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)

Sucrose gap recordings from the ventral roots of isolated, hemisected frog spinal cords were used to evaluate the effects of high concentrations of serotonin (5-HT) and alpha-methyl-5-HT (alpha-Me-5-HT) on the changes in motoneuron potential produced by dorsal root stimulation and by excitatory amino acids and agonists. Bath application of 5-HT in concentrations of 10 microM or greater produced a concentration-dependent motoneuron depolarization. Polysynaptic ventral root potentials evoked by dorsal root stimuli were reduced in both amplitude and area by 5-HT or alpha-Me-5-HT (both 100 microM). This may result from a reduction of the postsynaptic sensitivity of motoneurons to excitatory amino acid transmitters because 5-HT significantly depressed motoneuron depolarizations produced by addition of L-glutamate and L-aspartate to the superfusate. Similarly, 5-HT reduced depolarizations produced by the excitatory amino acid agonists N-methyl-D-aspartate (NMDA), quisqualate, alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), and kainate. alpha-Me-5-HT reduced NMDA depolarizations. Tetrodotoxin (TTX) did not affect the ability of 5-HT to attenuate NMDA or kainate depolarizations, but did eliminate the 5-HT-induced attenuation of quisqualate and AMPA depolarizations. The glycine receptor site associated with the NMDA receptor did not appear to be affected by 5-HT because saturation of the site by excess glycine did not alter the 5-HT-induced depression of NMDA responses. The 5-HT1C/2 antagonist ketanserin and the 5-HT1A/2 antagonist spiperone significantly attenuated the 5-HT-induced depression of NMDA-depolarizations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of 5-HT1C/2 receptors depresses polysynaptic reflexes and excitatory amino acid-induced motoneuron responses in frog spinal cord. 132 Apr 45

1. The present study assessed the potential antidepressant action of gepirone hydrochloride, an azapirone serotonin (5-HT1A) partial agonist in patients with major depression. 2. Overall, gepirone demonstrated a significant antidepressant activity within the entire patient group (p less than 0.001). However, when subjects were stratified based upon the presence or absence of DSM III-R melancholic features, the melancholic depressives showed little change in weekly depression ratings compared to patients without melancholic symptoms (p less than 0.001). 3. Similarly, patients who were more severely ill at the pretreatment period had less improvement compared to those with more modest illness severity (p less than 0.001). 4. These observations compliment those of prior studies suggesting antidepressant activity for gepirone. 5. However, a consistent efficacy comparable to conventional neuronal reuptake inhibitor antidepressants remains to be established in patients with more severe depression characterized by melancholic features.
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PMID:Gepirone, a selective serotonin (5HT1A) partial agonist in the treatment of major depression. 135 Mar 53

Several classes of drugs that modify serotonin (5-HT) neurotransmission are either currently used, or are being evaluated for their potential use in the treatment of anxiety, schizophrenia, and depression. 5-HT1A agonists are considered potential anxiolytics, while some atypical antipsychotics are potent 5-HT2 antagonists (and also have modest dopamine D2 affinity). Furthermore, there is a diverse group of serotonergic drugs that may be effective antidepressants. Secretion of ACTH, corticosterone/cortisol, prolactin, renin, oxytocin and vasopressin are stimulated by activation of different 5-HT receptor subtypes, while other neurotransmitter receptors also influence the secretion of these hormones. We compared the receptor binding profiles of 5-HT anxiolytics, antipsychotics and antidepressants with their endocrine effects. These comparisons could aid in understanding both the therapeutic and side effects of these drugs.
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PMID:Endocrine and receptor pharmacology of serotonergic anxiolytics, antipsychotics and antidepressants. 135 27

