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)

The present study characterized the effects of the novel, selective, and potent 5-hydroxytryptamine1A (serotonin) (5-HT1A) receptor agonist, alnespirone [S-20499, (S)-N-4-[5-methoxychroman-3-yl)propylamino)butyl- 8-azaspiro-(4,5)-diacetamide, hydrochloride] on offensive and defensive resident-intruder aggression in wild-type rats and compared its actions with those of the prototypical full 5-HT1A agonist 8-hydroxy-2- dipropylaminotetralin (8-OH-DPAT), the partial 5-HT1A agonists ipsapirone and buspirone, and the mixed 5-HT1A/1B agonist eltoprazine. All five agonists exerted effective dose-dependent decreases of offensive aggressive behavior in resident rats; 8-OH-DPAT was the most potent (ID50 = 0.074 mg/kg), followed by eltoprazine (0.24), buspirone (0.72), ipsapirone (1.08), and alnespirone (1.24). However, in terms of selectivity of the antiaggressive effects as determined by the absence of decrements in social interest and general motor activity, alnespirone appeared to be superior. In the defensive aggression test, neither alnespirone nor any of the other four agonists changed defensive behaviors in the intruder rats. The involvement of 5-HT1A receptors in the antiaggressive actions of these drugs was confirmed by showing that the selective 5-HT1A receptor antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride), which was inactive alone, fully prevented the antiaggressive effects of alnespirone, 8-OH-DPAT, and buspirone and partly reversed those of ipsapirone and eltoprazine. The data clearly indicate that alnespirone effectively suppresses offensive aggression with an advantageous profile of action compared with other full or partial 5-HT1A agonists. These selective antiaggressive actions of alnespirone are mediated by stimulating 5-HT1A receptors, presumably the somatodendritic autoreceptors at the raphe nuclei. Furthermore, the data provide evidence for a major involvement of these 5-HT1A receptors in the modulation of aggressive behavior by 8-OH-DPAT, ipsapirone, buspirone, and eltoprazine.
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PMID:Selective antiaggressive effects of alnespirone in resident-intruder test are mediated via 5-hydroxytryptamine1A receptors: A comparative pharmacological study with 8-hydroxy-2-dipropylaminotetralin, ipsapirone, buspirone, eltoprazine, and WAY-100635. 1002 50

Intermale offensive aggressive behavior is facilitated by gonadal steroids and inhibited by serotonin (5-HT), presumably through its effects at 5-HT1A and 5-HT1B receptor sites. To examine the interaction between these neuroendocrine and neurochemical regulatory systems, CF-1 male mice were gonadectomized and implanted with silastic capsules containing either diethylstilbestrol (DES, a synthetic estrogen), the nonaromatizable androgens methyltrienolone (R1881) or dihydrotestosterone (DHT), or testosterone (T). Two weeks later, they were given 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT1A agonist; 0.1 or 1.0 mg/kg), CGS12066B (a 5-HT1B agonist; 4.0 or 8.0 mg/kg), 0.1 or 1.0 mg/kg 8-OH-DPAT + 4.0 mg/kg CGS12066B, or vehicle, and tested for aggression. In the presence of DES, the higher 8-OH-DPAT dose given in combination with CGS attenuated aggression in comparison to vehicle controls. When given nonaromatizable androgen (R1881 or DHT), all drug treatments except 0.1 mg/kg 8-OH-DPAT significantly reduced offensive attack behavior. In the presence of T, which provides estrogenic and androgenic stimulation, aggression scores were significantly reduced when males were given the high dose of 8-OH-DPAT or CGS12066B, as well as in the 1.0 mg/kg 8-OH-DPAT + CGS12066B condition. Assessments of changes in motor behavior showed significant impairment when 8.0 mg/kg CGS12066B was administered across all hormonal conditions, indicating that reductions in offensive aggression in these treatment groups were nonspecific. The results demonstrate differential effects of the steroidal environment on the ability of 5-HT1A and 5-HT1B agonists to modulate aggression, with estrogens producing a more restrictive environment than androgens for serotonergic inhibition of male-typical aggressive behavior.
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PMID:Androgens and estrogens modulate 5-HT1A and 5-HT1B agonist effects on aggression. 1007 87

