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)

1. Studies of the biochemical mechanism of action of antidepressant drugs show that virtually all drugs, regardless of acute biochemical effects, result in the down regulation of CNS beta-1 adrenergic, serotonin-2 (5HT2), and perhaps 5HT1A receptors in rats in a time course which parallels the onset of antidepressant action in patients with major depressive disorder. 2. Recently, neuroendocrine techniques have been described which allow the study of 5HT receptor subtypes in man. These include fenfluramine-induced changes in ACTH, cortisol and prolactin secretion (perhaps for 5HT2 receptors) and ipsapirone-induced changes in ACTH and cortisol (for 5HT1A receptors). 3. Depressed subjects treated with antidepressants down regulate these markers of both 5HT2 and 5HT1A receptors in a time course consistent with their recovery from depression. 4. Studies in progress are attempting to demonstrate links between these receptor changes and clinical antidepressant responses.
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PMID:Neuroendocrine markers of serotonin responsivity in depression. 149 23

The potentiation of fluoxetine by buspirone is described in three cases of treatment-resistant depression. All three patients improved markedly with very few side-effects from the medication. The possibility of synergy between drugs that affect serotonin reuptake inhibition, 5HT1A receptors and 5HT2 receptors is discussed.
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PMID:Fluoxetine potentiation by buspirone: three case histories. 179 May 22

5HT has been implicated in mechanisms of anxiety and depression for many years but the evidence is contradictory. Perhaps one error has been to think of 5HT as a unitary system when in reality it is highly differentiated. There has been an explosive increase in knowledge about different 5HT receptor subtypes and it has long been known that there are different anatomical subsystems. Evidence will be summarised that the different systems subserve different psychological functions and that dysfunction in the different systems results in depression, anxiety, panic and OCD in an understandable way. Much evidence is compatible with the idea that 5HT systems reduce the impact of impending or actual aversive events. Anticipation of an aversive event is associated with anxiety and this motivates avoidance behaviour--a normal adaptive response. There is evidence that this is mediated by projections of the dorsal raphe nucleus and associated 5HT2 and 5HT3 receptors. Projections of the median raphe nucleus and associated 5HT1A receptors appear to mediate resilience to aversive events once they have occurred or if they persist. When this system breaks down depression results. It will be argued that all effective antidepressants act on 5HT1A, natural mechanisms of resilience.
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PMID:Depression and 5HT. 180 32

Two specific 5-HT1A agonists, 8-OH-DPAT (0-300 micrograms/kg), and buspirone (0-3.0 mg/kg), were tested on variable-interval, threshold-current self-stimulation of rat lateral hypothalamus. Buspirone produced a prolonged monotonic depression of responding, whereas the effects of 8-OH-DPAT were biphasic: 3.0 micrograms/kg produced a sustained enhancement of responding while higher doses (100-300 micrograms/kg) produced a relatively short-lasting depression. This biphasic pattern parallels previously reported effects of 8-OH-DPAT on food intake and on various other behaviours. Threshold-current self-stimulation is highly sensitive to alterations in dopaminergic transmission but relatively insensitive to changes in 5-HT. Thus the facilitatory effect of low-dose 8-OH-DPAT seems most plausibly interpreted in terms of enhanced dopaminergic transmission. This could be brought about by 5HT1A autoreceptor-mediated inhibiton of 5-HT release and consequent disinhibition of dopaminergic transmission. Depression of self-stimulation by higher doses of 8-OH-DPAT may reflect the activity of 8-OH-DPAT at postsynaptic 5-HT receptors, with consequent inhibition of DA transmission. Suppression of responding after buspirone at all doses tested may reflect the action of this compound as a partial agonist at postsynaptic 5-HT receptors, and/or its effects on other systems.
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PMID:5-HT1A agonists and dopamine: the effects of 8-OH-DPAT and buspirone on brain-stimulation reward. 182 41

