Disease relevance of Htr1a

• In mice TVX Q 7821 produced a dose-dependent inhibition of the hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) with an ED50 of 5.3 mg/kg suggesting that TVX Q 7821 was an antagonist of the presynaptic (possibly somato-dendritic) 5-HT1A receptor [1].
• The presence of receptor RNA in differentiated SN-48 cells correlated with the appearance of functional responses (i.e., pertussis toxin-sensitive inhibition of cAMP accumulation) to 5-HT1A agonists in differentiated but not in undifferentiated cells [2].
• Since fluoxetine has been shown to be useful in the treatment of eating disorders and to promote weight loss in obese humans, although at doses greater than those required for the treatment of depression, a combination of fluoxetine with a 5HT1A receptor antagonist could be of clinical utility in the treatment of eating disorders and obesity [3].
• Besides their proved anxiolytic action, agonists of the 5-HT1A receptor subtype show prospects as antidepressants or neuroprotective agents in case of ischemia [4].
• Medial hypothalamic 5-hydroxytryptamine (5-HT)1A receptors regulate neuroendocrine responses to stress and exploratory locomotor activity: application of recombinant adenovirus containing 5-HT1A sequences [5].

Psychiatry related information on Htr1a

• Finally, the 5-HT1A agonist 8-OH-DPAT (0.2-1.2 mg/kg, s.c.) induced in both strains a reduction in the amount of paradoxical sleep [6].
• We have previously shown that MDMA or 5-HT1A/1B receptor agonist RU24969 fails to stimulate locomotor activity in 5-HT1B receptor-null mice [7].
• However, sleep deprivation decreased the potency of the 5-HT1A agonist 8-OH-DPAT to inhibit 5-HT neuronal firing in wild-type mice, whereas it had no effect in GR-i animals [8].
• Administration of T3 together with electroconvulsive shock did not alter the effects of electroconvulsive shock on 5-HT1A-mediated hypothermia, but markedly potentiated its actions on 5-HT2-mediated responses [9].
• Using measurements of rodent behaviour in the mouse light and dark test box and rat social interaction, anxiolytic agents such as diazepam and putative anxiolytic agents such as the 5-HT1A and 5-HT3 receptor ligands 8-OH-DPAT and low doses of tropisetron release behaviour suppressed by the aversive situation [10].

High impact information on Htr1a

• Recently a new drug, 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT), has been identified which shows high selectivity for binding to 5-HT1 (possibly 5-HT1A) receptors and which binds to presynaptic serotonin autoreceptors in some regions of rat brain [11].
• However, the hyperlocomotor effect of the 5-HT1A/1B agonist RU24969 was absent in mutant mice, indicating that this effect is mediated by 5-HT1B receptors [12].
• The outward currents evoked by agonists for GABA(B) receptors, 5HT1A receptors, and adenosine A1 receptors were essentially absent in mutant mice, while the inward current evoked by muscarinic receptor activation was unaltered [13].
• Local increase of 5-hydroxytryptamine 1a receptor expression in medial amygdala may contribute to these changes [14].
• Heterozygote 5-HT1A mutants expressed approximately one-half of wild-type receptor density and displayed intermediate phenotypes in most behavioral tests [15].

Chemical compound and disease context of Htr1a

• The data suggest that TVX Q 7821 is a good presynaptic 5-HT1A antagonist in mice, as indicated by the 8-OH-DPAT-induced hypothermia and 5-HT synthesis rate studies [1].
• Propranolol impaired neither the hypothermia induced by an agonist at the 5-HT 1A receptors: 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) nor the increase in spontaneous motor activity induced by an agonist at the 5-HT 1B receptors: 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)1-H indole (Ru 24,969) [16].
• This, together with the fact that the hypothermia induced by B-20991 in mice was also antagonized by WAY 100635, suggests that the new compound acts upon somatodendritic 5-HT1A receptors [4].
• In the mouse SAP test, the benzodiazepine receptor agonists, diazepam (0.5 mg/kg s.c.) and chlordiazepoxide (2 mg/kg s.c.), and the 5-HT1A receptor agonists, buspirone (1 and 3 mg/kg s.c.), ipsapirone (3 mg/kg s.c.) and 8-OH-DPAT (0.2 mg/kg s.c.), all significantly decreased the frequency of SAP without impairing motor activity [17].
• In vivo, upon s.c. administration, S 14671 acted as a high efficacy agonist in models of 5-HT1A receptor-mediated activity: induction of flat-body posture, spontaneous tail-flicks, hypothermia and corticosterone secretion and inhibition of morphine-induced antinociception [18].

Biological context of Htr1a

• 5-HT1A knockout (KO) mice display an anxious-like phenotype, whereas 5-HT1B KOs are over-aggressive [19].
• Furthermore, we compared 5-HT1A receptor knockout (1AKO) and 1BKO mice to further test the suggested opposite behavioral profiles in these two genotypes [20].
• The 2.4 kb cDNA contained a single open reading frame that displayed high (> 85% predicted amino acid identity) homology to the human and rat 5-HT1A receptor genes [2].
• 3-amino-3,4-dihydro-2H-1-benzopyran derivatives as 5-HT1A receptor ligands and potential anxiolytic agents. 2. Synthesis and quantitative structure-activity relationship studies of spiro[pyrrolidine- and piperidine-2,3'(2'H)-benzopyrans] [21].
• Taken together, these findings indicate that activation of the 5-HT1A receptor leads to a number of neurotropic events by activating a series of signal transduction molecules leading to long-term changes required for neurogenesis [22].

