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)

Allopregnanolone (3alpha,5alpha-TH PROG) and 5alpha-dihydroprogesterone (5alpha-DH PROG), the two most important neuroactive steroids synthesized in the brain, potently modulate neuronal activity by allosterically regulating GABA action at GABA(A) receptors or by changing specific GABA(A) receptor subunit gene expression, respectively. We recently reported [Proc. Natl. Acad. Sci. USA 95 (1998) 3239] that in patients with severe depression there is a decrease in the CSF levels of 3alpha,5alpha-TH PROG, which is normalized by treatment with drugs (i.e. fluoxetine) that improve psychopathology. The mechanism by which fluoxetine and other selective serotonin reuptake inhibitors normalize 3alpha,5alpha-TH PROG CSF levels appears to involve a direct stimulation of 3alpha-hydroxysteroidoxidoreductase (3alpha-HSD), an enzyme that catalyses the reduction of 5alpha-DH PROG into 3alpha,5alpha-TH PROG. Here, we propose the use of socially-isolated mice that have a downregulation of 3alpha,5alpha-TH PROG and of 5alpha-DH PROG expression to establish a model to study the behavioral consequences of this deficiency. After 4-6 weeks of isolation, these mice exhibit increased anxiety and aggressive behavior and also a decreased response to the administration of GABA-mimetic drugs. In these mice, the decrease in 3alpha,5alpha-TH PROG is selectively normalized by the use of fluoxetine in doses that reduce behavioral abnormalities. In addition, the expression of 5alpha-reductase Type I mRNA and protein was lower in socially-isolated mice than that in group-housed mice whereas 3alpha-HSD mRNA expression remained unchanged. The results of these studies may enable us to design drugs that specifically affect neurosteroidogenic enzymatic activities and may provide an efficacious treatment for the psychopathologies associated with psychiatric disorders.
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PMID:The socially-isolated mouse: a model to study the putative role of allopregnanolone and 5alpha-dihydroprogesterone in psychiatric disorders. 1174 79

Long-term depression (LTD) in the basolateral amygdala, following low frequency stimulation (1 Hz/900 pulses) of the lateral amygdala, was studied in an in vitro slice preparation of 2-3 weeks and 2-4 months old mice. Whole-cell patch-clamp recordings of neurons, visualized by means of infrared videomicroscopy, and extracellular field potential recordings were performed. Loading single neurons with the calcium chelator BAPTA (30 mM) did not reduce the excitatory postsynaptic currents following low frequency stimulation. However, buffering presynaptic calcium with BAPTA-AM, and application of the specific Ca2+/calmodulin-stimulated protein kinase II antagonist KN-62 (1-[N,O-bis(5-isoquinoline sulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperizine), blocked low frequency stimulation-induced LTD. The induction of LTD was reduced by the competitive N-methyl-D-aspartate receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid (50 microM), and blocked by the metabotropic glutamate receptor antagonist (-)-amino-4-carboxy-methyl-phenylacetic acid (1 mM), and by 5-hydroxytryptamine (5-HT; 30 microM) via the activation of 5-HT(1A) receptors. Also blocking GABA(A) receptor-mediated synaptic transmission with bicuculline (10 microM) or picrotoxin (20 microM) reduced the induction of LTD. Visually and electrophysiologically identified interneurons in slices from 2 weeks old mice, expressed in contrast to adult mice (2-4 months), pronounced LTD. Principal neurons showed only weak LTD after low frequency stimulation.A synopsis of these findings suggests a pivotal role of GABAergic interneurons and serotonergic afferents in the induction of LTD in the basolateral nucleus of the amygdala.
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PMID:Long-term depression in the basolateral amygdala of the mouse involves the activation of interneurons. 1174 49

How the brain mediates general anesthesia is not known. We report that two interconnected structures in the forebrain, the medial septum and the hippocampus, participate in maintaining awareness and movements during general anesthesia. In the awake, freely behaving rat, inactivation of the medial septum or the hippocampus by local injection of a GABA(A) receptor agonist, muscimol, decreased the dose of a general anesthetic needed to induce a loss of the tail-pinch response or a loss of righting reflex. Septohippocampal inactivation also suppressed the behavioral hyperactivity or the delirium stage associated with general anesthesia. An increase and decrease of 30-50 Hz (gamma) waves in the hippocampus correlated with an increase and decrease in behavioral activity, respectively. Similar results were found for both volatile (halothane and isoflurane) and nonvolatile (propofol and pentobarbital) anesthetics. We conclude that the behavioral hyperactivity induced by a general anesthetic is mediated in part by the septohippocampal system, and that depression of the septohippocampal system increases the potency of a general anesthetic. It is suggested that more potent general anesthetics or adjuvants may be developed by maximizing the pharmacological depression of the septohippocampal system.
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PMID:The septohippocampal system participates in general anesthesia. 1178 12

