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)

Intracellular recordings were made from motoneurons in transverse spinal cord slices from immature (12-20 day) rats and the effects of 5-HT on dorsal root evoked excitatory (EPSPs) and inhibitory (IPSPs) postsynaptic potentials were assessed. With or without causing a membrane polarization, 5-HT (1-300 microM) depressed synaptic responses; the IC50 was 6 microM. The inhibitory effect was potentiated by the uptake inhibitor fluoxetine. The 5-HT1A/1B agonists 5-CT and 8-OH-DPAT and the 5-HT1B/1C agonist TFMPP reduced the synaptic responses as well, with an IC50 of 0.26, 2.2 and 0.28 microM, respectively. The synaptic depressant effect was not antagonized by methysergide (0.1-1 microM), ketanserin (1-5 microM) and MDL 72222 (1-10 microM). Methysergide alone diminished the synaptic responses in some of the motoneurons. Spiperone (1-10 microM) partially and fully antagonized the depressant effect of 5-HT and 8-OH-DPAT, but was ineffective against 5-CT and TFMPP. The 5-HT-induced synaptic depression was not accompanied by a concomitant reduction of glutamate-induced depolarizations; the latter were enhanced after repeated exposure to 5-HT in some motoneurons. Finally, 5-HT reduced the afterhyperpolarization following a single spike or a train of spikes. The results indicate that 5-HT inhibits synaptic responses in motoneurons via presynaptic 5-HT1 receptors, the activation of which reduces the liberation of excitatory and inhibitory transmitters from respective nerve endings.
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PMID:Serotonin via presynaptic 5-HT1 receptors attenuates synaptic transmission to immature rat motoneurons in vitro. 168 86

The partial dopamine receptor agonists SDZ 208-911 (N-[(8-alpha)-2,6-dimethylergoline-8-yl]-2,2-dimethylpropanamid e), SDZ 208-912 (N-[8-alpha)-2-chloro-6-methylergoline-8-yl]-2,2- dimethylpropanamide) and terguride (transdihydrolisuride; TDHL) were tested in biochemical, behavioral (locomotor activity) and electrophysiological assays in male rats. In reserpine-pretreated rats, SDZ 208-911 and terguride dose-dependently reduced striatal DOPA formation (NSD 1015 treatment) with similar efficacy (-80%) and potency as the selective D2 receptor agonist quinpirole (LY 171555). SDZ 208-912 only produced a partial reduction (-32%) at the highest dose tested. SDZ 208-911 and terguride partially reversed (by approximately 50%) the gamma-butyrolactone (GBL)-induced increase in striatal DOPA accumulation. Quinpirole produced a 100% reversal while SDZ208-912, per se, was inactive. While quinpirole decreased DOPA accumulation, all three partial agonists elevated striatal DOPA accumulation in non-pretreated rats with SDZ 208-912 being as potent and efficacious as haloperidol. The three partial agonists displayed comparatively high affinities in vitro for the dopamine D2 (3H-spiperone) receptor site and somewhat lower affinity for the 5-HT1A (3H-8-OH-DPAT) receptor site. SDZ 208-911 and SDZ 208-912 also showed high affinities for central alpha 2 (3H-idazoxane) receptors. In line with these findings, the partial ergoline agonists dose-dependently elevated the DOPA accumulation in the noradrenaline-rich cortical brain region and decreased the 5-HT synthesis rate (5-HTP accumulation) in the limbic brain region. Furthermore, high doses of SDZ 208-911 and terguride produced weak signs of the 5-HT behavioral syndrome (flat body posture) in reserpinized rats. In the locomotor activity studies in non-pretreated rats, SDZ 208-911, SDZ 208-912 and terguride reduced the activity to 10-20% of controls with SDZ 208-912 being approximately ten times less potent than the other two compounds. Weak postsynaptic dopamine receptor agonist effects of the partial agonists were demonstrated only in reserpine-pretreated rats; all three partial agonists tested produced occasional forward locomotion and the so-called "jerking" behavior. Extracellular single unit recordings were carried out in chloral hydrate-anesthetized rats to investigate the effects on firing rates of dopamine neurons located in the substantia nigra pars compacta. Intravenous administration of SDZ 208-911 and terguride depressed the firing rate by 42 and 53%, respectively, while apomorphine completely inhibited the cells. SDZ 208-912 only reduced the firing by 16% and some cells displayed a biphasic response with a weak depression at low doses that disappeared at high doses.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of the partial dopamine receptor agonists SDZ 208-911, SDZ 208-912 and terguride on central monoamine receptors. A behavioral, biochemical and electrophysiological study. 168 86

