Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Methamphetamine (MA) and ethanol (EtOH) are two commonly abused drugs. Previous behavioral studies indicated that MA may synergistically alter EtOH responses. In the present study, we found that local application of MA did not potentiate ethanol-induced depressions of the spontaneous activity of Purkinje neurons in urethane-anesthetized rats. We and others previously found that, in cerebellar Purkinje neurons, EtOH and gamma-amino-butyric acid (GABA)-mediated depressions can be enhanced by norepinephrine (NE) acting via beta-adrenergic receptors while these responses are decreased by activation of alpha-adrenergic receptors. In the present experiment, after blocking alpha-adrenergic receptors with prazocin, MA significantly enhanced EtOH responses in most of neurons studied. It has been reported that MA may directly and indirectly enhance alpha-adrenergic and beta-adrenergic receptor-mediated responses. The present study may suggest that MA can negatively modulate (antagonize) the depressant effects of ethanol via the alpha-adrenergic receptor, which oppose the positive modulatory mechanism (potentiation of EtOH depression) via actions of the beta-adrenergic receptors. We found that lesioning NE neurons with N-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP4), a selective noradrenergic neurotoxin, enhance the MA-facilitated ethanol responses, suggesting that this action of MA may not require NE. Since it has been reported that MA increases serotonin (5-HT) and catecholamine release from their nerve terminals, MA may potentiate EtOH depressions by facilitating the release of NE and 5-HT. Taken together, our data suggested that MA may modulate EtOH responses via catecholaminergic and serotonergic mechanisms in cerebellar Purkinje neurons.
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PMID:Methamphetamine facilitates ethanol-induced depressions in cerebellar Purkinje neurons of prazocin- or DSP4-treated rats. 861 6

We have investigated the effect of a number of group I, II and III metabotropic glutamate (mGlu) receptor agonists and antagonists on paired pulse depression in the medial perforant path of the rat dentate gyrus in vitro. A triphasic pattern of a large depression at short intervals (10-50 ms), a reduction of this depression at intermediate intervals (50-200 ms) and again a large depression at late intervals (> 200 ms) was observed. The group I mGlu receptor agonist, (S)-3,5-dihydroxy phenylglycine ((S)-DHPG; 20 microM) had no significant effect on paired pulse depression at any interstimulus intervals. The mGlu receptor group II and III agonists, L-CCG-1 ((2S,3S,4S)-alpha-(carboxy-cyclopropyl)-glycine), DCG-IV ((2S,1'R,2'R,3'R)-2-2',3'-dicarboxy cyclopropylglycine), 1S,3R-ACPD (1S,3R-1-aminocyclopentate-1,3-dicarboxylic acid) and L-AP4 (L-2-amino-4-phosphono butyric acid) reduced paired pulse depression at interstimulus intervals of 200 ms or less. Application of the non specific mGlu receptor antagonist, MCPG (alpha-methyl carboxy-phenylglycine; 200 microM) completely inhibited the 1S,3R ACPD-induced reduction in paired pulse depression but was without effect on the L-AP4 response. The relatively specific group II antagonist MCCG ((2S,3S,4S)-2-methyl-2-carboxy cycloproprylglycine) at 200 microM and 500 microM, attenuated but did not completely inhibit the DCG-IV induced reduction of paired pulse depression. The putative group III pre-synaptic mGlu receptor antagonist alpha-methyl-L-AP4 and MSOP ((RS)-alpha-methylserine-O-phosphate) both at 200 microM inhibited the L-AP4-induced reduction in paired pulse depression at intermediate phase interstimulus intervals but not at early interstimulus intervals. These results specifically demonstrate the involvement of group III and III mGlu receptor ligands in the modulation of paired pulse depression in the medial perforant pathway.
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PMID:Group II and III metabotropic glutamate receptors modulate paired pulse depression in the rat dentate gyrus in vitro. 952 4

1. Corticothalamic (CT) EPSPs evoked at <= 0.1 Hz were recorded from thalamocortical neurones in the rat dorsal lateral geniculate nucleus in vitro, with both GABAA and GABAB receptors blocked. 2. The group III metabotropic glutamate (mGlu) receptor agonists L-2-amino-4-phosphono-butyric acid (L-AP4) and O-phospho-L-serine (L-SOP) both caused a concentration-dependent depression of the CT EPSP. The maximum depression and EC50 values for these effects were 64.4 +/- 3.8 % and 88.0 +/- 24.7 microM for L-AP4, and 42.0 +/- 2.5 % and 958 +/- 492 microM for L-SOP, respectively (means +/- s.e.m.). Neither agonist had any effect on membrane potential or input resistance. 3. The depression of the CT EPSP caused by L-AP4 was reversed using the group III antagonist (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4, 1 mM), and the group II/III antagonist LY341495 (3 microM), but not using the group II antagonist (2S)-alpha-ethylglutamic acid (300 microM). The potencies of L-AP4, L-SOP and LY341495 indicate that this action of L-AP4 is mediated via mGlu7 and mGlu8 and not mGlu4 receptors. 4. Neither MAP4 nor LY341495 had any effect on the CT EPSPs evoked by 10 Hz trains of five stimuli, indicating the lack of endogenous activation of group III mGlu receptors in the thalamus during short bursts of cortical input. However, the magnitude of the depression caused by L-AP4 indicates that any physiological activation of group III mGlu receptors would have a profound effect on the CT input to the thalamus, and hence cortical control of thalamic function.
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PMID:Group III metabotropic glutamate receptors control corticothalamic synaptic transmission in the rat thalamus in vitro. 1045 64

