UNIPROT:P08908 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are conflicting results on the function of 5-HT in anxiety and depression. To reconcile this evidence, Deakin and Graeff have suggested that the ascending 5-HT pathway that originates in the dorsal raphe nucleus (DRN) and innervates the amygdala and frontal cortex facilitates conditioned fear, while the DRN-periventricular pathway innervating the periventricular and periaqueductal gray matter inhibits inborn fight/flight reactions to impending danger, pain, or asphyxia. To study the role of the DRN 5-HT system in anxiety, we microinjected 8-OH-DPAT into the DRN to inhibit 5-HT release. This treatment impaired inhibitory avoidance (conditioned fear) without affecting one-way escape (unconditioned fear) in the elevated T-maze, a new animal model of anxiety. We also applied three drug treatments that increase 5-HT release from DRN terminals: 1) intra-DRN microinjection of the benzodiazepine inverse agonist FG 4172, 2) intra-DRN microinjection of the excitatory amino acid kainic acid, and 3) intraperitoneal injection of the 5-HT releaser and uptake blocker D-fenfluramine. All treatments enhanced inhibitory avoidance in T-maze. D-Fenfluramine and intra-DRN kainate also decreased one-way escape. In healthy volunteers, D-fenfluramine and the 5-HT agonist mCPP (mainly 5-HT2C) increased, while the antagonists ritanserin (5-HT2A/2C) and SR 46349B (5-HT2A) decreased skin conductance responses to an aversively conditioned stimulus (tone). In addition, D-fenfluramine decreased, whereas ritanserin increased subjective anxiety induced by simulated public speaking, thought to represent unconditioned anxiety. Overall, these results are compatible with the above hypothesis. Deakin and Graeff have suggested that the pathway connecting the median raphe nucleus (MRN) to the dorsal hippocampus promotes resistance to chronic, unavoidable stress. In the present study, we found that 24 h after electrolytic lesion of the rat MRN glandular gastric ulcers occurred, and the immune response to the mitogen concanavalin A was depressed. Seven days after the same lesion, the ulcerogenic effect of restraint was enhanced. Microinjection of 8-OH-DPAT, the nonselective agonist 5-MeO-DMT, or the 5-HT uptake inhibitor zimelidine into the dorsal hippocampus immediately after 2 h of restraint reversed the deficits of open arm exploration in the elevated plus-maze, measured 24 h after restraint. The effect of the two last drugs was antagonized by WAY-100135, a selective 5-HT1A receptor antagonist. These results are compatible with the hypothesis that the MRN-dorsal hippocampus 5-HT system attenuates stress by facilitation of hippocampal 5-HT1A-mediated neurotransmission. Clinical implications of these results are discussed, especially with regard to panic disorder and depression.
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PMID:Role of 5-HT in stress, anxiety, and depression. 872 50

The effects of flesinoxan, a potent and selective 5-HT1A agonist, were studied in two pilot studies in panic disorder patients to explore the role of 5-HT1A receptors in the mechanism of action of antipanic agents. This paper reports on the results of these two studies with flesinoxan. In study I, using a single-blind crossover design, five patients were treated for 1 week with placebo, 4 weeks with flesinoxan (up to 2.4 mg per day), and 2 weeks with placebo. In study II, 15 patients were enrolled in a double-blind, three-armed study with placebo and two dosages of flesinoxan. After a single-blind placebo run-in phase of 1 week, patients were treated for 8 weeks with placebo, 0.6 or 1.2 mg/day flesinoxan. In pilot study I patients' condition worsened during the 4-week flesinoxan treatment period. Anxiety was frequently reported as an adverse event. Symptoms returned to the pre-treatment level during the 2-week placebo washout period. In pilot study II, no treatment effects in either group were observed. Anxiety as an adverse event was less prominent than in the first pilot study. A lowering of mood was seen in some patients. The sample sizes of these two pilot studies are too small to draw firm conclusions on the efficacy of flesinoxan in panic disorder, but the present data are not encouraging in this respect. The worsening of symptoms seen with the highest dose of flesinoxan is intriguing and might give a clue to the understanding of the mechanism underlying similar effects seen with antidepressants in panic disorder patients.
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PMID:Effects of the 5-HT1A receptor agonist flesinoxan in panic disorder. 888 84

