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

5-HT1B receptors play a specific role as one of the many receptors regulating serotonergic activity. This endogenous peptide was recently isolated and characterized. Specific interaction has been demonstrated. 5-HT-moduline appears to be implicated in central nervous system response to various stimuli, particularly stress. It might play an important role in adaptation/inadaptation mechanisms (stress, anxiety, depression).
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PMID:[5HT-moduline an new peptide specifically interactive with the serotonergic system: physiopathologic implications]. 977 5

A role for serotonin in migraine has been supported by changes in circulating levels of serotonin and its metabolites during the phases of a migraine attack, along with the ability of serotonin-releasing agents to induce migraine-like symptoms. The development of serotonin receptor agonists with efficacy in the clinic for the alleviation of migraine pain further implicates serotonin as a key molecule in migraine. Several theories regarding the etiology of migraine have been proposed. The vasodilatory theory of migraine suggested that extracranial arterial dilation during an attack was related to migraine pain; a theory supported when vasoconstrictors such as sumatriptan alleviated migraine pain. The neurological theory of migraine proposed that migraine resulted from abnormal firing in brain neurons. Cortical spreading depression, one facet of the neurological theory, could explain the prodrome of migraine. The neurogenic dural inflammation theory of migraine supposed that the dural membrane surrounding the brain became inflamed and hypersensitive due to release of neuropeptides from primary sensory nerve terminals. Substance P, calcitonin gene related peptide and nitric oxide are all though to play a role in the dural inflammatory cascade. Animal models of migraine have been utilized to study the physiology of migraine and develop new pharmaceutical therapies. One model measures the shunting of blood to arteriovenous anastomoses based on a proposal that migraine primarily involves cranial arteriovenous vasodilation. Another model utilizes electrical stimulation of the trigeminal ganglion to induce neurogenic dural inflammation quantified by the resulting extravasation of proteins. Pharmacological agents such as meta-chlorophenylpiperazine (mCPP) and nitroglycerin have also been used to induce dural extravasation in animals. Both compounds also induce migraine attacks in individuals with a history of migraine. In addition, Fos, a protein produced by activation of the c-fos gene, has been measured as an index of migraine-like pain transmission to the CNS following chemical or electrical stimulation of the trigeminal nerve. A role for serotonin in migraine is further supported by the efficacy of serotonin receptor ligands. Sumatriptan is an agonist at 5-HT1D and 5-HT1B receptor subtypes, and effective in treating migraine pain and associated symptoms. Recently, selective 5-HT1F agonists have been proposed for the treatment of migraine, without the side effects associated with the present 5-HT1D and 5-HT1B receptor agonists. A role for 5-HT2B receptors has also been suggested the initiation of migraine, supporting use of selective 5-HT2B receptor antagonists in migraine. Thus, agents that modulate 5-HT1B, 5-HT1D, 5-HT1F and 5-HT2B receptors either have or may have clinical utility in the therapy of migraine headache.
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PMID:Serotonin in migraine: theories, animal models and emerging therapies. 994 63

The use of lithium in combination with various antidepressant drugs (e.g., heterocyclics and monoamine oxidase inhibitors) has been reported rapidly to improve antidepressant response in otherwise treatment-resistant patients. Carbamazepine and sodium valproate have also been shown to be effective in the treatment of several forms of affective disorders, such as treatment-resistant depression and bipolar depression. The present study, using the mouse forced swimming test, was undertaken to test the hypothesis of the action of lithium, carbamazepine or sodium valproate on some 5-HT receptor subtypes. Results showed that lithium significantly potentiated the anti-immobility effects of RU 24969 (P<0.01) and anpirtoline (P<0.01). Pretreatment with lithium did not induce any significant antidepressant-like effects when tested in combination with 8-OH-DPAT, NAN-190 or (+/-) pindolol. Pretreatment with carbamazepine provoked anti-immobility effects when tested in combination with RU 24969 (P<0.01) and 8-OH-DPAT (P<0.01), whereas prior administration of sodium valproate enhanced the antidepressant-like effects of (+/-) pindolol (P<0.01), 8-OH-DPAT (P<0.01) and RU 24969 (P<0.01). In conclusion, the results of the present study suggest that lithium may be acting through 5-HT1B receptors, whereas the action of carbamazepine and sodium valproate seems to involve 5-HT1A receptors in the mouse forced swimming test. However, considering the complexity of the actions of these compounds, it is possible that other neurotransmitter systems/receptors may be involved.
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PMID:Evidence of the activity of lithium on 5-HT1B receptors in the mouse forced swimming test: comparison with carbamazepine and sodium valproate. 1009 Jun 44