Both noradrenergic (NE) and serotonergic (5-HT) systems have been implicated in anxiety and depression, as well as in the therapeutic actions of drugs treating these conditions. We have used microelectrode recordings of nerve cell impulse frequencies and in vivo voltammetric recordings of monoamine release to evaluate effects of the arylpiperazine 5-HT1A anxiolytics, buspirone and ipsapirone. Both buspirone and ipsapirone significantly depressed 5-HT neuronal firing rates in dorsal raphe (DR), but significantly increased NE neuronal firing rates in locus coeruleus (LC). In CA1 region of hippocampus, both buspirone and ipsapirone significantly depressed NE release with potencies greater than those required for the significant depression of 5-HT release. It is concluded that, contrary to the belief that the 5-HT1A arylpiperazines act primarily through 5-HT mechanisms, alterations in NE function may be critically important for their therapeutic effects, just as is the case for the benzodiazepine anxiolytics and the tricyclic antidepressants.
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PMID:5-HT1A agonists uncouple noradrenergic somatodendritic impulse flow and terminal release. 168 26

Quantitative autoradiography was used to evaluate the effects of sex and either 1 or 5 daily 2-hour sessions of restraint stress on binding at 5-HT1A, 5-HT1C and 5-HT2 receptors in the rat dorsal hippocampus. Neither sex nor restraint stress were found to have effects on binding at 5-HT1C or 5-HT2 receptors. However, restraint stress increased binding of [3H]8-hydroxy-2-(di-n-propylamino)tetralin at 5-HT1A receptors in the CA4 region and in the infrapyramidal dentate gyrus. In addition, levels of binding at 5-HT1A receptors in the oriens and lacunosum moleculare layers of the CA1 region were significantly higher in female rats. Neither estradiol benzoate nor estradiol benzoate plus progesterone had effects on binding at hippocampal 5-HT1A receptors in ovariectomized rats, making it unlikely that the sex differences were related to stages of the estrous cycle. Stress-induced levels of corticosterone (CORT) were higher in females. Although CORT levels in blood obtained during restraint decreased from session 1 to session 5 in both male and female rats, the decrease became significant in females only. Female rats also displayed higher levels of activity in the open field. Although activity in the open field was reduced in male and female rats after restraint, these decreases were not significant. Results are discussed in relation to anxiety and depression.
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PMID:Autoradiographic analyses of the effects of restraint-induced stress on 5-HT1A, 5-HT1C and 5-HT2 receptors in the dorsal hippocampus of male and female rats. 174 60

1. Azapirones, selective partial agonists at the 5-HT1A receptor subtype, induce hypothermia and corticotropin (ACTH)/cortisol release as specific functional correlates of central 5-HT1A receptor activation. 2. Compared to controls, hypothermic and ACTH/cortisol responses to the azapirone ipsapirone are attenuated in patients with unipolar depression and panic disorder but not in patients with obsessive-compulsive disorder. The impaired thermic and neuroendocrine responses are associated with increased basal cortisol secretion in depressed patients but not in patients with panic disorder. 3. Chronic treatment with the selective 5-HT reuptake inhibitor fluoxetine decreases 5-HT1A receptor-mediated responses in patients with obsessive-compulsive disorder, while long-term treatment with the tricyclic antidepressant amitriptyline further decreases hypothermia following ipsapirone but has no effect on ACTH/cortisol release. 4. Alteration of the 5-HT1A receptor and/or its signal transduction pathways may play a role in the pathophysiology and treatment of anxiety disorders and depression.
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PMID:5-HT1A receptor responsivity in anxiety disorders and depression. 176 90