The escape behaviour induced in rats by injecting D,L-homocysteic acid (DHL) into the dorsal periaqueductal grey area (DPAG) was used as an animal model of panic attacks to investigate the effect of imipramine, a drug used for the treatment of panic disorder, on the sensitivity of 5-HT1A receptors in the DPAG. Rats given imipramine (10 mg/kg per day SC for 3 weeks or IP for 2-3 days) received 250 nl saline or the 5-HT1A agonist 8-OH-DPAT (8.6 nmol) into the DPAG 10 min before inducing the escape response with DLH. As expected, 8-OH-DPAT produced a marked decrease in the average speed of the DLH-induced flight response. The short-term treatment with imipramine changed neither the DLH-induced escape behaviour nor the effect of prior 8-OH-DPAT administration on this response. In contrast, long-term treatment with imipramine enhanced the 5-HT1A-mediated inhibition, as the decrement in the amplitude of the flight response produced by 8-OH-DPAT was 96% after this treatment compared to 41% in controls. The injection of 8-OH-DPAT also significantly decreased the amplitude of the freezing behaviour observed at the end of the flight response in rats given imipramine for 3 weeks, but not in controls. The long-term imipramine treatment, however, did not significantly decrease the amplitude of DLH-induced flight and freezing behaviours in absence of prior 8-OH-DPAT administration. Finally, 8-OH-DPAT failed to inhibit the DLH-induced flight and freezing behaviours in rats withdrawn from imipramine after long-term treatment (10 mg/kg per day x 21 days). It is suggested that an alteration at the level of the DPAG-5-HT1A receptor system is implicated in the therapeutic and withdrawal effect of imipramine in panic disorder.
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PMID:Effect of imipramine treatments on the 5-HT1A-receptor-mediated inhibition of panic-like behaviours in rats. 922 33

Numerous procedures have been developed to facilitate preclinical research on the behavioural pharmacology of anxiety and, as a result of this application, are often referred to as animal models of 'anxiety'. This is an unfortunate misnomer, not only because of the apparent inability of many tests to detect novel anxiolytics consistently, but also because the term implies that anxiety is a unitary emotion. Such difficulties have arisen largely as a consequence of test development strategies which, by emphasizing pharmacological (i.e. benzodiazepine) validation, have yielded models predictive of a specific type of anxiolytic activity. The present review argues that the refinement of existing tests as well as the development of new procedures requires urgent attention to the much neglected issue of behavioural validation. From an evolutionary perspective, normal human anxiety may be conceptualized as a repertoire of defence reactions tailored to meet different forms of threats, and disorders of anxiety as the inappropriate activation or exaggeration of these usually adaptive response patterns. In this context, consideration of the defensive reactions typically observed in our animal models reveals substantially greater commonality in the behavioural effects of benzodiazepine and 5-HT1A anxiolytics than would otherwise be apparent. Therefore, with the exception of the conventional plus-maze paradigm (discussed at some length), better correspondence is seen in tests involving unconditioned response to potential threat (e.g. social interaction, distress vocalizations and light/dark exploration) than in tests of conditioned fear reactions. Even within the latter grouping, however, greater commonality is seen in procedures based on reactions to proximal threat (e.g. freezing, startle, ultrasonic vocalizations, burying) than those involving reactions to distal threat (e.g. avoidance/flight). Significantly, very similar findings have been reported in tests specifically designed to study defensive reactions (e.g. rat and mouse defence test batteries) or which incorporate a more detailed knowledge of defence into established procedures (e.g. ethological plus-maze and defensive burying paradigms). Furthermore, recent evidence also suggests that drugs with proved clinical efficacy in panic attacks/panic disorder have reliably stronger effects on flight responses than other components of the defensive repertoire. It is concluded that a focus on defensive behaviour patterns improves test validity (predictive/face/construct), offers a more rational basis for test selection in drug development programmes, and provides a firmer theoretical framework for future methodological and therapeutic advance.
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PMID:Animal models of 'anxiety': where next? 983 64