The purpose of the investigation was to ascertain whether (a) the antiaggressive effects of the 5-HT1A partial agonist, Gepirone, could be mediated via its anxiolytic action; (b) the selective 5-HT1A antagonist, WAY 100635, reversed these effects, and (c) the modulation of "stress hyperthermia" could be attributed to direct effects of the drugs. Isolated male mice were treated with WAY 100635 (0, 1.5, 2.5, and 5 mg/kg) given 15 min prior to Gepirone (0, 2.5, 5, and 7.5 mg/kg). Rectal temperature was taken before the first injection and again prior to the behavioral tests. In the first session only, subjects were tested for anxiety on the elevated plus-maze before the resident-intruder test. Gepirone reduced aggression in a dose-dependent manner. This effect was counteracted by all doses of WAY 100635. On the elevated plus maze, Gepirone increased open-arm entries and duration and reduced risk assessment. The largest dose of WAY 100635 had a mild direct anxiolytic action, but all doses reduced the anxiolytic action of the largest dose of Gepirone. Body temperature was decreased dose dependently by Gepirone, an effect prevented by WAY 100635. The results justify attributing the involvement of the 5-HT1A receptors in the modulation of aggression and anxiety.
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PMID:Antiaggresive and anxiolytic effects of gepirone in mice, and their attenuation by WAY 100635. 1008 Feb 43

LB50016 was characterized as a selective and potent 5-HT1A receptor agonist and evaluate its anxiolytic and antidepressant activities. It shows high affinity for 5-HT1A receptor, moderate affinity for alpha 2 adrenergic and 5-HT2A receptors and no significant affinity for other receptors tested. Hypothermia and increased serum corticosterone level were observed in LB50016-treated rats, which are mediated mostly by post synaptic 5-HT1A receptor activation. In the mouse forced swim model for depression, LB50016-elicited dose-dependent reductions in immobility time, showing ED50 of approximately 3 mg/kg i.p., which was blocked by pretreatment of NAN-190, 5-HT1A antagonist. In face-to-face test for anxiolytic activity in mice, estimated ED50 was 2 mg/kg, i.p. In isolation-induced aggression test with mice, fifty-fold increases in latency to attack were observed at 30 min and last up to 4 h after LB50016 treatment (3 mg/kg, i.p.). Taken together, LB50016-induced pharmacological activities are mediated by activation of 5-HT1A receptors, offering an effective therapeutic candidate in the management of anxiety and depression in humans.
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PMID:Pharmacological characterization of LB50016, N-(4-amino)butyl 3-phenylpyrrolidine derivative, as a new 5-HT1A receptor agonist. 1023 May 6

Mice deficient in the neural cell adhesion molecule (NCAM) show behavioral abnormalities as adults, including altered exploratory behavior, deficits in spatial learning, and increased intermale aggression. Here, we report increased anxiety-like behavior of homozygous (NCAM-/-) and heterozygous (NCAM/-) mutant mice in a light/dark avoidance test, independent of genetic background and gender. Anxiety-like behavior was reduced in both NCAM+/+ and NCAM-/- mice by systemic administration of the benzodiazepine agonist diazepam and the 5-HT1A receptor agonists buspirone and 8-OH-DPAT. However, NCAM-/- mice showed anxiolytic-like effects at lower doses of buspirone and 8-OH-DPAT than NCAM+/+ mice. Such increased response to 5-HT1A receptor stimulation suggests a functional change in the serotonergic system of NCAM-/- mice, likely involved in the control of anxiety and aggression. However, 5-HT1A receptor binding and tissue content of serotonin and its metabolite 5-hydroxyindolacetic acid were found unaltered in every brain area of NCAM-/- mice investigated, indicating that expression of 5-HT1A receptors as well as synthesis and release of serotonin are largely unchanged in NCAM-/- mice. We hypothesize a critical involvement of endogenous NCAM in serotonergic transmission via 5-HT1A receptors and inwardly rectifying K+ channels as the respective effector systems.
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PMID:Anxiety and increased 5-HT1A receptor response in NCAM null mutant mice. 1044 Jul 34

These studies examined the neurochemistry and neuroanatomy of the serotonin (5-HT) system innervating the anterior hypothalamus (AH) and the interaction of 5-HT receptor agonists with arginine vasopressin (AVP) in the regulation of offensive aggression in golden hamsters. Because specific 5-HT1A, 5-HT1B, and AVP V1A binding sites were observed within the AH by in vitro autoradiography, the hamsters were tested for offensive aggression after microinjections of AVP in combination with either the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetraline (DPAT) or the 5-HT1B agonist CGS-12066A (CGS) directly within the AH. Though treatment with DPAT resulted in a dose-dependent inhibition of AVP-facilitated offensive aggression, CGS was ineffective. In addition, a retrograde tracer was injected within the AH to localize the distribution of 5-HT neurons projecting to the area. Retrogradely labeled 5-HT neurons were found within the dorsal, median, and caudal linear raphe nuclei and are suspected to inhibit AVP-facilitated offensive aggression by an activation of 5-HT1A receptors in the AH.
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PMID:Serotonin regulation of aggressive behavior in male golden hamsters (Mesocricetus auratus). 1049 88