Central nervous system (CNS) selective amino acid transporters provide an important function in maintaining tonic extracellular levels of amino acids that act as neurotransmitters, synaptic modulators or neurotransmitter precursors. Small molecule inhibitors of these transporters have been postulated and in some cases demonstrated to be useful in the treatment of a range of CNS driven disorders such as epilepsy, anxiety, psychosis, depression, pain and neurodegenerative disease. Although much of the research to date in this field has focussed on inhibition of the gama-amino butyric acid (GABA) transporters more recent reports have also generated interest in modulation of glycine, glutamate and proline transporters. This article will review the current medicinal chemistry literature and structure activity relationships known for mammalian CNS selective amino acid transporters.
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PMID:Inhibitors of mammalian central nervous system selective amino acid transporters. 1063 62

Compounds that inhibit histone deacetylase may enable the re-expression of silenced regulatory genes in neoplastic cells, reversing the malignant phenotype. Although several molecules that inhibit histone deacetylase are undergoing preclinical development, butyric acid derivatives have undergone clinical investigation for several years, initially for non-malignant indications and more recently for the treatment of cancer. Of the butyric acid derivatives, sodium phenylbutyrate has undergone the most extensive systematic investigation. Administration of phenylbutyrate by iv. and oral routes is well-tolerated clinically at concentrations which effect acetylation of histones in vitro. Higher doses lead to reversible CNS depression. The studies presented to date have been Phase I studies and do not enable assessment of efficacy. However, current development of phenylbutyrate is proceeding in combination with other agents based on rational biologically-based in vitro studies. The parallel development of combination therapy including phenylbutyrate and early clinical development of other, more potent histone deacetylase inhibitors will hopefully lead to feasible, clinically tolerable strategies for altering the malignant phenotype of cancer cells.
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PMID:Modifying histones to tame cancer: clinical development of sodium phenylbutyrate and other histone deacetylase inhibitors. 1109 62

Depression is a common psychiatric disorder prevalent in 10-15% in general population. To know the biology of the disease many hypotheses have been proposed. Genetic basis for depression is provided by family studies which show higher risk of depression among first degree relatives. Abnormalities in serotonergic activity in depression can occur in one or more levels. Other neurotransmitters like gamma amino butyric acid (GABA) and dopamine are also considered to have some role in depression. Hormonal abnormalities like hypercortisolaemia are found in patients with depression. Structural and functional neuro-imaging studies in depression suggest the involvement of brain in depressive disorders.
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PMID:The biology of depression. 1120 58

In the CA3 region of rat hippocampal slices gamma-amino-butyric acid (GABA)(A/B) receptor antagonists induce low frequency bursting activity that was either inhibited (in 21% of slices) or increased by the selective 5-HT receptor agonists 5-carboxy-tryptamine (0.1-1 microM) and 8-hydroxydipropylaminotetralin (8-OH-DPAT). The selective 5-HT1A receptor antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexane carboxamide (WAY 100635) reversed the depression of bursting activity whereas the 5-HT7 receptor antagonist, (R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970; 1-10 microM), but not the 5-HT1A, 4 or 6 receptor antagonists WAY100635 (10 microM), SB-204070 (10 microM) and SB-271046 (10 microM), reversed the increase in bursting activity. The apparent -log10 K(D) value (8.4) for the effect of SB-269970 was consistent with a selective action at 5-HT7 receptors. Accompanying the 5-CT-induced increase in bursting frequency there was a shortening of the burst event waveform and a reduction in the after-hyperpolarization following each bursting event both of which were inhibited by SB-269970. These effects appeared to result predominantly from a direct 5-HT(7) receptor-mediated inhibition of a Ca2+ activated K+ channel.
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PMID:5-HT7 receptors modulate synchronized network activity in rat hippocampus. 1175 Sep 18

