Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recent discovery and characterization of three new 5-HT1 receptor clones and the pharmacological characterization of one orphan receptor (dog RDC4) has revealed a surprising complexity within the 5-HT1D receptor subfamily. This receptor subfamily, which is believed to be the target of the anti-migraine drug sumatriptan and may regulate feeding behavior, anxiety, depression, cardiac function and movement, can now be approached on a molecular level. These cloning discoveries have also taught us an important general lesson about the molecular pharmacology of G protein-coupled receptor genes: species homologues of a gene (the equivalent gene in different species) may be highly homologous in amino acid sequence yet display very different pharmacological properties. Conversely, two different genes in the same species (intraspecies subtypes) that display only moderate degrees of transmembrane amino acid homology can display nearly indistinguishable pharmacological properties. In discussing the implications of these findings for both 5-HT receptors and G protein-linked receptors in general, Paul Hartig, Theresa Branchek and Richard Weinshank approach the question: why have so many receptor subtypes been preserved in the genome? In addition, controversy has been raging for several years over the classification of 5-HT1B receptors (found only in rat brain) and 5-HT1D receptors. Were they different subtypes or simply species homologues of the same receptor? Recent cloning studies have apparently complicated this issue, but the answer to the question is, in fact, becoming clearer.
 ...
PMID:A subfamily of 5-HT1D receptor genes. 158 9

Serotonin basic neuroscience discoveries are evolving at a very fast pace and are leading to innovations in clinical psychiatry and in drug development. Numerous novel pharmacological tools, each selective for a given serotonin receptor subtype, are being applied to several psychiatric disorders. The strategy employed is theory driven and hypothesis oriented, aiming for new drug development that selectively targets receptors that are rational sites for therapeutic actions. Thus, serotonin uptake inhibitors are targeting not only depression, but also obsessive-compulsive disorder (OCD). Serotonin1A agonists are targeting not only depression and anxiety, but also mixed anxiety depression. These and other agents selective for additional receptors are being tested in impulse control disorders; eating disorders; addictive disorders; and aggressive, violent, self-destructive, and suicidal behaviors. Serotonin research is an excellent example of how basic science discoveries in the 1990's "Decade of the Brain" are resulting in important advances in therapeutics for psychiatry.
 ...
PMID:Serotonin neuroscience discoveries usher in a new era of novel drug therapies for psychiatry. 160 40

Utilizing current-clamp and single electrode voltage-clamp techniques we have studied the actions of serotonin (5-HT) on a transient outward voltage-dependent potassium current in adult rat Purkinje cells (PCs) in vitro. Under voltage-clamp, bath-applied 5-HT (10 nM-100 microM) reversibly depressed a transient outward potassium current in a dose-dependent manner in 24 of 26 neurons. This depression was apparent at all test command voltages. In current clamp, with normal bathing medium, 5-HT decreased the latency to first spike firing and increased the number of spikes in response to depolarization. Similar effects were evident when 4-aminopyridine was applied. In bathing medium containing TTX, Cs+ and Ni2+ to block voltage-activated currents, 5-HT increased the trajectory of the electrotonic membrane response elicited by depolarizing current injection. Enhanced responsiveness of PCs by 5-HT was not related to changes in membrane potential or input resistance. These experiments indicate that one mechanism by which 5-HT can increase the excitability of PCs is via reduction of a transient outward current.
 ...
PMID:Serotonin reduces a voltage-dependent transient outward potassium current and enhances excitability of cerebellar Purkinje cells. 161 3

Patients with obsessive-compulsive disorder (OCD) have been shown to be preferentially responsive to serotonin (5-HT) uptake-inhibiting antidepressants including clomipramine, fluoxetine, fluvoxamine, and sertraline. The nontricyclic antidepressant, trazodone, also possesses serotonin reuptake inhibiting properties and has been reported to be efficacious in OCD in several case reports and open trials. In order to investigate trazodone's potential antiobsessive efficacy in a controlled fashion, 21 patients with OCD were entered into a double-blind, parallel design comparison of trazodone and placebo. There were no significant differences in baseline rating scores of OCD or depressive symptoms between those who entered the trazodone phase (N = 13) versus those who entered the placebo phase (N = 8). As measured by standardized OCD and depression rating scales, there was no significant difference in OCD or depressive symptoms in the 17 patients who completed 10 weeks of trazodone (N = 11, mean daily dose, 235 +/- 10 mg) versus 10 weeks of placebo (N = 6) administration. In comparison to clomipramine and fluoxetine treatment which we have found to be associated with greater than 95% reduction in platelet 5-HT concentration, there was only a 26% mean reduction in platelet 5-HT concentration after 10 weeks of trazodone administration. These results indicate that trazodone lacks substantial antiobsessive effects and is associated with only modest reductions in platelet 5-HT concentrations.
 ...
PMID:A double-blind, placebo controlled study of trazodone in patients with obsessive-compulsive disorder. 162 80