We have investigated whether attenuated growth hormone (GH) and prolactin (PRL) responses to L-tryptophan in depression return to normal with clinical recovery. Ten patients who had received intravenous infusions of L-tryptophan (100 mg/kg) when depressed were retested at least 3 months after full recovery and cessation of treatment. In recovered depressives growth hormone responses showed considerable recovery, in all but three cases to within a few units of their healthy age- and sex-matched controls. Prolactin responses increased with clinical recovery in all six male subjects. Results in females were inconclusive because of the effect of weight loss on prolactin responses. The results suggest that GH and PRL responses to tryptophan are state-dependent abnormalities rather than indicators of predisposition to depression. This allows the possibility that impaired functioning in systems with a 5HT1A or 5HT1D receptor link may be part of the causal chain in depression.
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PMID:Blunted growth hormone and prolactin responses to L-tryptophan in depression; a state-dependent abnormality. 182 42

Effects of water deprivation and restraint were compared in the rat elevated X-maze. Water deprivation for 12-48 h increased corticosterone and had a duration-dependent "anxiolytic" effect in the elevated X-maze, increasing the ratio of open/total arm entries (OTR) and the proportion of time spent on the open arms (% time) without affecting total entries. Brain 5HIAA/5HT was increased only after 24 or 48 h deprivation. Restraint for 15 min also increased plasma corticosterone and brain 5HIAA/5HT but had no effect on behaviour in the elevated X-maze when rats were tested immediately afterwards. However, 1 h restraint was "anxiogenic" in the elevated X-maze immediately after release, reducing OTR and % time, but with a less consistent reduction in total entries; reductions in OTR and % time were still present 24 h later. The 5HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (0.1-0.2 mg/kg), administered 10 min before testing in the elevated X-maze, had "anxiogenic" actions in non-stressed rats. The effect of 0.1 mg/kg 8-OH-DPAT was not significantly altered by 24 or 48 h water deprivation but was abolished by restraint for 1 h immediately beforehand, despite the "anxiogenic" effect of restraint alone. Similar mutual antagonism of 8-OH-DPAT and restraint occurred when the dose of 8-OH-DPAT was increased to 0.2 mg/kg. Twenty-four hours after restraint, restrained rats which had received 8-OH-DPAT (0.1-0.2 mg/kg) still did not show any significant "anxiogenic effect" compared with non-restrained vehicle treated controls. Restraint-induced deficits in elevated X-maze exploration may prove a useful model with which to study the pharmacology of depression-related anxiety. However, the effects of the stressors examined, and their interaction with 8-OH-DPAT in the elevated X-maze, appear to depend on the nature of the stressor.
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PMID:Effects of two stressors on behaviour in the elevated X-maze: preliminary investigation of their interaction with 8-OH-DPAT. 753 13

The aim of the present study was to further investigate the behavioural and biochemical pharmacology of the directly acting dopamine (DA) receptor agonist bromocriptine (BRC). BRC produced an initial depression of locomotion followed after about an hour by a weak but significant locomotor stimulation. The stimulation was potentiated by concomitant administration of the D1 agonist SKF38393. Ex vivo biochemical determinations indicated that reductions in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels occurred in the striatum after BRC injection without a significant change in DA levels, indicating a reduced DA turnover. An increase in 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid (5HIAA) levels occurred in the striatum leading to a significant increase in turnover (i.e. ratio of 5HIAA to 5HT). Noradrenaline concentrations increased in the striatum. In the cortex, sharp falls in HVA and DOPAC levels without a corresponding change in DA were observed. While there was no significant change in noradrenaline levels in this brain region, an increase in 5HIAA, but not in 5HT, levels occurred. These changes indicate an increase in 5HT turnover (ratio of 5HIAA to 5HT). In vivo dialysis indicated that extracellular levels of DA, DOPAC and HVA in the striata of freely moving rats were sharply reduced for at least 6 h after injection. In vitro binding studies showed that BRC exhibited high (Ki values in low nanomolar range) affinities for DA D2A, D2B, D3, alpha 1 and alpha 2 adrenergic receptors together with unexpectedly high affinity (about 1 nM) for 5HT1A receptors. The data indicate that the initial behavioural depression and later locomotor stimulation induced by BRC are accompanied by a sharp monophasic fall in striatal extracellular DA levels as indicated by dialysis studies. Since the behavioural stimulation was augmented by concomitant D1 receptor stimulation, the data suggest that the reduced DA turnover is influencing the amount of DA available to stimulate postsynaptic D1 receptors. However, the biochemical studies indicated that BRC has a high affinity for 5HT1A receptors and affects the turnover of 5HT in the brain. Thus, the behavioural effects of BRC may depend not only on effects on the DA system but also on 5HT systems.
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PMID:Time course of bromocriptine induced excitation in the rat: behavioural and biochemical studies. 753 23

