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.
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ABSTRACT: Serotonin type 7 receptors (5-HT7) are expressed in several brain areas, regulate brain development, synaptic transmission and plasticity, and therefore are involved in various brain functions such as learning and memory. A number of studies suggest that 5-HT7 receptors could be potential pharmacotherapeutic target for cognitive disorders. Several abnormalities of serotonergic system have been described in patients with autism spectrum disorder (ASD), including abnormal activity of 5-HT transporter, altered blood and brain 5-HT levels, reduced 5-HT synthesis and altered expression of 5-HT receptors in the brain. A specific role for 5-HT7 receptors in ASD has not yet been demonstrated but some evidence implicates their possible involvement. We have recently shown that 5-HT7 receptor activation rescues hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome, a monogenic cause of autism. Several other studies have shown that 5-HT7 receptors modulate behavioral flexibility, exploratory behavior, mood disorders and epilepsy, which include core and co-morbid symptoms of ASD. These findings further suggest an involvement of 5-HT7 receptors in ASD. Here, we review the physiological roles of 5-HT7 receptors and their implications in Fragile X Syndrome and other ASD.Frontiers in Cellular Neuroscience 08/2014; 8:250. · 4.47 Impact Factor
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ABSTRACT: Indirect-acting serotonin (5-HT) receptor agonists (e.g., selective 5-HT reuptake inhibitors [SSRI]) stimulate multiple 5-HT receptors, although the role of particular receptors as well as interaction(s) among different receptors in the therapeutic effects of SSRIs is not fully understood. Relatively few studies have systematically examined direct-acting agonists in combination. This study examined the 5-HT(1A) receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin hydrochloride (8-OH-DPAT; 0.01-10.0 mg/kg) and 3-chloro-4-fluorophenyl-4-fluoro-4-([(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl)-piperidin-1-yl-methanone (F13714; 0.01-1.0 mg/kg) and the 5-HT(2A) receptor agonists 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM; 0.32-10.0 mg/kg) and dipropyltryptamine (DPT; 1.0-32.0 mg/kg), alone and in combination, in rats responding under a fixed ratio schedule of food presentation. When administered alone, each drug decreased the rate of responding in a dose-related manner with the potency order being F13714 > 8-OH-DPAT > DOM > DPT. WAY100635 (5-HT(1A) receptor antagonist; 0.01-0.1 mg/kg) attenuated the rate-decreasing effects of 8-OH-DPAT and F13714 while MDL100907 (5-HT(2A) receptor antagonist; 0.01-0.1 mg/kg) attenuated the rate-decreasing effects of DOM and DPT. Dose addition analysis showed that the interaction between 8-OH-DPAT and F13714, as well as the interaction between DOM and DPT, was additive. In contrast, the interaction between 8-OH-DPAT and DOM, as well as the interaction between F13714 and DOM, was infra-additive. This study shows that for some dose combinations, agonist actions at one 5-HT receptor subtype attenuate agonist actions at another 5-HT receptor subtype; thus, the combined neuropharmacological actions and therapeutic effects of indirect-acting agonists are not likely to be adequately characterized by examining in isolation activity at particular 5-HT receptor subtypes.Psychopharmacology 02/2011; 213(2-3):489-97. · 4.06 Impact Factor
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ABSTRACT: Social defeat leads to selective avoidance of familiar opponents as well as general avoidance of novel, non-threatening intruders. Avoidance of familiar opponents represents a fear-related memory whereas generalized social avoidance indicates anxiety-like behavior. We have previously shown that serotonin signaling alters responses to social defeat in Syrian hamsters, although it is unclear whether serotonin modulates defeat-induced fear, anxiety, or both. In this study we focus on 5-HT1A receptors, in part, because their activation had been linked to the acquisition of conditioned fear. We hypothesized that pharmacological activation of 5-HT1A receptors prior to social defeat would reduce avoidance of familiar opponents and impair Arc expression in the basolateral amygdala (BLA), but not alter anxiety-like behavior. We administered 8-OH-DPAT, a 5-HT1A receptor agonist, prior to 3, 5-minute social defeats and 24 h later exposed hamsters to a social interaction test to measure the conditioned defeat response immediately followed by either a Y-maze test or an open field test. In a separate experiment, we administered 8-OH-DPAT prior to 3, 5-minute social defeats and later removed the brains for Arc immunohistochemistry. Social defeat increased the number of Arc immunopositive cells in the central amygdala (CeA), prelimbic cortex (PL), and BLA, and 8-OH-DPAT treatment reduced Arc immunoreactivity in the PL. These results suggest that 5-HT1A receptor activation impairs the fear memory associated with social defeat, but does not alter defeat-induced anxiety. Overall, 5-HT1A receptor activation may impair Arc expression in select brain regions such as the PL and thereby disrupt the development of a fear memory essential for the conditioned defeat response.Pharmacology Biochemistry and Behavior 01/2014; · 2.82 Impact Factor