Depression is a heterogeneous disease state characterised by complex alterations in several CNS neurotransmitter and receptor systems. All antidepressants are thought to act by causing postsynaptic adaptive changes (e.g. in transducers or second messengers) within these systems. Thus, the mechanism of action of selective serotonin reuptake inhibitors (SSRIs) cannot simply be explained in terms of inhibition of serotonin (5-hydroxytryptamine) [5-HT] reuptake. Fluvoxamine, sertraline and fluoxetine downregulate central beta-adrenoceptors, and all SSRIs are believed to normalise central 5-HT1A- and 5-HT2-receptor density and function in patients with depression. SSRIs are as effective as tricyclic antidepressants in the treatment of depression, but have distinct tolerability advantages--they are not associated with anticholinergic adverse effects, cardiotoxicity, sedation or weight gain. However, gastrointestinal reactions (e.g. nausea, diarrhoea/loose stools, constipation) are relatively common during SSRI therapy. Additionally, in contrast to tricyclic antidepressants, SSRI dosage adjustments appear to be unnecessary in elderly depressed patients. Fluvoxamine has a much shorter elimination half-life than fluoxetine and its active metabolite, norfluoxetine, and therefore a reduced potential for drug interactions. Only small amounts of fluvoxamine and fluoxetine, but large quantities of paroxetine, are secreted in breast milk. Furthermore, genetic polymorphism has not been documented for fluvoxamine metabolism, whereas slow and fast metabolisers of paroxetine, and fast metabolisers of fluoxetine have been identified. SSRIs have a better tolerability profile than tricyclic antidepressants, as indicated by lower mean rank scores for behavioural toxicity. Moreover, SSRIs are associated with a much lower incidence of fatal toxicity than tricyclics, and appear to be relatively safe in overdosage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological differences of serotonin reuptake inhibitors and possible clinical relevance. 137 71

The effects of different doses of buspirone, 3-dipropyl-amino-5-hydrochromar (NDO 008) and 8-hydroxydipropyl-aminotetralin (8-OH-DPAT) (administered intraperitoneally) were studied in tests of anxiolytic and antidepressant action in rats. These tests included the elavated plus maze test, the forced swim test, stress-induced suppression of open-field behavior, and the differential-reinforcement-of-low-rates-of-behaviour-72 sec (DRL 72 s) test. Buspirone (0.125 mg/kg) and NDO 008 (1.0 to 2.0 mg/kg) produced anxiolytic activity in the elevated plus maze, whereas 8-OH-DPAT did not in the doses employed. All three compounds increased activity in the forced swim test, although buspirone did so at a lower dose than NDO 008 and 8-OH-DPAT. In the stress-induced suppression test of open field activity all three compounds induced an antidepressant-like effect at different doses dependent on whether footshock (stressor) was presented 24 hr before or just prior to the open-field test. All three compounds even caused some reduction of activity in the non-shocked rats. 8-OH-DPAT (1.0 mg/kg) produced a significant and reliable increase in the Reinforcement/Response rate quotient in the DRL 72s test. These diverse results may provide an indication of potential clinical efficacy of the 5-HT1A agonists in the treatment of anxiety and depression.
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PMID:5-Hydroxytryptamine1A receptor agonists in animal models of depression and anxiety. 138 35