An overview of the behavioral, electrophysiological and neurochemical data found in the literature concerning the involvement of serotonin (5-HT) receptors in the regulation of anxiety was presented on the basis of animal models. At present, 5-HT receptors are classified into 7 families including at least 14 subtypes. Among these 5-HT receptors, it is conceivable that 5-HT1A-receptor-mediated effects are the most important part of the mechanism of anxiety. The demonstrated efficacy of 5-HT1A-receptor partial agonists in anxiety disorders has emphasized the importance of these receptors. Enhanced anxiety was observed in mutant mice lacking 5-HT1A receptors. In 5-HT1B receptors knockout mice, on the other hand, aggressive behavior was increased. Some of the selective antagonists acting on 5-HT2 and 5-HT3 receptors have shown the anxiolytic effects in various animal models. Inactivation of mRNA encoding 5-HT6 receptors using antisense oligonucleotide produced decreases in cortical 5-HT release enhanced by anxiety. These observations lead to the suggestion that different mechanisms, mediated by various 5-HT receptors, are involved in the pathogenesis of anxiety.
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PMID:[Possible involvement of serotonin receptors in anxiety disorders]. 1087 14

Treatment of aggression in schizophrenic patients is a major challenge. We sought to examine the efficacy of augmentation of antipsychotic treatment with pindolol in the amelioration of aggression. Thirty male inpatients meeting DSM-IV criteria for schizophrenia, aged 20-65 years involved in four or more aggressive incidents in the two previous months, were enrolled in a double-blind crossover study. Aggression was evaluated per incident, with the Overt Aggression Scale (OAS). Positive and Negative Syndrome Scale (PANSS) was administered at baseline, crossover and at endpoint. Patients received either pindolol or placebo augmentation 5 mg x three times a day until crossover, then switched. No significant differences were found in the PANSS scores between the placebo and pindolol treatments. OAS scores were significantly reduced for number of aggressive incidents towards objects and other persons during pindolol treatment (0.59 versus 1.46, F = 6.09, P < 0.02; 1.96 versus 3.23, F = 4.17, P < 0.05, respectively). Similar results were obtained for severity of incidents (0.89 versus 3.58, F = 19.42, P < 0.0001; 2.89 versus 6.85, F = 10.11, P < 0.004, respectively). Pindolol, with its dual beta and 5-HT1A blocking effect ameliorated both number and severity of aggressive acts. Influence on severity may be associated with a 5-HT1A antagonistic effect.
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PMID:Pindolol augmentation in aggressive schizophrenic patients: a double-blind crossover randomized study. 1123 69

A new subtype of depression is proposed, named: anxiety/aggression-driven depression. The psychopathological, psychopharmacological and biochemical evidence on which this construct is based, is being discussed. Selective postsynaptic 5-HT1A agonists together with CRH and/or cortisol antagonists are hypothesized to be a specific biological treatment for this depression type, in conjunction with psychological interventions to raise the stressor-threshold and to increase coping skills. The development of this depression construct has been contingent on the introduction of two new diagnostic procedures, called functionalization and verticalization of psychiatric diagnosis. These procedures are explained and it is stressed that they are essential to psychiatric diagnosing, in order to put this process on a scientific footing.
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PMID:Anxiety/aggression--driven depression. A paradigm of functionalization and verticalization of psychiatric diagnosis. 1138 84

Previous reports indicate that the behavioural effects (including anxiolytic-like actions, hypothermia, "serotonergic syndrome," maternal behaviour and aggression and reduction in ambulation) of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), are completely blocked in lactating rats. The present study compares the behavioural effects of buspirone (1.25, 2.5 and 5.0 mg/kg) and diazepam (0.5, 1.0, 2.0 and 4.0 mg/kg) between ovariectomized and mid-lactating rats. The study was carried out on Wistar female rats under inverted light/dark cycle conditions, by using the burying behaviour paradigm, the elevated plus maze and a general activity test. In both ovariectomized and lactating rats, diazepam produced a dose-dependent reduction in burying behaviour and an increase in the time spent in open arms, responses interpreted as anxiolytic. Buspirone at all doses (1.25, 2.5 and 5.0 mg/kg) produced clear motor impairments in lactating, but not in ovariectomized animals, indicating that the effects of this drug on the anxiety paradigms are unspecific. Diazepam, by contrast, at the highest dose (4.0 mg/kg) similarly inhibited ambulation in both conditions. In the elevated plus maze, control lactating subjects spent more time in the open arms compared with saline-treated ovariectomized subjects, suggesting an anxiolytic-like effect of lactation per se. The present results support the idea that some behavioural actions of drugs acting at the serotonergic system vary between ovariectomized and lactating rats.
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PMID:Diazepam, but not buspirone, induces similar anxiolytic-like actions in lactating and ovariectomized Wistar rats. 1156 45


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