1. The intersegmental coordination during undulatory locomotion in lamprey is characterized by a constant phase lag between consecutive segments, that is, the ratio between the intersegmental time lag and the cycle duration remains constant. It is shown that the spinal 5-HT (serotonin) system can, in a graded fashion, control the phase lag value from a rostrocaudal to a caudorostral lag corresponding to a reversed direction of swimming. These effects can be explained by a 5-HT-induced depression of Ca(2+)-dependent K+ channels (KCa channels) in network neurons. 2. The actions of the spinal 5-HT system were analyzed in the lamprey spinal cord preparation in vitro. Fictive swimming was induced by bath application of N-methyl-D-aspartate (NMDA). The intersegmental phase lag between ventral root burst activities was measured along the ipsilateral side of the spinal cord. The chamber with the preparation was partitioned into two pools so that the rostral and caudal halves of the preparation could be perfused independently with solutions containing the same level of NMDA (100-150 microM) with or without additional 5-HT or a 5-HT uptake blocker (citalopram). 3. Addition of 5-HT to one of these partitioned pools changed the intersegmental phase lag in this pool, whereas the cycle duration remained unchanged. It was determined by the activity in the "non-5-HT" pool. Addition of 5-HT to the caudal pool resulted in an increased rostrocaudal phase lag. When 5-HT was added to the rostral pool, on the other hand, the phase lag shifted direction to a backward coordination.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Local serotonergic modulation of calcium-dependent potassium channels controls intersegmental coordination in the lamprey spinal cord. 162 70

The mechanisms by which benzodiazepines produce muscle relaxation and respiratory depression are not known, but they may include actions on peripheral benzodiazepine receptors or central GABA receptors, or a direct action on airway smooth muscle may also be involved. We have compared, therefore, the effects of diazepam, flunitrazepam and midazolam on airway tone by measuring isometric tension of guineapig trachealis muscle. Cumulative concentrations of diazepam, flunitrazepam and midazolam caused concentration-dependent relaxation of resting tone in the tracheal smooth muscle with no significant differences in pD2 values (-log EC50--an index of potency) or intrinsic activities (% of maximum response) for relaxations for the three compounds. Pretreatment with propranolol 10(-6) mol litre-1, flumazenil 10(-7) and 10(-6) mol litre-1 or PK11195 10(-6) mol litre-1 had no effect on diazepam- or midazolam-induced relaxation. Diazepam 3 x 10(-6) mol litre-1 pretreatment shifted the concentration-response curves for acetylcholine, histamine and serotonin (5-HT) to the right by a factor of approximately 2. Flunitrazepam 3 x 10(-6) mol litre-1 pretreatment also shifted the curves for histamine and 5-HT similarly to the right, whereas midazolam pretreatment did not inhibit any agonist-induced contractions. These results suggest that benzodiazepines relax airway smooth muscle, not via neural pathways or central and peripheral benzodiazepine receptors, but by a direct action on airway smooth muscle.
 ...
PMID:Comparison of the relaxant effects of diazepam, flunitrazepam and midazolam on airway smooth muscle. 163 6