Extracellular field potentials, evoked by stimulation of the cortico-NAcc border, were recorded from the nucleus accumbens (NAcc) in horizontal slices of rat ventral forebrain. The peak amplitude of the population spike/excitatory postsynaptic potential complex (PEC, N2 component) was reduced by 78+/-2% ( n=44) by the antagonist of AMPA-type glutamate receptors, 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX, 10 microM). Dopamine (100 microM) reversibly depressed the peak amplitude of the PEC by 40+/-3% ( n=44). The GABA(A) receptor antagonists picrotoxin (10, 30 microM), or bicuculline methiodide (BMI, 20 microM), significantly reduced the PEC depression caused by dopamine (100 microM) to 9+/-3% ( n=20), 12+/-7% ( n=8) and 13+/-3% ( n=4) of control respectively, which, in the case of BMI, was reversible on washout of BMI. In slices with the frontal cortex removed (decorticated), dopamine (100 microM) was without effect on the PEC ( n=14). In contrast, the inhibition of the PEC by adenosine (by 40+/-9% in control, n=4), which was blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 200 nM), was unaffected by picrotoxin (50 microM, n=4), and persisted in decorticated slices, albeit increased to 88+/-2% ( n=4) of control. These results indicate that the depression of the cortico-NAcc synaptic transmission by dopamine in this preparation is due to an action in frontal, possibly piriform, cortex, which may involve modulation of intracortical GABAergic circuitry. In contrast, depression by adenosine is consistent with a presynaptic action via A1 receptors on intra-NAcc glutamate-releasing terminals, although there may be an additional action of adenosine within the cortex that also influences the cortico-NAcc PEC.
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PMID:Depression of excitatory cortico-nucleus accumbens synaptic transmission in rat brain slices by dopamine, but not adenosine, depends upon intracortical mechanisms. 1181 Jan 49

GABA(A) receptor-mediated Cl(-) currents were evoked by rapid and short (0.75-1.5 ms), focal iontophoretic applications of GABA to proximal dendrites of cultured striatal neurones. The mean amplitude (232 +/- 21.0 pA) was in the range of large miniature inhibitory postsynaptic currents (mIPSCs), while the 10-90% rise times (3.4 +/- 0.20 ms) and the time constants of decay (60.0 +/- 8.4 ms) were three times slower. Responses to paired-pulse application of GABA at inter-pulse intervals (IPIs) of 30, 100 and 300 ms showed no depression of the second response (R2) relative to the first (R1). At short IPIs, at which R1 and R2 showed temporal summation, the net amplitude of R2 (R2(net)) was partially occluded. Lowering the iontophoretic intensity during paired-pulse application at an IPI of 30 ms reduced R1 by 69.5 +/- 3.3%, while occlusion of R2(net) decreased significantly, indicating that the receptor occupancy had been lowered. During the course of ten pulses of GABA at 10 Hz, responses declined by 8.7 +/- 3.9%, which probably reflects slow cumulative desensitization. In conclusion, rapid focal iontophoresis of exogenous GABA onto GABA(A) receptors does not result in activity-dependent depression of the postsynaptic response. This result suggests that fast desensitization is unlikely to occur during repetitive GABA(A) receptor-mediated synaptic transmission in striatal neurones.
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PMID:Repetitive activation of postsynaptic GABA(A )receptors by rapid, focal agonist application onto intact rat striatal neurones in vitro. 1188 67