Serotonergic transmission is thought to be central to the aetiology of depression and the therapeutic actions of antidepressant drugs, and the latters' delayed effect has given rise to the hypothesis that an adaptive change may be involved, possibly at the level of gene expression. We have examined this hypothesis by treating rats over a time course of up to 32 days with either imipramine, mianserin, fluvoxamine, citalopram, amoxapine or saline and measuring the levels of mRNAs encoding the 5HT1A, 5HT1B, 5HT1C and 5HT2 receptors, the enzymes tryptophan hydroxylase and aromatic amino acid decarboxylase, and the 5HT transporter. None of the treatments gave rise to significant changes in any of the mRNA levels at any time point. These results suggest that the reported changes in 5HT receptor numbers do not occur as a result of changes in the abundance of their encoding mRNAs, and that changes to the latter is not central to the therapeutic effects of antidepressant drugs.
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PMID:Lack of effect of antidepressant drugs on the levels of mRNAs encoding serotonergic receptors, synthetic enzymes and 5HT transporter. 798 81

Microdialysis was used to characterize the effect of serotonergic input on cholinergic interneurons in the nucleus accumbens (NAC) of freely moving rats. Local infusion of 5-hydroxytryptamine (5-HT) or the serotonin reuptake blocker fluoxetine significantly decreased extracellular acetylcholine (ACh) in the NAC. This decrease in ACh was blocked by the 5-HT1 (and beta-adrenergic) antagonist propranolol. To test suggests that 5-HT inhibits ACh interneurons via one of the 5-HT1 receptor types. The 5HT1A agonist 8-OH-DPAT given systemically again decreased extracellular levels of ACh, and the effect was dose-dependent. The 5-HT1A effect was probably exerted in the NAC, because local infusion of 8-OH-DPAT mimicked systemic injections. These microdialysis results are similar to in vitro studies which suggest an inhibitory impact of 5-HT on ACh release in basal ganglia slices and homogenates. The decrease in extracellular ACh as measured in vivo is apparently mediated, at least in part, through a 5-HT1A receptor in the accumbens. Given the role of the NAC in behavior reinforcement, this 5-HT-ACh interaction may be involved in serotonergic treatment of depression.
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PMID:In vivo modulation of acetylcholine in the nucleus accumbens of freely moving rats: I. Inhibition by serotonin. 837 97

Serotonergic pathway disturbances have been implicated in neuropsychiatric disorders such as Tourette's syndrome (TS), substance abuse, and depression. In order to search for the presence of an association between these neuropsychiatric disorders and particular serotonin receptors isolated from these patients, we have started to analyze the structure of these receptor genes. We now report that a missense nucleotide change in the 5HT1A receptor gene produces a variant form of the 5HT1A receptor (Arg(219) to Leu) identified in DNA extracted from a TS patient. Also, in several DNA samples examined, both in controls and in the patients, we found a second missense nucleotide change which resulted in an amino acid change (Asn(417) to Lys) located in the carboxyl tail of the receptor. Several other polymorphic changes have been reported previously in the human 5HT1A receptor and we have also confirmed these findings in our samples.
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PMID:A serotonin receptor gene (5HT1A) variant found in a Tourette's syndrome patient. 864 69


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