Anatomical context of Htr1a

• Among 5-HT1 receptors, the 5-HT1A receptor transcript is expressed densely in E14.5-16.5 thalamus, in hippocampus, and in a medial to lateral gradient in cortex, whereas the 5-HT1B receptor mRNA is expressed in more lateral parts of the dorsal thalamus and in the striatum at these ages [23].
• Using receptor subtype-specific riboprobes and in situ hybridization, we observed that all 5-HT1 receptor subtypes are expressed as early as embryonic day (E) 14.5 in the forebrain, typically in gradients within specific structures [23].
• Moreover, all members of the 5-HT1 receptor class are strongly and transiently expressed in the embryonic dorsal thalamus, which suggests a potential role for serotonin in early thalamic development [23].
• Opposite responses in the same pyramidal neuron could be evoked by stimulating the raphe nuclei at different coordinates, suggesting a precise connectivity between 5-HT neuronal subgroups and 5-HT1A and 5-HT2A receptors in pyramidal neurons [24].
• In hippocampal neuronal cultures, 5-HT1A receptors are expressed on somatodendritic membranes but are absent from axons [25].

Associations of Htr1a with chemical compounds

• Regional changes in density of serotonin transporter in the brain of 5-HT1A and 5-HT1B knockout mice, and of serotonin innervation in the 5-HT1B knockout [19].
• 4. RU 24969 (7.5 mg kg-1 i.p.)-induced hyperlocomotion was inhibited by the (-)-, but not (+)-isomers of pindolol (4 mg kg-1) and propranolol (20 mg kg-1) but not by metoprolol (10 mg kg-1) or ICI 118,551 (5 mg kg-1), consistent with an involvement of 5-HT1A or 5-HT1B receptors [26].
• Spiperone, propranolol and pindolol (mixed 5-HT1A and 5-HT1B antagonists) effectively reversed both the tail-flick facilitation and the antagonistic effect on morphine sulfate-induced antinociception produced by 8-OH-DPAT and 5-CT [27].
• This effect of 8-OH-DPAT was minimally attenuated by the selective 5-HT1A receptor antagonist WAY 100635 but was reversibly and significantly reduced in the presence of ritanserin, a mixed 5-HT(2/7) receptor antagonist [28].
• The effect of the selective 5-hydroxytryptamine1B (5-HT1B) receptor agonist 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine (CP 94253) and the 5-HT1A/1B/1D receptor agonist 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU 24969) in maximal electroshock- and pentylenetetrazol-induced seizures in mice was examined [29].

Physical interactions of Htr1a

• Regulation of hippocampal 5-HT1A receptor mRNA and binding in transgenic mice with a targeted disruption of the glucocorticoid receptor [30].
• In lymphocytes and the central nervous system, the 5HT1A receptor is coupled to regulation of adenylate cyclase [31].

Regulatory relationships of Htr1a

• (ii) 5-HTT is down-regulated in several brain regions of 5-HT1A and 5-HT1B KO mice [19].
• Role of the inhibitory adrenergic alpha 2 and serotonergic 5-HT1A components of cocaine's actions on the DOI-induced head-twitch response in 5-HT2-receptor supersensitive mice [32].
• The 5HT1A receptor agonists inhibit activation of adenylate cyclase [31].
• In the hippocampus, 5-HT1A receptor-stimulated [35S]GTP gamma S binding was significantly attenuated in BDNF (+/-) mice [33].
• High intensity social conflict in the Swiss albino mouse induces analgesia modulated by 5-HT1A receptors [34].

Other interactions of Htr1a

• In the present group of experiments, we evaluate the role of 5-HT1A, 5-HT1B and 5-HT2A receptors in mCPP-induced hyperactivity in 5-HT2C KO mice [35].
• The effectiveness with which M100907 antagonizes the behavioral actions of this compound, coupled with the lack of significant antagonist effects of WAY-100635, strongly suggests that the 5-HT 2A receptor is an important site of action for 5-MeO-DIPT, despite its apparent in vitro selectivity for the 5-HT 1A receptor [36].
• Moreover, activation of 5-HT7 receptors in the mouse SCN, but not 5-HT1A receptors, also results in a reduction in the amplitude of the optic nerve-evoked EPSC [28].
• Blockade of HHTC activation induced by the presence of females appears to involve 5-HT1A and 5-HT2C receptors, while activation involves 5-HT2A and 5-HT3 receptors [37].
• Glucocorticoid receptor-dependent desensitization of 5-HT1A autoreceptors by sleep deprivation: studies in GR-i transgenic mice [8].

Analytical, diagnostic and therapeutic context of Htr1a

• Serotonin receptor 1A knockout: an animal model of anxiety-related disorder [15].
• These animals lack functional 5-HT1A receptors as indicated by receptor autoradiography and by resistance to the hypothermic effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) [38].
• To evaluate the contribution of serotonin 5-HT1A receptors to the regulation of these processes, we have used gene-targeting technology to generate 5-HT1A receptor-mutant mice [38].
• Northern blot analysis demonstrated the presence of a single 10.9 kilobase (kb) 5-HT1A receptor RNA species in differentiated SN-48 cells, which was not detected in undifferentiated SN-48 cells [2].
• Microdialysis experiments showed that the increase in local 5-HT release evoked by the activation of 5-HT2A receptors in mPFC by DOI (5-HT2A/2C receptor agonist) was reversed by co-perfusion of 5-HT1A agonists [24].

References