The whole-cell patch-clamp technique was used to examine the effects of retigabine, a novel anticonvulsant drug, on the electroresponsive properties of individual neurons as well as on neurotransmission between monosynaptically connected pairs of cultured mouse cortical neurons. Consistent with its known action on potassium channels, retigabine significantly hyperpolarized the resting membrane potentials of the neurons, decreased input resistance, and decreased the number of action potentials generated by direct current injection. In addition, retigabine potentiated inhibitory postsynaptic currents (IPSCs) mediated by activation of gamma-aminobutyric acid(A) (GABA(A)) receptors. IPSC peak amplitude, 90-to-10% decay time, weighted decay time constant, slow decay time constant, and, consequently, the total charge transfer were all significantly enhanced by retigabine in a dose-dependent manner. This effect was limited to IPSCs; retigabine had no significant effect on excitatory postsynaptic currents (EPSCs) mediated by activation of non-N-methyl-D-aspartate ionotropic glutamate receptors. A form of short-term presynaptic plasticity, paired-pulse depression, was not altered by retigabine, suggesting that its effect on IPSCs is primarily postsynaptic. Consistent with the hypothesis that retigabine increases inhibitory neurotransmission via a direct action on the GABA(A) receptor, the peak amplitudes, 90-to-10% decay times, and total charge transfer of spontaneous miniature IPSCs were also significantly increased. Therefore, retigabine potently reduces excitability in neural circuits via a synergistic combination of mechanisms.
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PMID:Effects of the anticonvulsant retigabine on cultured cortical neurons: changes in electroresponsive properties and synaptic transmission. 1190 Dec 32

The horizontal vestibulo-oculomotor reflex was studied in pigmented rats during the first 5 days after a unilateral chemical or surgical vestibular deafferentation. Spontaneous eye movements in darkness and slow phase velocity gain of compensatory eye movements during horizontal sinusoidal rotation were evaluated. The most evident vestibulo-oculomotor symptom immediately after a unilateral vestibular loss was a spontaneous nystagmus, which gradually abated during the following days. Further, an asymmetry between ipsi- and contra-lesional gains was evident during sinusoidal vestibular stimulation. Single systemic doses of the GABA(B) receptor antagonist [3-[1-(S)-[[3-(cyclohexylmethyl)-hydroxyphosphinoyl]-2-(S)-hydroxypropyl]amino]ethyl]-benzoic acid (CGP 56433A), the agonist baclofen, or the GABA(A) receptor agonist (4,5,6,7-tetrahydroisoxazolo-[5,4-c]-pyridin-3-ol (THIP) were given at different intervals after unilateral vestibular deafferentation. CGP 56433A highly aggravated the vestibulo-oculomotor symptoms, observed as an increase in spontaneous nystagmus and slow phase velocity gain asymmetry. This effect was most pronounced during the first 2 days after unilateral vestibular loss, when CGP 56433A even decompensated the vestibular system to the extent that all vestibular responses were abolished. Baclofen caused no effect during the first days after unilateral vestibular loss, but in parallel with the abatement of spontaneous nystagmus, the drug equilibrated or even reversed the remaining spontaneous nystagmus with corresponding effects on the slow-phase velocity gain asymmetry. The effects of baclofen were very similar after both chemical and surgical deafferentation. THIP caused a slight depression of all vestibular responses. All single dose effects of the drugs were transient. Altogether these results reveal that endogenous stimulation of GABA(B) receptors in GABA-ergic vestibulo-oculomotor circuits are important for reducing the vestibular asymmetry during the early period after unilateral vestibular deafferentation. A possible role for GABA(B) receptors in the reciprocal inhibitory commissural pathways in the vestibular nuclei is suggested.
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PMID:Early compensation of vestibulo-oculomotor symptoms after unilateral vestibular loss in rats is related to GABA(B) receptor function. 1203 49

It was shown recently that Delta9-tetrahydrocannabinol, like several other drugs eliciting euphoria, stimulates dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens. The aim of the present work was to clarify the mechanism of this stimulatory effect. Our hypothesis was that cannabinoids depress the GABAergic inhibition of dopaminergic neurons in the VTA. Electrophysiological properties of VTA neurons in rat coronal midbrain slices were studied with the patch-clamp technique. GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs) were evoked by electrical stimulation in the vicinity of the recorded neurons. The amplitude of IPSCs was depressed by the synthetic mixed CB1/CB2 cannabinoid receptor agonist WIN55212-2 (10(-6) and 10(-5) m). The CB1 cannabinoid receptor antagonist SR141716A (10(-6) m) prevented the inhibition produced by WIN55212-2 (10(-5) m). Two observations showed that IPSCs were depressed with a presynaptic mechanism. WIN55212-2 (10(-5) m) did not change the amplitude of miniature IPSCs recorded in the presence of tetrodotoxin. Currents evoked by pressure ejection of muscimol from a pipette were also not changed by WIN55212-2 (10(-5) m). The results indicate that activation of CB1 cannabinoid receptors inhibits GABAergic neurotransmission in the VTA with a presynaptic mechanism. Depression of the GABAergic inhibitory input of dopaminergic neurons would increase their firing rate in vivo. Accordingly, dopamine release in the projection region of VTA neurons, the nucleus accumbens, would also increase.
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PMID:Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids. 1209 13