To examine possible interactions between fast depression and modulation of inhibitory synaptic transmission in the hippocampus, we recorded from pairs of synaptically connected basket cells (BCs) and granule cells (GCs) in the dentate gyrus of rat brain slices at 34 degrees C. Multiple-pulse depression (MPD) was examined in trains of 5 or 10 inhibitory postsynaptic currents (IPSCs) evoked at frequencies of 10-100 Hz under several conditions that inhibit transmitter release: block of voltage-dependent Ca2+ channels by Cd2+ (10 microM), activation of gamma-amino-butyric acid type B receptors (GABA(B)Rs) by baclofen (10 microM) and activation of muscarinic acetylcholine receptors (mAchRs) by carbachol (2 microM). All manipulations led to a substantial inhibition of synaptic transmission, reducing the amplitude of the first IPSC in the train (IPSC1) by 72%, 61% and 29%, respectively. However, MPD was largely preserved under these conditions (0.34 in control versus 0.31, 0.50 and 0.47 in the respective conditions at 50 Hz). Similarly, a theta burst stimulation (TBS) protocol reduced IPSC1 by 54%, but left MPD unchanged (0.40 in control and 0.39 during TBS). Analysis of both fractions of transmission failures and coefficients of variation (CV) of IPSC peak amplitudes suggested that MPD had a presynaptic expression site, independent of release probability. In conclusion, different types of presynaptic modulation of inhibitory synaptic transmission converge on a reduction of synaptic strength, while short-term dynamics are largely unchanged.
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PMID:Presynaptic short-term depression is maintained during regulation of transmitter release at a GABAergic synapse in rat hippocampus. 1185 May 13

Selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines are frequently used to treat maternal depression during pregnancy, however the effect of increased serotonin (5HT) and gamma-amino-butyric acid (GABA) agonists in the fetal human brain remains unknown. 5HT and GABA are active during fetal neurologic growth and play early roles in pain modulation, therefore, if prolonged prenatal exposure alters neurodevelopment this may become evident in altered neonatal pain responses. To examine biologic and behavioral effects of prenatal exposure, neonatal responses to acute pain (phenylketonuria heel lance) in infants with prolonged prenatal exposure were examined. Facial action (Neonatal Facial Coding System) and cardiac autonomic reactivity derived from the relationship between respiratory activity and short term variations of heart rate (HRV) were compared between 22 infants with SSRI exposure (SE) [fluoxetine (n = 7), paroxetine (n = 11), sertraline (n = 4)]; 16 infants exposed to SSRIs and clonazepam (SE+) [paroxetine (n = 14), fluoxetine (n = 2)]; and 23 nonexposed infants during baseline, lance, and recovery periods of a heel lance. Length of maternal SSRI use did not vary significantly between exposure groups-[mean (range)] SE:SE+ 183 (31-281):141 (54-282) d (p > 0.05). Infants exposed to SE and SE+ displayed significantly less facial activity to heel lance than control infants. Mean HR increased with lance, but was significantly lower in SE infants during recovery. Using measures of HRV and the transfer relationship between heart rate and respiration, SSRI infants had a greater return of parasympathetic cardiac modulation in the recovery period, whereas a sustained sympathetic response continued in the control group. Prolonged prenatal SSRI exposure appears to be associated with reduced behavioral pain responses and increased parasympathetic cardiac modulation in recovery following an acute neonatal noxious event. Possible 5HT-mediated pain inhibition, pharmacologic factors and the developmental course remain to be studied.
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PMID:Prolonged prenatal psychotropic medication exposure alters neonatal acute pain response. 1191 25

It was well established that compounds which decrease glutamatergic transmission via blockade of NMDA or group I mGlu receptors produce anxiolytic- and antidepressant-like action in animal tests and models. Since group III metabotropic glutamate receptor (mGluR) agonists are known to reduce glutamatergic neurotransmission by the inhibition of glutamate release, we decided to investigate potential anxiolytic- and/or antidepressant-like effects of group III mGluR agonists, after central administration in rats. It was found that group III mGluR agonists, (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) and 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (HomoAMPA), given intrahippocampally, produced a dose-dependent anxiolytic-like effect in the conflict drinking test. The effects of ACPT-I and HomoAMPA were reversed by (RS)-alpha-cyclopropyl-4-phosphonophenyl glycine (CPPG), group III mGluR antagonist. Moreover, a dose-dependent antidepressant-like action of group III mGluR agonists, ACPT-I and (RS)-4-phosphonophenylglycine (RS-PPG), but not HomoAMPA, was found in behavioral despair test, after intracerebroventricular injections, and the effect of ACPT-I was reversed by CPPG. The results obtained indicate that group III mGluR agonists produce anxiolytic- as well as antidepressant-like effects in behavioral tests, after central administration in rats. The reduction of glutamate release by group III mGluR activation may be a possible mechanism underlying anxiolytic- and antidepressant-like properties of the tested compounds. In conclusion, the results of our studies indicate that group III mGlu receptor agonists may play a role in the therapy of both anxiety and depression.
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PMID:Group III mGlu receptor agonists produce anxiolytic- and antidepressant-like effects after central administration in rats. 1468 Jul 55


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