Quantitative autoradiography was used to evaluate the effects of adrenalectomy (ADX) and corticosterone (CORT) on binding at 5-HT1A and 5-HT1B receptors in the dorsal hippocampus and cortex of the rat. ADX increased binding of [3H]8-hydroxy-2-(di-n-propylamino)tetralin at 5-HT1A receptors in the oriens and lacunosum moleculare layers of CA2 and CA3, in the lacunosum moleculare layer of CA4 region, and in the dentate gyrus. In restraint-stressed ADX rats, binding was increased only in the oriens and lacunosum moleculare layers of CA2. Restoration of baseline levels of CORT reversed the effects of ADX on 5-HT1A receptors in the hippocampus, while high levels of CORT decreased binding at 5-HT1A receptors in the dentate gyrus. No treatment affected binding at 5-HT1A receptors in the CA1 region of the hippocampus or in the cortex. ADX increased binding of [125I]iodocyanopindolol at 5-HT1B receptors in the infrapyramidal dentate, but this effect was not observed in ADX rats that were restrained. CORT treatment in both ADX and SHAM (adrenally intact) rats resulted in binding at 5-HT1B receptors that was lower than that in untreated ADX and SHAM rats in the infrapyramidal dentate, and lower than that in ADX rats in the suprapyramidal dentate and CA4. In ADX and SHAM rats, CORT also reduced binding at 5-HT1B receptors in area 2 of the cortex. It is suggested that decreases in binding at 5-HT1A and 5-HT1B/1D receptors resulting from chronic exposure to high levels of CORT may also occur in animals that fail to adapt to chronic severe stress. Such changes in binding may play important roles in the etiology of depression.
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PMID:Autoradiographic analyses of the effects of adrenalectomy and corticosterone on 5-HT1A and 5-HT1B receptors in the dorsal hippocampus and cortex of the rat. 153 16

Thirty-three years ago, Gaddum and Picarelli classified the serotonin receptors in the guinea pig ileum into D and M types based on the activity of dibenzyline and morphine to block contractions of intestinal smooth muscle caused by serotonin. The subsequent location of specific ligand binding sites for serotonin in the brain has led to the identification of at least eight serotonin receptor sub-types in rat brain. While there is some controversy over the functional importance of many of these receptor sub-types, there is evidence that they fall into two major groups according to the nature of their coupling to secondary messengers or ion channels. Thus the 5-HT1 and 5-HT2 receptors appear to occupy the G protein receptor sub-family which may be coupled either to adenylate cyclase (most 5-HT1 sub-types) or phosphatidyl inositol (5-HT2 sub-types). The central "M" receptors (now termed 5-HT3) appear to occupy a ligand gated ion channel super-family. The cloning of three of the serotonin receptor sub-types in 1989 (5-HT1A, 5-HT1C and 5-HT2) has been of importance in enabling the receptor sub-types to be classified as specific protein molecules encoded by specific genes. The problem now arises with regard to the linking of the changes in the cellular activity of the various receptor sub-types with the plethora of behavioural changes that arise as a consequence of the actions of serotonin in the brain. The present review summarizes the evidence implicating the role of specific serotonin receptor sub-types in eating disorders, sleep, sexual activity, anxiety states, aggression, schizophrenia and depression. A summary of the relationship between these receptor sub-types and their possible involvement in the aetiology of these diseases is shown in Table 2.
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PMID:Sub-types of serotonin receptors: biochemical changes and pharmacological consequences. 162 53

Hormonal modulation of neurotransmission emerged as a concept from the recognition that adrenocortical steroids exert profound effects at the level of receptors, G-proteins and effector units. G-proteins, a family of guanine nucleotide binding regulatory components that couple neurotransmitter receptors to various types of intracellular effector systems, appear to be a key target of glucocorticoid (GC) action in the CNS. It is thought that Gs/Gi mediates stimulation/inhibition of adenylate cyclase (AC system), which forms cyclic AMP as second messenger, while receptors stimulating phospholipase C do so through Go to produce two second messengers, inositol 1,4,5-triphosphate and diacylglycerol (PI system). Recent evidence suggests that GC increase Gs alpha-and decrease Gi alpha-protein subunit expression without affecting Go alpha. Activation of central pre- and postsynaptic 5-HT1A receptors which are linked to the Gi-AC complex, induces hypothermia and ACTH/cortisol release in rodents and humans. Compared with controls, patients with a major depressive disorder exhibit increased basal cortisol secretion associated with decreased hypothermic and ACTH/cortisol responses. The attenuated neuroendocrine and thermoregulatory response to 5-HT1A receptor activation may reflect a GC-dependent feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) system and subsensitivity of the presynaptic 5-HT1A-Gi-AC complex function. Differential regulation of 5-HT1A and 5-HT2 function leading to a relative 5-HT2-Go-PI complex supersensitivity may maintain HPA hyperactivity during the course of depression. These findings corroborate recent reports that GC, via GC-GC receptor (GR) complex activated promotion of gene transcription, modify the expression 5-HT1A-coupled Gi (but not 5-HT2-coupled Go) resulting in altered sensitivity of 5-HT1A-mediated signal transduction and further support the hypothesis of a differential regulation of 5-HT1A and 5-HT2 receptor function and a GC-GR/5-HT1A-G-protein--effector system-related abnormality in depression.
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PMID:The 5-HT receptor--G-protein--effector system complex in depression. I. Effect of glucocorticoids. 164 69

