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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of antidepressant drugs on central 5-HT receptor activity were studied in rats and mice. Antidepressant drugs were evaluated for their ability to displace 3H-5-HT and 3H-d-LSD from membrane binding sites in the dorsal neocortex of rats in vitro and for their ability to block 5-HTP and d-LSD induced behavioral effects in mice. The degree of blockade of head-twitches in mice produced by the antidepressants was highly correlated with their affinity for 3H-d-LSD binding sites. A number of antidepressant drugs such as amitriptyline, nortriptyline, mianserine, doxepine, nomifensine and dibenzepine appear to possess marked 5-HT receptor blocking activity at some type of 5-HT receptors in brain. New antidepressant drugs such as zimelidine, which specifically inhibit 5-HT reuptake and do not block 5-HT receptor sites, may after chronic treatment also reduce the functional activity of 5-HT systems by producing adaptive changes in postsynaptic 5-HT mechanisms. Thus, a new indoleamine hypothesis of depression is presented: the therapeutic action of antidepressant drugs may in part be due to a reduced functional acitivity of some central 5-HT systems.
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PMID:Reevaluation of the indoleamine hypothesis of depression. Evidence for a reduction of functional activity of central 5-HT systems by antidepressant drugs. 57 36

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

1. Isolated rings of rabbit external jugular vein (RbJV) and rat thoracic aorta (RA) were used to study the effect of the NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME) on muscarinic and 5-hydroxytryptamine (5-HT) receptor-stimulated, endothelium-dependent vascular relaxations. 2. In RbJV relaxations produced by the endothelial 5-HT receptor agonist alpha-methyl-5-HT were potently and non-surmountably inhibited by L-NAME (10 microM), whereas acetylcholine relaxations in this tissue were unaffected by this concentration of inhibitor. By contrast, acetylcholine relaxations in RA were virtually abolished by 10 microM L-NAME. In each case an equivalent concentration of D-NAME was without effect on agonist-induced relaxations. 3. The different effect of L-NAME on acetylcholine relaxations in RbJV and RA was not due to muscarinic receptor differences. Affinity estimates for acetylcholine (pKA = 6.12 +/- 0.09; 6.09 +/- 0.08 respectively) and for 4-diphenyl-acetoxy-N-methylpiperidine methobromide (4-DAMP, pKB = 9.01 +2- 0.012; 9.24 +/- 0.16 respectively) indicated that the receptors in both tissues belong to the same M3 class. Tissue differences resulting from the release of a cyclo-oxygenase product or a glibenclamide-sensitive K(+)-channel-linked hyperpolarizing factor were also ruled out by selective inhibition of these pathways. 4. When phenoxybenzamine was used to reduce the efficacy of acetylcholine in RbJV so that it behaved as a partial agonist in this tissue, L-NAME (10 microM) now produced non-surmountable inhibition of relaxation responses. In untreated tissues the same concentration of L-NAME also profoundly inhibited responses produced by butyrylcholine and pilocarpine, both of which behave as partial agonists at the M3 receptor in RbJV. 5. A simple model was developed which describes the theoretical behaviour of receptor-stimulated synthesis and release of NO. The model predicts that competitive inhibition of NO formation results in parallel displacements of the agonist response curve in the case of high efficacy agonist, but right-shift with concomitant depression of the curve maximum in the case of low efficacy agonists. Simulations based on the model showed reasonable agreement with the experimental data. 6. It is concluded that analogues of L-arginine demonstrate tissue- and agonist-dependence in terms of their ability to inhibit receptor-mediated events involving the liberation of NO. This behaviour can reflect differences in agonist efficacy in the receptor systems being studied, a possibility that should be ruled out before apparent resistance to inhibition is taken as evidence for the involvement of heterogeneous endothelium-derived relaxing factors (EDRFs).
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PMID:Inhibition of endothelium-dependent vasorelaxation by arginine analogues: a pharmacological analysis of agonist and tissue dependence. 162 52