Anxiety disorders are heterogeneous and existing animal models do not discriminate specific types of anxiety. The elevated T-maze is being developed to fulfill this purpose. The apparatus consists of three elevated arms, one enclosed and two open. Inhibitory avoidance--representing learned fear--is measured by recording the time taken to leave the enclosed arm in three consecutive trials. Unconditioned fear is evaluated by recording the time to escape from the open arm. Restraining the animals at the end of the enclosed arm for 30 s did not change the first (baseline) withdrawal latency, indicating that rats are not escaping from the experimenter's hand. In addition, rats trained in a T-maze with the three arms enclosed did not show the usual increase in withdrawal latency over the three consecutive trials. These results indicate that open arm experience, not handling, motivates inhibitory avoidance learning. The same experiment also showed that the latency to leave the open arm did not undergo habituation over five consecutive trials, thereby providing evidence of an aversive motivation for this response. The anxiolytic agents diazepam (benzodiazepine), buspirone and ipsapirone (5-HT1A agonists) as well as ritanserin (5-HT2 antagonist) selectively impaired inhibitory avoidance while leaving one-way escape unchanged. Similar results were obtained with three putative anxiolytics: the 5-HT2B/2C antagonists SB 200646A and SER 082, and the 5-HT2A antagonist SR 46349B. However, RP 62203, another 5-HT2A antagonist, was ineffective on both tasks. In contrast to the above anxiolytics, the anxiogenic agents yohimbine, TFPP and mCPP facilitated inhibitory avoidance. Escape was not affected by yohimbine, but was moderately attenuated by the two 5-HT2C/2B agonists. The 5-HT releaser and uptake inhibitor D-fenfluramine tended to enhance inhibitory avoidance, while impairing one-way escape in a dose-dependent way. The antidepressant clomipramine also had an anxiogenic-like effect on inhibitory avoidance, but did not affect escape from the open arm. Conversely, the phenethylamine hallucinogen ALEPH 2 did not affect inhibitory avoidance while impairing escape. Nevertheless, the similar compound and 5-HT2A agonist DOI was devoid of any effect. Also ineffective were the psychomotor stimulants D,L-amphetamine and caffeine, the reversible monoaminoxidase-A inhibitor moclobemide and the neuroleptic haloperidol. Finally, micro-injection into the dorsal raphe nucleus of two drugs that stimulate 5-HT neurons, the excitatory amino acid kainic acid and the benzodiazepine inverse agonist FG 7142, facilitated inhibitory avoidance. Kainate also significantly impaired escape. In contrast, intra-raphe 8-OH-DPAT, which inhibits 5-HT neurons, selectively impaired inhibitory avoidance in a manner similar to systemically administered anxiolytics. These behavioral and pharmacological results support the view that inhibitory avoidance in the elevated T-maze may be related to generalized anxiety disorder, while one-way escape may be associated with panic disorder.
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PMID:The elevated T-maze as an experimental model of anxiety. 988 16

Acute systemic administration of the selective serotonin (5-HT)1A receptor full agonist flesinoxan enhanced the sensitivity of rats to the panic-like aversion elicited by local stimulation of the dorsolateral periaqueductal grey (dPAG). This experimental paradigm in rats has previously been validated as a simulation of acute anxiety with particular relevance to panic disorder. The dose-dependent decrease in threshold for acute fear responses recorded in rats following intraperitoneal administration of flesinoxan (1-10 mg/kg) was similar to that induced by the panic precipitating agent yohimbine and opposite to the threshold increase induced by the antipanic drug alprazolam. The proaversive effect of flesinoxan observed in rats is consistent with the reported aggravation of the condition of panic patients following oral flesinoxan treatment. Thus, the model adequately detects drug-induced panicogenic-like properties. Data suggest that selective activation of 5-HT1A receptors (pre- and/or post-synaptic in brain and/or periphery) following systemic administration of 5-HT1A receptor full agonists exacerbates aversion in animals or patients with panic anxiety; activation of these receptor subtypes may probably mediate the panicogenic action reported under certain circumstances with non-selective 5-HT mimetics.
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PMID:The 5-HT1A receptor agonist flesinoxan increases aversion in a model of panic-like anxiety in rats. 1047 23

In patients with panic disorder and /or agoraphobia (PDA) an increased sensitivity of central 5-HT2C receptors and a decreased responsiveness of 5-HT1A receptors has been postulated. In the present study, neuroendocrine challenges were performed using oral doses of the non-selective 5-HT2C agonist m-chlorophenylpiperazine (m-CPP) (0.4 mg/kg), the selective 5-HT1A antagonist ipsapirone (0.3 mg/kg), and placebo in 40 patients with PDA and 12 healthy controls in order to compare 5-HT2C and 5-HT1A-specific psychobehavioural and neuroendocrine response patterns. At baseline, all psychobehavioural variables and the plasma concentration of noradrenaline (NE) were significantly increased in the patient group compared to the controls. The administration of m-CPP or ipsapirone was followed by comparable psychological symptoms and, in 55% of all patients, panic attacks. In comparison to the control subjects, patients were characterized by significantly higher psychological reactions to both challenge agents and a significantly higher NE response to m-CPP. In the patient group, there was also a trend towards an increased cortisol response after administration of m-CPP and a decreased cortisol and hypothermia response after administration of ipsapirone compared to the control group. The neuroendocrine findings of our study support earlier reports of opposite changes in the responsiveness of 5-HT2C and 5-HT1A-related receptors in PDA patients. The behavioural hypersensitivity to both, m-CPP and ipsapiron, shows that the provocation of anxiety and other psychological symptoms might be influenced by
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PMID:Increased psychological responses and divergent neuroendocrine responses to m-CPP and ipsapirone in patients with panic disorder. 1087 Aug 73