The challenges for the design of new antidepressant drugs are threefold: rapid onset of antidepressant response, broader efficacy, and fewer adverse effects. While progress has been made to reduce side-effects, the currently available drugs show no convincing evidence for a shorter delay of onset nor for improved efficacy. This review summarizes some of the hypotheses that try to explain the delayed onset and that are currently used for antidepressant drug design. These approaches include combinations of SSRI activity with either NA reuptake inhibition or 5-HT1A-, 5-HT2-, or alpha 2-adrenergic receptor specificity, as well as targeting interactions with specific receptor subtypes (5-HT1A, 5-HT1A/5-HT2, 5-HT1B/D, alpha 2/5-HT2, D2/D3). Structure activity relationship studies to obtain molecular entities with the desired pharmacological profile are discussed. Many structural modifications have exploited successfully the acquired knowledge on structural features that are necessary for monoamine reuptake inhibition as well as for affinities at various receptors. Most of the current drug design efforts are focused on these approaches, which are based on the monoamine theory of depression; however, novel biological concepts of depression involving other receptor systems or intracellular targets are briefly mentioned. Although their impact on the onset of antidepressant response is only a matter of speculation at this moment, they may lead to the identification of targets for truly novel antidepressants.
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PMID:New approaches to rapid onset antidepressants. 1019 44

Dysfunctions of the serotonergic system have been implicated in a number of psychiatric disorders including depression, anxiety and disorders of impulse control. To model these disorders we have generated mice with altered serotonergic systems. Specifically, we have created mice that lack or express reduced levels of two serotonin receptors: 5-HT1A and 5-HT1B receptors. These receptors are localized both on serotonergic neurons where they act as autoreceptors and on non-serotonergic neurons. As a result, the 5-HT1A and 5-HT1B receptors control the tone of the serotonergic system and mediate some of the postsynaptic effects of serotonin. Agonists of these receptors are currently used in the treatment of migraine and anxiety disorders. Mice lacking these receptors develop, feed, and breed normally and do not display any obvious abnormalities. However, when analyzed in a number of behavioral paradigms, the 5-HT1A and 5-HT1B knockout mice display a number of contrasting phenotypes. While the 5-HT1B knockout mice are more aggressive, more reactive, and less anxious than the wild-types, the 5-HT1A knockouts are less reactive, more anxious, and possibly less aggressive than the wild-types. We are currently investigating with tissue-specific knockout mice which neural circuits are responsible for these phenotypes.
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PMID:Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors. 1043 89

Rats were given a single dose of reserpine (5 mg/kg s.c.) and behavioural responses to agonists at 5-HT receptor subtypes compared with those of control animals 21 days later. The following effects of activating postsynaptic 5-HT1A receptors by the agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) were significantly increased: tail-flick, reciprocal forepaw treading, flat body posture. The hyperphagic effect of activating presynaptic 5-HT1A receptors by 8-OH-DPAT tended to increase and hypothermia on activating postsynaptic 5-HT1A sites tended to decrease. The hyperlocomotor effect of activating 5-HT1A sites also tended to decrease possibly as a result of a dependence of this response on the known depletion of catecholamines by reserpine. Head shakes on activating 5-HT2A receptors by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and two effects of activating 5-HT2C receptors by 1-(3-chlorophenyl) piperazine (mCPP) were significantly increased (hypophagia, anxiety) and a third effect, hypolocomotion tended to increase but hypophagia on activating postsynaptic 5-HT1B receptors by CP-94, 253 was significantly attenuated. The results are discussed with particular reference to altered 5-HT function in depression.
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PMID:Effect of reserpine on behavioural responses to agonists at 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptor subtypes. 1046 92

Current theories propose that the primary dysfunction in migraine occurs within the CNS and that this evokes changes in blood vessels within pain-producing intracranial meningeal structures that give rise to headache pain. Migraine is now thought of as a neurovascular disorder. It has been proposed that genetic abnormalities may be responsible for altering the response threshold to migraine specific trigger factors in the brain of a migraineur compared to a normal individual. The exact nature of the central dysfunction that is produced in migraineurs is still not clear and may involve spreading depression-like phenomena and activation of brain stem monoaminergic nuclei that are part of the central autonomic, vascular and pain control centers. It is generally thought that local vasodilatation of intracranial extracerebral blood vessels and a consequent stimulation of surrounding trigeminal sensory nervous pain pathways is a key mechanism underlying the generation of headache pain associated with migraine. This activation of the 'trigeminovascular system' is thought to cause the release of vasoactive sensory neuropeptides, especially CGRP, that increase the pain response. The activated trigeminal nerves convey nociceptive information to central neurons in the brain stem trigeminal sensory nuclei that in turn relay the pain signals to higher centers where headache pain is perceived. It has been hypothesized that these central neurons may become sensitized as a migraine attack progresses. The 'triptan' anti-migraine agents (e.g. sumatriptan, rizatriptan, zolmitriptan naratriptan) are serotonergic agonists that have been shown to act selectively by causing vasoconstriction through 5-HT1B receptors that are expressed in human intracranial arteries and by inhibiting nociceptive transmission through an action at 5-HT1D receptors on peripheral trigeminal sensory nerve terminals in the meninges and central terminals in brain stem sensory nuclei. These three complementary sites of action underlie the clinical effectiveness of the 5-HT1B/1D agonists against migraine headache pain and its associated symptoms.
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PMID:Pathophysiology of migraine--new insights. 1056 28

