8-OH-DPAT acts on both 5-HT1A and 5-HT7 receptors to induce hypothermia in rodents
ABSTRACT Studies using selective drugs and knockout mice have demonstrated that the 5-HT(7) receptor plays an instrumental role in serotonin-induced hypothermia. There is also evidence supporting an involvement of the 5-HT(1A) receptor, although mainly from studies using 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT(1A/7) receptor agonist. Here we studied the effects of 8-OH-DPAT and selective antagonists for the 5-HT(1A) and 5-HT(7) receptors on body temperature in rats, wild-type (5-HT(7)(+/+)) mice and knockout (5-HT(7)(-/-)) mice. At lower doses (0.3-0.6 mg/kg, i.p.), 8-OH-DPAT decreased body temperature in 5-HT(7)(+/+) mice but not in 5-HT(7)(-/-) mice. At a higher dose (1 mg/kg, i.p.) 8-OH-DPAT induced hypothermia in both 5-HT(7)(-/-) and 5-HT(7)(+/+) mice. The 5-HT(1A) receptor antagonist (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide (WAY-100135) (10 mg/kg, i.p.) inhibited the effect of 8-OH-DPAT at all doses in rats and mice. In 5-HT(7)(+/+) mice the selective 5-HT(7) receptor antagonist (R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970) (10 mg/kg, i.p.) fully inhibited the hypothermia induced by 0.3 mg/kg 8-OH-DPAT, but not that of higher doses. In rats, SB-269970 caused a 60% inhibition of the hypothermia induced by 0.3 mg/kg 8-OH-DPAT. Thus, both 5-HT(7) and 5-HT(1A) receptors are involved in a complex manner in thermoregulation, with the 5-HT(7) receptor being more important at lower, possibly more physiological, concentrations.
- SourceAvailable from: Luc Zimmer
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- "One of them, 8-OH-DPAT, is an aminotetralin derivative which was developed in the 1980s and was one of the first major 5-HT 1A receptor agonists to be discovered . 8-OH-DPAT has been extensively used in pharmacological studies characterizing 5-HT 1A , although it was later found to act as a 5-HT 7 receptor agonist . Other compounds acting on 5-HT 1A receptors exhibit similar complex pharmacological profiles. "
ABSTRACT: Serotonin and its various receptors are involved in numerous brain functions and neuropsychiatric disorders. The 5-HT1A family is the best characterized subtype of the fourteen currently known 5-HT receptors. The 5-HT1A receptor is closely involved in the pathogenesis of anxiety, depression, epilepsy and eating disorders and therefore is an important target for drug therapy. The development in the 1980s of molecules specifically targeting this receptor was followed by the rapid development of corresponding PET neuroimaging. Because this receptor represents a crucial target in neuroscience, a large number of radioligands have been developed by academic and industry centers for visualization and quantification, first in living animals and ultimately in humans. After a brief account of some of the structural and functional characteristics of brain 5-HT1A receptors, this review focuses on the main lines of evolution opened up by preclinical and clinical 5-HT1A PET radiopharmaceuticals, illustrating the potential value of PET for clinical research and drug development.Current Medicinal Chemistry 08/2013; DOI:10.2174/09298673113209990215 · 3.85 Impact Factor
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- "In addition, (±)-8-OH-DPAT effectively alleviated the fluoxetine enhancement of haloperidol-induced EPS. Although (±)- 8-OH-DPAT has an affinity not only for 5-HT 1A receptors, but also for 5-HT 7 receptors (Hedlund et al., 2004), the reversal of the fluoxetine enhancement of EPS with (±)-8-OH-DPAT was abolished by the selective 5-HT 1A antagonist (S)-WAY-100135. The dosage (5–20 mg/kg) of fluoxetine used herein was in a range that reportedly inhibits 5-HT reuptake and increases the extracellular level of 5-HT (Paez and Leibowitz, 1993; Perry and Fuller, 1992). "
ABSTRACT: We previously demonstrated that 5-HT stimulants, including selective serotonin reuptake inhibitors (SSRIs), potentiated antipsychotic-induced extrapyramidal symptoms (EPS) by stimulating 5-HT2A/2C, 5-HT3 and 5-HT6 receptors. Here, we studied the effects of the 5-HT1A agonist (±)-8-hydroxy-2-(di-n-propylamino) tetralin ((±)-8-OH-DPAT) on the fluoxetine enhancement of EPS (i.e., bradykinesia and catalepsy) to determine if the 5-HT1A agonist can counteract the serotonergic potentiation of EPS. Fluoxetine did not induce EPS signs by itself, but significantly potentiated haloperidol-induced bradykinesia in mice. (±)-8-OH-DPAT (0.1-1 mg/kg, i.p.) significantly attenuated the fluoxetine enhancement of haloperidol-induced bradykinesia in a dose-dependent manner. A selective 5-HT1A antagonist (s)-WAY-100135 completely reversed the anti-EPS action of (±)-8-OH-DPAT. Microinjection studies using rats revealed that local application of (±)-8-OH-DPAT into the dorsolateral striatum or the motor cortex significantly diminished fluoxetine-enhanced catalepsy. In contrast, (±)-8-OH-DPAT injected into the medial raphe nucleus failed to affect EPS induction. The present results illustrate that 5-HT1A agonist can alleviate the SSRI enhancement of EPS by activating postsynaptic 5-HT1A receptors in the striatum and cerebral cortex.Progress in Neuro-Psychopharmacology and Biological Psychiatry 07/2013; 46. DOI:10.1016/j.pnpbp.2013.06.016 · 4.03 Impact Factor
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- "This probe was lubricated with vaseline and inserted 2 cm into the rectum. Temperature recordings were made 20 s following insertion of the probe, as previously described  . "
ABSTRACT: No study has ever examined the effect of 5-HT(7) receptor agonists on nociception by using 5-HT(7) receptor knockout mice. Basal sensitivity to noxious heat stimuli and formalin-induced nociception in both phase I and II of the formalin test did not differ in 5-HT(7) receptor knockout mice and paired wild-type controls. Similarly, there was no significant difference in basal body temperature between both genotypes. Subcutaneous administration of 5-HT(7) receptor agonists AS-19 (10 mg/kg), E-57431 (10 mg/kg), and E-55888 (20 mg/kg) significantly reduced formalin-induced licking/biting behavior during the phase II of the test in wild-type but not in 5-HT(7) receptor knockout mice. At these active analgesic doses, none of the three 5-HT(7) receptor agonists modified the basal body temperature neither in wild-type nor in 5-HT(7) receptor knockout mice. However, a significant decrease in body temperature was observed at a higher dose (20 mg/kg) of AS-19 and E-57431 in both genotypes. Our data strongly suggest that the 5-HT(7) receptor agonists AS-19, E-57431, and E-55888 produce antinociception in the formalin test by activating 5-HT(7) receptors. These results also strengthen the idea that the 5-HT(7) receptor plays a role in thermoregulation, but by acting in concert with other receptors.Advances in Pharmacological Sciences 06/2012; 2012:312041. DOI:10.1155/2012/312041