Several developments in serotonin neuropharmacology have implications for psychiatric disorders and have already begun to impact their treatment. Selective inhibitors of serotonin uptake, which enhance serotonergic function by preventing the removal of serotonin from the synaptic cleft via the membrane transporter, have been introduced for the treatment of depression and may be effective in other disorders. Precursor loading can increase serotonin concentrations in the synaptic cleft, and tryptophan--which has been available in health food stores and drug stores--had become increasingly used for self-medication of depression, insomnia, and premenstrual syndrome. Conversion to serotonin is not the major metabolic pathway for tryptophan, and large increases in other tryptophan metabolites (such as quinolinic acid, a substance that is excitotoxic at high concentrations) accompany small increases in extracellular serotonin. The recent epidemic of the eosinophilia-myalgia syndrome associated with tryptophan now appears due to a trace contaminant in the product from a single manufacturer. A major advance in serotonin pharmacology has been the elucidation of serotonin receptor heterogeneity. At least seven receptor subtypes (5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2, 5-HT3, 5-HT4) have been identified in brain. Direct-acting agonists and antagonists can have selective affinity for specific receptor subtypes. Selective activation of 5-HT1A receptors seems to cause anxiolytic and possibly antidepressive effects. Selective antagonists of 5-HT2 or 5-HT3 receptors may be useful in treating anxiety and schizophrenia. Drugs that enhance serotonergic function suppress aggression in animals, but the specific receptor subtypes involved are not known. The advances being made in serotonin pharmacology will help define the role of this brain neurotransmitter in psychiatric and other disorders and can be expected to lead to further therapeutic advances.
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PMID:Role of serotonin in therapy of depression and related disorders. 167 51

The 5-HT1A agonists buspirone, gepirone and ipsapirone have been shown to possess antidepressive-like properties in several animal models of depression as well as in clinical studies. These compounds are metabolized to 1-(2-pyrimidinyl)-piperazine (1-PP) in rats and humans. In the learned helplessness paradigm, buspirone exhibits a biphasic action: at low or moderate doses it shows an antidepressant-like effect but this action progressively disappears as the doses are increased. In order to establish whether 1-PP affects the reversal of helpless behaviour induced by the 5-HT1A agonists at high doses in rats, we have investigated its role in the learned helplessness. Thus, 1-PP has been evaluated alone (0.06-4 mg/kg/day) or in combination with a selective 5-HT1A agonist 8-OH-DPAT (0.25 mg/kg/day) which is not metabolized to 1-PP and buspirone (0.5 mg/kg/day). In addition, buspirone at a higher dose (2 mg/kg/day) has also been examined in the presence of proadifen which inhibits oxidative metabolism. Our results show that i) daily injections of 1-PP did not reverse helpless behaviour, ii) the reversal of helpless behaviour by 8-OH-DPAT or active dose of buspirone was antagonized by daily coadministration of 1-PP, iii) in rats pretreated with proadifen, the highest "inactive" dose of buspirone induces a reversal of helpless behaviour. These results strongly suggest that up to a certain concentration 1-PP can impair the effects of the parent drug in the learned helplessness.
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PMID:1-(2-pyrimidinyl)-piperazine may alter the effects of the 5-HT1A agonist in the learned helplessness paradigm in rats. 167 95


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