5-HT1A receptor function in depression : effect of chronic amitriptyline treatment
TL;DR: The results indicate a subsensitive (presynaptic) 5-HT1A receptor and/or a defective post-receptor signalling pathway in depression and are consistent with the hypothesis that 5- HT1A receptors are down-regulted during AMI treatment.
Abstract: Hypothermic responses to 5-HT1A receptor activation by the selective ligand ipsapirone (IPS) were attenuated in depressed patients as compared to controls. Chronic treatment with amitriptyline (AMI) further impaired 5-HT1Amediated hypothermia. The results indicate a subsensitive (presynaptic) 5-HT1A receptor and/or a defective post-receptor signalling pathway in depression and are consistent with the hypothesis that 5-HT1A receptors are down-regulted during AMI treatment.
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TL;DR: Serotonin-1A receptor BP is abnormally decreased in the depressed phase of familial mood disorders in multiple brain regions and may be associated with histopathological changes involving the raphe, convergence evidence from postmortem studies of mood disorders suggests.
659 citations
TL;DR: The evidence in the present review indicates that the FSL rat model of depression fulfills the criteria of face, construct, and predictive validities.
391 citations
TL;DR: This study attempted to replicate the original findings in an independent sample of subjects selected according to the criteria for primary recurrent depression applied in a prior study, and showed reduced 5-HT1AR binding potential in the mesiotemporal cortex (MTC) and raphe in depressives with primary recurrent familial mood disorders.
374 citations
Cites result from "5-HT1A receptor function in depress..."
...These data were compatible with the results of 5-HT1AR agonist challenge studies, which showed that unmedicated MDD subjects have blunted hypothermic and adrenocorticotropin (ACTH)/cortisol release relative to controls in response to ipsapirone or buspirone [43–45]....
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...[44] Lesch KP, Disselkamp-Tietze J, Schmidtke A....
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TL;DR: That tryptophan depletion did not rapidly worsen depression argues that serotonin function is not linearly related to the level of depression and if reduced serotonin function does cause depression, then it is either as predisposing factor or due to a postsynaptic deficit in the utilization of serotonin.
Abstract: Objective: To investigate the effects of tryptophan depletion in untreated depressed patients. Rapid dietary depletion of the precursor of serotonin synthesis, tryptophan, causes a transient return of depression in 67% of patients who have had a therapeutic antidepressant response. Method: Forty-three untreated depressed patients underwent tryptophan depletion in a double-blind, placebocontrolled cross-over study. After testing, they received open sequential antidepressant treatment. Results: Mood did not change when tryptophan was depleted but did change on the day after the depletion test. Relative to the control test, 37% of the patients had 10-point or greaterdecreasein Hamilton Depression Rating Scale (Ham-D) score, while 23% had a 10-point or greaterincreasein Ham-D score on the day after the tryptophan depletion test. Change in mood was correlated to treatment response after testing. Patients whose condition worsened proved to be highly refractory to treatment while those who showed improvment were more likely to respond. Conclusions: That tryptophan depletion did not rapidly worsen depression argues that serotonin function is not linearly related to the level of depression and if reduced serotonin function does cause depression, then it is either as predisposing factor or due to a postsynaptic deficit in the utilization of serotonin.
299 citations
Journal Article•
TL;DR: Although the postgenomic era is still in its infancy, several milestones have already been reached: variation in gene expression has been confirmed to play a predominant role in individual differences, and gene-environment interactions have been established in humans and in a nonhuman primate model.
Abstract: Depression is a group of brain disorders with varied origins, complex genetics and obscure neurobiology. Definitions of clinical phenotypes are not rooted in their neurobiology, and animal models of behavioural despair have considerable limitations. Nevertheless, investigation of subtle alterations in gene expression, of correlations between genotype and brain activity, and of environmental variables interacting with genetic variants have advanced research into the genetics of depression. Although the postgenomic era is still in its infancy, several milestones have already been reached: variation in gene expression has been confirmed to play a predominant role in individual differences; gene-environment interactions have been established in humans and in a nonhuman primate model; gene-phenotype correlations have been substantiated by functional neuroimaging; and the notion of gene networks that control brain development is increasingly recognized. Given the etiologic and psychobiologic complexity of mood disorders, it is not surprising that the identification of specific genetic factors is extremely difficult and continues to be among the last frontiers of gene hunting.