The hippocampus receives major noradrenergic and serotoninergic (5-HT) innervations which interact with corticosteroid-sensitive cells. However, the subregional localization of these actions and the corticosteroid receptor types involved have not been defined and current ligand binding techniques for estimating corticosteroid receptors are hampered by several methodological limitations. We have developed in situ hybridization histochemical techniques to allow specific and sensitive estimation of glucocorticoid (GR) and mineralocorticoid receptor (MR) mRNA expression in rat hippocampus. Investigation of the effects of 5,7-dihydroxytryptamine lesions of 5-HT neurons showed significantly reduced GR and MR mRNA expression in some hippocampal subregions. Both abnormal 5-HT neurotransmission and excessive corticosteroid secretion are associated with major affective disorder, particularly depression. The crucial interaction between these two systems may occur, at least in part, at the level of regulation of hippocampal corticosteroid receptor expression.
 ...
PMID:Use of in situ hybridization to investigate the regulation of hippocampal corticosteroid receptors by monoamines. 165 90

The addition of lithium to the tricyclic antidepressant medication of 23 patients with major depression resulted in an increase in the prolactin response to intravenous L-tryptophan after both four days and four weeks of treatment. The extent of this increase did not distinguish the ten patients who were classified as clinical responders (greater than 50% reduction in score on the HRSD). Among the responders there was a modestly significant correlation between the decrease in score on the HRSD and the enhancement of tryptophan-induced prolactin release. Some responders, however, showed very little change in this endocrine response over the four weeks of lithium treatment. Lithium may increase brain 5-HT function in tricyclic-resistant depression but there is only limited support for the hypothesis that changes in brain 5-HT function are involved in the antidepressant effect of this treatment combination.
 ...
PMID:Lithium in tricyclic-resistant depression. Correlation of increased brain 5-HT function with clinical outcome. 165 18

The studies reviewed here represent a continuing search for mechanisms which play a role in neurological disturbances resulting from brain injury. Focal cortical freezing lesions in rats were shown to cause a widespread decrease in local cerebral glucose utilization (LCGU) in cortical areas of the lesioned hemisphere and this was interpreted as reflecting a depression of cortical activity. Such an interpretation was supported by the finding that in lesioned brain reduction of cerebral metabolism by pentobarbital and isoflurane was limited by the metabolic depression that has already occurred as a result of injury and by the demonstration that the energy status and substrate (glucose) supply in the cortical areas in the injured brain have not been compromised at the time when LCGU was decreased. Both the serotonergic and the noradrenergic neurotransmitter systems were implicated in functional alterations associated with injury. Cortical serotonin (5-HT) metabolism was increased throughout the lesioned hemisphere and complete inhibition of 5-HT synthesis with p-chlorophenylalanine ameliorated the decrease in cortical LCGU, interpreted as reflecting cortical functional depression. Cortical norepinephrine metabolism was bilaterally increased in focally injured brain, while prazosin, a selective alpha 1-noradrenergic receptor blocker, normalized cortical LCGU in the lesioned hemisphere. Low-affinity in vivo binding of [125I]HEAT, another selective alpha 1-receptor ligand, was specifically increased in cortical areas of the lesioned hemisphere at the time of the greatest depression in LCGU, suggesting that alpha 1-adrenoreceptors may be of functional importance in injured brain.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Brain injury: new insights into neurotransmitter and receptor mechanisms. 166 96

Influences of bulbar microinjections of some neuromodulator antagonists (methysergide, haloperidol, naloxone) on depression dynamics of spino-bulbo-spinal (SBS) reflex from the periaqueductal grey (PAG) stimulation were studied in chloralose anesthetized rats. Microinjections were made into the reticular gigantocellular nucleus which is a main supraspinal centre of SBS reflexes. It is found that methysergide administration (10(-5) mol/l) causes a considerable (two to four times as less) decrease of SBS-reflex depression evoked by PAG stimulation by a short high-frequency series of stimuli. Long-lasting depression evoked usually by a long train of PAG stimuli is less reduced: from 6-10 to 2.5-4 min. A considerable (2 to 5 times) shortening of this depression is revealed after naloxone injections (10(-5)-10(-4) mol/l). The most expressed diminution of all types of inhibitions is shown to occur after haloperidol administration. Data obtained evidence that all the studied neuromodulatory systems (5-HT, catecholamine and opioidergic ones) are involved to inhibitory action of PAG on high-threshold reflex activity of the reticular formation. Some properties of neurochemical mechanisms of the studied PAG-evoked depression are discussed.
 ...
PMID:[The neurochemical mechanisms of the inhibitory influences of stimulation of the central gray substance on the high-threshold reflex activity of the reticular formation]. 168 33


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>