1. Monosynaptic (MSR) and polysynaptic (PSR) segmental reflex responses were recorded from a ventral root of the neonate rat hemisected spinal cord. Amplitudes of the two components were monitored with a peak height detector. 2. 5-Hydroxytryptamine (5-HT) depressed the MSR and PSR in a concentration-dependent manner. The IC50 for MSR depression was 9.5 +/- 3.2 microM and for PSR depression was 9.0 +/- 4.8 microM. 3. Blockade of neuronal uptake of 5-HT by citalopram (0.1 microM) greatly increased sensitivity to 5-HT. In the presence of citalopram, the IC50 for MSR depression was 30 +/- 18 nM and for PSR depression was 89 +/- 23 nM. 4. 5-HT did not depress the MSR or the PSR by releasing glycine since strychnine (1 microM) did not prevent these actions of 5-HT. 5. 5-Carboxamidotryptamine (5-CT), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), RU 24969, 1-[3-(trifluoromethyl)phenyl]-piperazine (TFMPP) and methysergide were full agonists for depression of the MSR. The IC50 for 5-CT was 3.6 +/- 0.5 nM, for 8-OH-DPAT was 0.4 +/- 0.04 microM, for TFMPP was 0.93 +/- 0.3 microM and for methysergide was 21.8 +/- 3.0 nM. The order of potency was 5-CT greater than methysergide greater than 5-HT greater than 8-OH-DPAT greater than TFMPP. 6. 8-OH-DPAT, RU 24969, TFMPP and methysergide had either no or only a minor action in reducing the PSR. 5-CT caused a 50% depression at the highest concentration tested (30 nM). 7. Neither ketanserin (1 microM) nor spiperone (1 microM) caused appreciable blockade of 5-HT depression of the MSR or 5-HT depression of the PSR. 8. Blockers of neuronal 5-HT uptake (citalopram 0.1 or 1 microM, fluvoxamine 1 microM) usually reduced the MSR and, to a lesser extent, the PSR. Reflex depressions were reversed by ketanserin (1 microM). 9. It was concluded that 5-HT has a potent depressant action on segmental reflexes; depression of the MSR is unrelated to depolarization of motoneurones. Although depression of the MSR was mimicked by 5-HTIA receptor ligands, the action of endogenous 5-HT may be mediated through 5-HT2 receptors. Exogenous 5-HT may act at a mixture of 5-HT receptor subtypes to depress the MSR.
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PMID:Inhibition of reflex responses of neonate rat lumbar spinal cord by 5-hydroxytryptamine. 193 39

The selective 5-HT1A receptor ligand ipsapirone (IPS) induces hypothermia in humans. To explore 5-HT1A receptor-mediated thermoregulation in depression, 24 subjects (12 patients with unipolar depression and 12 individually matched controls) received 0.3 mg/kg IPS or placebo in random order. Compared with controls, the depressed patients exhibited significantly attenuated hypothermic responses to IPS. The impaired hypothermic response following 5-HT1A receptor activation in unipolar depression could have resulted from subsensitivity of the (presynaptic) 5-HT1A receptor and/or related effector mechanisms, thus supporting the hypothesis that altered serotonergic activity may be present in affective disorders. Future studies of the hypothermic response to direct-acting 5-HT1A ligands, such as IPS should facilitate the assessment of 5-HT receptor function in various affective disorders and its involvement in psychotropic drug effects.
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PMID:Subsensitivity of the 5-hydroxytryptamine1A (5-HT1A) receptor-mediated hypothermic response to ipsapirone in unipolar depression. 197 1

The effects of 5-HT are varied and widely distributed throughout the human body. At this time, 5-HT research is a field ripe for "plucking." Not only is there a great demand for more selective agonists and antagonists, but there is more than enough work needed in receptor binding studies to keep pharmacologists employed for years to come. The clinical benefits of 5-HT receptor pharmacology are just starting to be developed and explored. Novel treatments for hypertension, migraine headaches, anxiety, and depression using 5-HT are just the beginning. It will be exciting to see what the future holds for 5-HT clinically.
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PMID:Serotonin receptor subtypes: functional, physiological, and clinical correlates. 202 90

Most evaluations of the contributions of possible alterations in serotonergic neurotransmission to the etiology and treatment of neuropsychiatric disorders preceded the recent explosion of information regarding multiple serotonin (5-HT) receptors and brain 5-HT subsystems. This review provides an appraisal of some examples where drugs acting at different 5-HT receptor subtypes have provided new treatment or have contributed to the development of knowledge regarding various neuropsychiatric disorders, including anxiety, panic disorder, obsessive-compulsive disorder, depression, schizophrenia, alcoholism, migraine, sexual dysfunction, and Alzheimer's disease.
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PMID:Neuropsychiatric disorders and the multiple human brain serotonin receptor subtypes and subsystems. 207 79

