor antagonists. Pairs of stimuli were given at different interstimulus intervals (ISI), ranging from 25 ms to 1 s to study the depression of the second of evoked IPSCs (paired pulse depression; PPD). Maximal PPD of IPSCs was 60 +/- 14% (SE) (of the conditioning pulse amplitude), at ISI between 150 and 200 ms. PPD was observed with IPSCs evoked at stimulus intensities where they had no GABA(A)R component. PPD of small evoked IPSCs was not affected by the GABA(A)R antagonist bicuculline but significantly attenuated by 10-30 microM CGP52432, a specific GABA(B) receptor antagonist. These data indicate that, under conditions where GABA released is insufficient to affect postsynaptic GABA(A)Rs at lamina I inhibitory synapses, significant activation of presynaptic GABA(B) receptors can occur.
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PMID:GABA(B) receptors are the first target of released GABA at lamina I inhibitory synapses in the adult rat spinal cord. 1093 23

Olfactory receptor neurons of the nasal epithelium send their axons, via the olfactory nerve (ON), to the glomeruli of the olfactory bulb (OB), where the axon terminals form glutamatergic synapses with the apical dendrites of mitral and tufted cells, the output cells of the OB, and with juxtaglomerular (JG) interneurons. Many JG cells are GABAergic. Here we show that, despite the absence of conventional synapses, GABA released from JG cells activates GABA(B) receptors on ON terminals and inhibits glutamate release both tonically and in response to ON stimulation. Field potential recordings and current-source density analysis, as well as intracellular and whole cell recording techniques were used in rat OB slices. Baclofen (2-5 microM), a GABA(B) agonist, completely suppressed ON-evoked synaptic responses of both mitral/tufted cells and JG cells, with no evidence for postsynaptic effects. Baclofen (0.5-1 microM) also reversed paired-pulse depression (PPD) of mitral/tufted cell responses to paired-pulse facilitation (PPF), and reduced depression of JG cell excitatory postsynaptic currents (EPSCs) during repetitive ON stimulation. These results suggest that baclofen reduced the probability of glutamate release from ON terminals. The GABA(B) antagonists CGP35348 or CGP55845A increased mitral/tufted cell responses evoked by single-pulse ON stimulation, suggesting that glutamate release from ON terminals is tonically suppressed via GABA(B) receptors. The same antagonists reduced PPD of ON-evoked mitral/tufted cell responses at interstimulus intervals 50-400 ms. This finding suggests that a single ON impulse evokes sufficient GABA release, presumably from JG cells, to activate GABA(B) receptors on ON terminals. Thus GABA(B) heteroreceptors on ON terminals are activated by ambient levels of extrasynaptic GABA, and by ON input to the OB. The time course of ON-evoked, GABA(B) presynaptic inhibition suggests that neurotransmission to M/T cells and JG cells will be significantly suppressed when ON impulses arrive in glomeruli at 2.5-20 Hz. GABA(B) receptor-mediated presynaptic inhibition of sensory input to the OB may play an important role in shaping the activation pattern of the OB glomeruli during olfactory coding.
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PMID:Tonic and synaptically evoked presynaptic inhibition of sensory input to the rat olfactory bulb via GABA(B) heteroreceptors. 1097 95

GABA is involved in both clinical depression and in animal models of depression; however, the roles of GABA(A) and GABA(B) receptors in specific brain regions are not clear. Changes in densities of both GABA(A) and GABA(B) receptors have been reported with the learned helplessness animal model of depression and with chronic antidepressant drug treatment. However, some of these findings are discrepant. Thus, we used quantitative autoradiography to study the GABA(A) and GABA(B) receptors in learned helplessness and we used an experimental paradigm that allows non-specific effects of stress to be differentiated from learned helplessness. Densities of GABA binding were measured in prefrontal cortex, septum, hippocampus, hypothalamus and amygdala. In the septum, learned helpless rats had increased densities of GABA(A) receptors and rats that did not become helpless after inescapable stress had decreased GABA(B) receptor densities. No significant group differences of GABA(A) or GABA(B) receptor densities were observed in any other brain region studied. These results suggest a unique role for the septum in modulating GABA in the learned helplessness animal model of depression.
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PMID:Effects of learned helplessness on brain GABA receptors. 1100 Apr 46


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