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

The effects of repeated treatment of rats with desipramine on 5-HT mechanisms within the nucleus accumbens (NAS) have been studied in a functional model. Local microinjections of 5-HT, quipazine as well as 5-HT1A receptor agonist buspirone, 8-OH-DPAT and NDO-008, inhibited rat locomotor activity in the open-field test. The effect of 5-HT and buspirone was blocked by serotonergic receptor antagonists methysergide and cyanopindolol, respectively. Chronic, but not acute treatment of rats with desipramine (10 mg/kg, PO, twice a day for 21 days, tests were performed 24 h after the last dose) significantly attenuated behavioral depression after 5-HT and quipazine microinjections, while the effect of buspirone was left unchanged. On the basis of present data, it may be concluded that whereas both accumbens 5-HT1A and 5-HT2 receptors appear to be important to regulation of animals' motility, only 5-HT2 receptors seem to be the most likely targets of antidepressive treatment. These data, along with previously reported changes in limbic noradrenergic and dopaminergic activity after antidepressive treatment, may explain the energizing influence of drugs and electroconvulsive shocks on psychomotor retardation, a part of endogenous depression.
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PMID:Serotonergic mechanisms in the nucleus accumbens affected by chronic desipramine treatment. 183 82

Recent literature has addressed a frequent comorbidity between alcoholism and anxiety/depression. These disorders have been interdigitated with the brain amines serotonin (5-HT) and norepinephrine. We investigated 51 dually diagnosed patients (generalized anxiety disorder with depressive features plus alcohol abuse/dependency) under a randomized, double-blind, placebo-controlled trial employing the 5-HT1A compound buspirone. Buspirone was superior to placebo as an anxiolytic. It was well tolerated and reduced the number of days patients desired alcohol. At the final study dose, the buspirone metabolite 1-pyrimidinylpiperazine (1-PP) was significantly related to improvement in anxiety, global depressive symptoms, and number of days not using alcohol. Analysis using the Hamilton Rating Scale for Depression and its retardation cluster revealed significant improvement secondary to anxiolysis. Thus, buspirone (especially via its 1-PP metabolite) may be an effective treatment strategy in the anxious or mixed anxious-depressive patient with comorbid alcoholism when other conventional anxiolytics may be contraindicated.
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PMID:The association of buspirone and its metabolite 1-pyrimidinylpiperazine in the remission of comorbid anxiety with depressive features and alcohol dependency. 192 64

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 5-HT1A agonist properties of gepirone were used to test for effects on serum cortisol levels in humans, 90 min after a 10 mg oral dose. Fourteen patients with major depression were tested in a single-blind, within-subjects, placebo design. Serum cortisol levels were significantly higher 90 min after gepirone compared to placebo (p less than 0.05). Baseline Hamilton depression ratings were correlated with the serum cortisol levels after acute administration of gepirone (r = 0.54, p less than 0.05), but not placebo. Cortisol levels after a 10 mg gepirone challenge were significantly (p less than 0.02) attenuated after 3-6 weeks chronic administration of gepirone. These preliminary findings suggest that relatively low doses of gepirone may stimulate human cortisol secretion in depressed patients, and cortisol levels after gepirone challenge may correlate with depression severity. Furthermore, a desensitization to gepirone's effects on cortisol may occur after chronic gepirone administration.
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PMID:Cortisol and growth hormone responses to the 5-HT1A agonist gepirone in depressed patients. 197 5


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