Reduced 5-HT1A-receptor responsiveness has been reported in patients with panic disorder(PD) and/or agoraphobia (PDA). Although many of these patients are regular smokers, it has not been examined whether psychological or neurobiological effects induced by the selective 5-HT1A-receptor agonist, ipsapirone, are affected by the smoking status of the patients. In order to clarify this question neuroendocrine challenges with oral doses of ipsapirone (0.3 mg/kg) and placebo were performed in 39 patients with PDA, and results were compared between patients who smoked (>10 cigarettes per day, n = 17) and patients who had been non-smokers for at least two years (n = 22). Patients who were smokers (but did not smoke during the challenge procedure) had significantly reduced baseline concentrations of cortisol and a significantly lower body temperature. In comparison to placebo, administration of ipsapirone was associated with significant increases of various psychological symptoms and plasma cortisol concentrations. The subgroup of PD patients who were smokers showed significantly higher cortisol responses to ipsapirone than non-smokers. In conclusion, smoking status has to be taken into account when assessing the responsiveness of 5-HT1A receptors in patients with psychiatric disorders. The prevention of smoking during challenge sessions might not be the ideal approach in heavy smokers, since sudden abstinence from smoking is likely to affect neurobiological and possibly psychological responses to ipsapirone.
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PMID:Smoking modulates neuroendocrine responses to ipsapirone in patients with panic disorder. 1209

The dorsal periaqueductal gray has been implicated in the modulation of escape behavior, a defensive behavior that has been related to panic disorder. Intra-dorsal periaqueductal gray injection of serotonin or drugs that mimic its effects inhibits escape induced by electrical or chemical stimulation of this brainstem area. In this study, we investigate whether intra-dorsal periaqueductal gray injection of 5-HT receptor agonists attenuates escape generated by an ethologically based model of anxiety, the elevated T-maze. This test also allows the measurement of inhibitory avoidance, which has been related to generalized anxiety disorder. The effects of the 5-HT receptor agonists were compared in animals with or without a previous exposure to the open arms of the elevated T-maze. In these two test conditions, intra-dorsal periaqueductal gray injection of the endogenous agonist serotonin or the 5-HT(2B/2C) receptor agonist m-chlorophenylpiperazine (mCPP) enhanced inhibitory avoidance, suggesting an anxiogenic effect. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) impaired this response, suggesting an anxiolytic effect, and the preferential 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) was ineffective. All these agonists inhibited escape behavior. Apart from mCPP, the effect on escape was detected only in animals pre-exposed to the open arm. None of the drugs tested affected locomotion in the open-field test. Taken altogether, our findings suggest that 5-HT1A and 5-HT2c receptors in the dorsal periaqueductal gray exert opposed control on inhibitory avoidance, implicating these receptors in anxiety conditioning. As previously observed in tests employing the aversive stimulation of the dorsal periaqueductal gray, 5-HT1A and 5-HT2A receptors in this brain area are involved in escape inhibition. Therefore, in different animal models, the activation of these two subtypes of receptors in the dorsal periaqueductal gray consistently attenuates the expression of a panic-related behavior.
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PMID:Serotonin in the dorsal periaqueductal gray modulates inhibitory avoidance and one-way escape behaviors in the elevated T-maze. 1289 33

Panic disorder is a common anxiety disorder which frequently co-occurs with agoraphobia. A functional promoter polymorphism in the serotonin receptor 1A (5-HT1A) gene has been found to be associated with major depression as well as anxiety- and depression-related personality traits. We investigated a possible association between this 5-HT1A gene promoter polymorphism and panic disorder by genotyping the 1019C>G single nucleotide polymorphism in 134 panic-disorder patients with and without agoraphobia and matched 134 controls. In our sample no significant evidence of allelic association in the combined panic-disorder group was found. However, our results show a significant association with the G allele in patients with panic disorder with agoraphobia (p=0.03, n=101). In conclusion, our findings do not support a major contribution of this polymorphism to the pathogenesis of panic disorder, but provide evidence for a possible role in the subgroup with agoraphobia.
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PMID:Association of a functional 1019C>G 5-HT1A receptor gene polymorphism with panic disorder with agoraphobia. 1498 28

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