Properties of GABA(A) receptor-mediated unitary inhibitory postsynaptic currents (uIPSCs) in pyramidal (P) cells, evoked by fast spiking (FS) and low-threshold spike (LTS) subtypes of interneurons in layer V of rat visual cortex slices were examined using dual whole cell recordings. uIPSCs evoked by FS cells were larger and faster rising than those evoked by LTS cells, consistent with the known primary projections of FS and LTS cell axons to perisomatic and distal dendritic areas of layer V pyramidal cells, respectively, and the resulting electrotonic attenuation for LTS-P synaptic events. Unexpectedly, the decay time constants for LTS-P and FS-P uIPSCs were not significantly different. Modeling results were consistent with differences in the underlying GABA(A) receptor-mediated conductance at LTS-P and FS-P synapses. Paired-pulse depression (PPD), present at both synapses, was associated with an increase in failure rate and a decrease in coefficient of variation, indicating that presynaptic mechanisms were involved. Furthermore, the second and first uIPSC amplitudes during PPD were not inversely correlated, suggesting that PPD at both synapses is independent of previous release and might not result from depletion of the releasable pool of synaptic vesicles. Short, 20-Hz trains of action potentials in presynaptic interneurons evoked trains of uIPSCs with exponentially decreasing amplitudes at both FS-P and LTS-P synapses. FS-P uIPSC amplitudes declined more slowly than those of LTS-P uIPSCs. Thus FS and LTS cells, with their differences in firing properties, synaptic connectivity with layer V P cells, and short-term synaptic dynamics, might play distinct roles in regulating the input-output relationship of the P cells.
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PMID:Synaptic inhibition of pyramidal cells evoked by different interneuronal subtypes in layer v of rat visual cortex. 1216 26

Paired pulse depression (PPD) is a common form of short-term synaptic plasticity. The aim of this study was to characterise PPD at the level of a single inhibitory bouton. Low-density collicular cultures were loaded with the Ca2+ indicator Oregon Green-1, active boutons were stained with RH414, and action potentials were blocked with TTX. Evoked IPSCs (eIPSCs) and presynaptic Ca2+ transients were recorded in response to direct presynaptic depolarisation of an individual bouton. The single bouton eIPSCs had a low failure rate (< 0.1), large average quantal content (3-6) and slow decay (tau(1) = 15 ms, tau(2) = 81 ms). The PPD of eIPSCs had two distinct components: PPD(fast) and PPD(slow) (tau = 86 ms and 2 s). PPD(slow) showed no dependence on extracellular Ca2+ concentration, or on the first eIPSC's failure rate or amplitude. Most probably, it reflects a release-independent inhibition of exocytosis. PPD(fast) was only observed in normal or elevated Ca2+. It decreased with the failure rate and increased with the amplitude of the first eIPSC. It coincided with paired pulse depression of the presynaptic Ca2+ transients (tau = 120 ms). The decay of the latter was accelerated by EGTA, which also reduced PPD(fast). Therefore, a suppressive effect of residual presynaptic Ca2+ on subsequent Ca2+ influx is considered the most likely cause of PPD(fast). PPD(fast) may also have a postsynaptic component, because exposure to a low-affinity GABA(A) receptor antagonist (TPMPA; 300 microM) counteracted PPD(fast), and asynchronous IPSC amplitudes were depressed for a short interval following an eIPSC. Thus, at these synapses, PPD is produced by at least two release-independent presynaptic mechanisms and one release-dependent postsynaptic mechanism.
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PMID:Presynaptic and postsynaptic mechanisms underlie paired pulse depression at single GABAergic boutons in rat collicular cultures. 1218 Dec 84


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