The 5-HT1A receptor is implicated in depression and anxiety. This receptor couples to G(i) proteins to inhibit adenylyl cyclase (AC) activity but can stimulate AC in tissues (e.g. hippocampus) that express ACII. The role of ACII in receptor-mediated stimulation of cAMP formation was examined in HEK-293 cells transfected with the 5-HT1A receptor, which mediated inhibition of basal and G(s)-induced cAMP formation in the absence of ACII. In cells cotransfected with 5-HT1A receptor and ACII plasmids, 5-HT1A agonists induced a 1. 5-fold increase in cAMP level. Cotransfection of 5-HT1A receptor, ACII, and Galpha(i2), but not Galpha(i1), Galpha(i3), or Galpha(o), resulted in an agonist-independent 6-fold increase in the basal cAMP level, suggesting that G(i2) preferentially coupled the receptor to ACII. The 5-HT1B receptor also constitutively activated ACII. Constitutive activity of the 5-HT1A receptor was blocked by pertussis toxin and the Gbetagamma antagonist, betaCT, suggesting an important role for Gbetagamma-mediated activation of ACII. The Thr-149 --> Ala mutation in the second intracellular domain of the 5-HT1A receptor disrupted Gbetagamma-selective activation of ACII. Spontaneous 5-HT1A receptor activity was partially attenuated by 5-HT1A receptor partial agonists with anxiolytic activity (e.g. buspirone and flesinoxan) but was not altered by full agonists or antagonists. Thus, anxiolytic activity may involve inhibition of spontaneous 5-HT1A receptor activity.
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PMID:Constitutive G(i2)-dependent activation of adenylyl cyclase type II by the 5-HT1A receptor. Inhibition by anxiolytic partial agonists. 1058 18

This article briefly summarizes, within the context of a brief review of the relevant literature, the outcome of our recent rat microdialysis studies on (1) the relative importance of serotonin (5-HT)1A versus 5-HT1B autoreceptors in the mechanism of action of 5-HT reuptake blocking agents, including putative regional differences in this regard, and (2) autoreceptor responsiveness following chronic SSRI administration. First, our data are consistent with the primacy of 5-HT1A autoreceptors in restraining the elevation of 5-HT levels induced by SSRIs, whereas nerve terminal 5-HT1B autoreceptors appear to have an accessory role in this regard. Second, there is an important interplay between cell body and nerve terminal 5-HT autoreceptors, and recent findings suggest that this interplay may potentially be exploited to obtain regionally preferential effects on 5-HT neurotransmission in the central nervous system, even upon systemic drug administration. In particular, emerging data suggest that somatodendritic 5-HT1A autoreceptor- and nerve terminal 5-HT1B autoreceptor-mediated feedback may be relatively more important in the control of 5-HT output in dorsal raphe-frontal cortex and median raphe-dorsal hippocampus systems, respectively. Third, 5-HT autoreceptors evidently retain the capability to limit the 5-HT transmission-promoting effect of SSRIs after chronic treatment. Thus, although the responsiveness of these sites is probably somewhat reduced, residual autoreceptor capacity still remains an effective restraint on large increases in extracellular 5-HT, even after prolonged treatment. If a further increase in extracellular 5-HT is crucial to the remission of depression in patients responding only partially to prolonged administration of antidepressants, then sustained adjunctive treatment with autoreceptor-blocking drugs may consequently prove useful in the long term.
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PMID:Serotonin autoreceptor function and antidepressant drug action. 1089 Mar 13

No current experimental model on migraine is fully satisfactory, and constructing a single model which takes into account all the various clinical and pharmacological aspects does not seem feasible. A critical review of the large number of experimental approaches developed over the past 20 years to investigate migraine attacks and an examination of recent research in the various fields of animal biology seems to be more pertinent in this context. A neurovascular cortical spreading depression could be one of the mechanisms involved in aura formation, but its association with headache is enigmatic, and the implication of hypoxia in its etiopathogenesis remains controversial. Intercritical neuronal hyperexcitability, which has been proposed as a possible biological basis for the onset of migraine, may trigger the development of aura, but also the activation of the trigeminovascular system. An independent but concomitant activation of both phenomena could be driven by a mesencephalic noradrenergic or cortical limbic generator. The trigemino-vascular model of perivascular neurogenic inflammation does not explain certain experimental and pharmacological properties of anti-migraine drugs. The clinical efficacy of the 5-HT1B/D agonists is based on a vasoconstrictive effect and on their inhibition of neurogenic inflammation, while calcitonin gene-related peptide (CGRP) plays a major role in vasodilatation and substance P in neurogenic inflammation. The initiation and initial development of migraine probably involve a prior peripheral sensitization of the trigeminal nociceptors, while the susceptibility to onset of an attack, maintenance of the migrainous state and the clinical variability must certainly rely on central sensitization within the trigeminal caudate nucleus. The numerous experimental approaches to the physiopathology of migraine developed over recent years, each of which provides a basis for the development of new classes of anti-migraine drugs, are not exclusive of one another. Rather, they contribute to providing various specific aspects of a physiopathogenic theory of migraine, which at the present time has to be both wide-ranging and adaptive.
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PMID:[Physiopathology of the migraine attack and mechanisms of action of anti-migraine agents: recent findings in animals]. 1107 37


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