272 citations
References
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TL;DR: The novel anti-anxiety agents buspirone, gepirone and ipsapirone which directly affect the serotonergic system by interacting with the 5- HT 1A subtype of the high affinity 5-HT 1 receptor.
411 citations
"5-HT1A receptor function in depress..." refers background in this paper
...Recently, our group has demonstrated that ipsapirone (IPS), a centrally acting pyrimidinylpiper azine derivative with a radioligand binding profile similar to that of 8-OH-DPAT ( Traber and Glaser, 1987; Peroutka, 1988), induces a dose-related hypothermia in humans (Lesch et aI., !989a, b). The hypothermic response is attenuated by the non-selective 5-HTln receptor antagonist metergoline and completely antagonized by the non-selective ......
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TL;DR: Current theoretical and experimental developments in serotonin research extend from the differentiated description of central cytoarchitectonic structures over the identification and characterization of multiple receptor subtypes by pharmacological and molecular biological methods to the elucidation of neurobiochemical and physiological mechanisms of interneuronal communication and postreceptor signal transduction.
Abstract: Current theoretical and experimental developments in serotonin research extend from the differentiated description of central cytoarchitectonic structures over the identification and characterization of multiple receptor subtypes by pharmacological and molecular biological methods to the elucidation of neurobiochemical and physiological mechanisms of interneuronal communication and postreceptor signal transduction. These advances parallel the modification and optimization of various strategies for researching the relevance of central serotonergic neurotransmission in the aetiopathogenesis of affective disorders. Strategies such as the paradigm of selective pharmacological provocation contribute significantly to the formulation of complex hypotheses on the physiological regulation of receptor sensitivity, on receptor function in depression and on the processes of therapeutically induced neuroadaptation. In addition it appears that the generation of hypotheses receives further input from fundamental advances at the level of molecular pharmacology and biology. Reviewing and integrating our current knowledge to define the present state of the art facilitates the assessment of the position of serotoninergic function in the pathophysiology of affective disorder and in the mechanisms of action of various therapeutic measures.
404 citations
TL;DR: A state of equilibrium has been achieved in which most of the 5-HT binding sites have been successfully correlated with multiple physiological, biochemical and behavioral effects of5-HT.
336 citations
TL;DR: Treatment of rats with ketanserin (3 mg/kg) completely prevented the hyperthermic effects of 5-MeODMT, and, in fact, converted ahyperthermic response to 5- MeODMT into a marked hypothermic response.
286 citations
TL;DR: It is concluded that 8-OH-DPAT probably produces its hypothermic effects by actions at 5-HT receptors located presynaptically on5-HT neurones, while the stereotyped components of the serotonin syndrome appear to be mediated by post-synaptic receptors.
Abstract: The hypothermic and motor behavioural responses to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) have been investigated in the rat. The dose-effect relationship showed that hypothermia appeared at a lower dose than a definite motor syndrome. The hypothermic response to 8-OH-DPAT was attenuated following depletion of 5-hydroxytryptamine (5-HT) by repeated intraperitoneal (IP) administration of parachlorophenylalanine (200 mg/kg) or by injection of 5,7-dihydroxytryptamine (5,7-DHT, 100 μg) into the region of the third ventricle; the motor behavioural response produced simultaneously was not. Indeed, after 5,7-DHT, it was increased. Quipazine (1 mg/kg, IP) antagonised the hypothermic response and facilitated the motor behaviour. Clenbuterol (2.5 mg/kg, IP) increased both hypothermic and motor responses. (±)-propranolol was without effect on the simple hypermotility produced by 8-OH-DPAT, although it is known to antagonise the hypothermic and stereotyped motor responses. It is concluded that 8-OH-DPAT probably produces its hypothermic effects by actions at 5-HT receptors located presynaptically on 5-HT neurones, while the stereotyped components of the serotonin syndrome appear to be mediated by post-synaptic receptors.
194 citations