The special role of behavioral studies in attempting to understand the substrates for the psychotherapeutic actions of 5-hydroxytryptamine1A (5-HT1A)-selective agents, such as buspirone and other azapirones, is reviewed. The effects of buspirone and related drugs is discussed in three different types of behavioral studies: (1) unconditioned behaviors elicited by 5-HT agonists; (2) drug discrimination studies; and (3) conditioned behaviors that predict clinical drug effects. These studies have helped define important neuropharmacologic actions on 5-HT receptors that may contribute to therapeutic effects in anxiety and depression. Finally, critical problems for advancing our understanding of the association between 5-HT receptor subtypes and behavior are discussed.
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PMID:5-Hydroxytryptamine1A receptors and behavioral responses. 207 81

In view of evidence that brain serotonin (5-HT) function is abnormal in depression, the ability to alter 5-HT function has been studied as a mechanism of antidepressant drug action. In preclinical studies, antidepressants had significant effects on 5-HT receptor sensitivity. In the clinical setting, the pharmacologic challenge paradigm has generated interest as a means of studying 5-HT function. Most frequently used in these studies has been intravenous L-tryptophan (L-TRP), which increases serum prolactin (PRL). The authors review the neuroendocrine effects of intravenous L-TRP in depression and other conditions, as well as the effects of thymoleptic drugs on the PRL response to L-TRP. Findings are discussed in light of recent evidence that experimentally reduced plasma TRP can reverse the therapeutic effects of some antidepressants.
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PMID:Clinical data on the role of serotonin in the mechanism(s) of action of antidepressant drugs. 218 16

Intracellular recordings were made from neurons of rabbit vesical pelvic (parasympathetic) ganglia (VPG). Application of 5-hydroxytryptamine (5-HT, 0.3-30 microM) produced an initial depression followed by a long-lasting facilitation of the fast excitatory postsynaptic potential (e.p.s.p.) evoked by stimulation of the pelvic preganglionic nerve. The facilitation of nicotinic transmission lasted for 30-120 min, even when 5-HT was removed from the superfusing solution. 5-HT (0.3-30 microM) did not change the depolarization induced by a direct application of acetylcholine (ACh) to the VPG neurons pretreated with 1 microM atropine. 5-HT also caused an initial depression followed by an increase in the quantal content of the fast e.p.s.p. It is, therefore, suggested that diphasic effect of 5-HT on the nicotinic transmission is due mainly to a modulation of the ACh-release from presynaptic nerve terminals. Methysergide (5 microM), mianserin (5-30 microM) and ICS 205-930 (100-300 nM) did not antagonize the presynaptic actions of 5-HT on the nicotinic transmission, suggesting that the presynaptic 5-HT receptor may belong to a class of 5-HT1 subtypes. Spiperone (1 microM), a selective 5-HT1A antagonist, blocked the 5-HT-induced inhibition of the fast e.p.s.p. Under the effect of spiperone, the facilitation appeared soon after application of 5-HT. The facilitation of the fast e.p.s.p. may be mediated through a 5-HT1B or 5-HT1C subtype. Lowering temperature of the external solution eliminated the 5-HT-induced facilitation of the nicotinic transmission. Forskolin produced a presynaptic facilitation of the fast e.p.s.p., without producing an initial depression. 3-Isobutyl-1-methylxanthine (10 microM) potentiated the facilitatory action of 5-HT. Bath-application of dibutyryl cyclic adenosine monophosphate (cAMP) (1-6 mM) and 8-bromo-cyclic AMP (2-5 mM) mimicked the effect of 5-HT in producing the facilitation of the fast e.p.s.p.s. All data presented are consistent with the hypothesis that 5-HT, acting on presynaptic 5-HT1 receptors, causes a facilitation in the release of ACh from preganglionic nerve terminals possibly mediated through an activation of adenylate cyclase.
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PMID:5-Hydroxytryptamine produces presynaptic facilitation of cholinergic transmission in rabbit parasympathetic ganglia. 254 88


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