Involvement of 5‐HT₂ receptors in the behaviours produced by intrathecal administration of selected 5‐HT agonists and the TRH analogue (CG 3509) to rats

Abstract

1 The behavioural effects of the intrathecal injection of a thyrotrophin-releasing hormone (TRH) analogue L-orotyl-L-histidyl-prolineamide (CG 3509, 0.5 /g), the non-selective 5-HT, and 5-HT2 receptor agonist 5-methoxy-N,N'-dimethyltryptamine (5-MeODMT, 2-100pg) and the selective 5-HT2 receptor agonist 2,5-dimethoxy-a,4-dimethyl-benzene ethamine hydrochloride (DOM, 2-25 ug) were compared with the response of systemically administered 5-MeODMT (2 mg kg-1, i.p.) in rats, to establish whether the agonist-induced behaviours were mediated by bulbospinal 5-HT, or 5-HT2 receptors. 2 Intrathecal injection of 5-MeODMT or DOM produced dose-related back muscle contractions (a previously undocumented behaviour) and wet-dog shakes which were both markedly attenuated by ritanserin pretreatment (1 mg kg 1, i.p.) indicating the involvement of 5-HT2 receptors. In contrast, reciprocal forepaw treading, flat body posture and Straub-tail were evoked by 5-MeODMT but not by DOM indicating that these behaviours were not produced by 5-HT2 receptor activation alone. However, as ritanserin pretreatment reduced the reciprocal forepaw treading induced by intrathecal 5-MeODMT, this behaviour may be facilitated by 5-HT2 receptor activation.3 Intrathecal 5,7-dihydroxytryptamine (5,7-DHT, 2 x 150pg) treatment decreased thoraco-lumbar spinal cord 5-HT (-95%) and potentiated the back muscle contractions produced by intrathecal DOM injection without altering the wet-dog shake behaviour. None of the components of the 5-HT syndrome produced by 5-MeODMT (2mgkg-1, i.p.), with the exception of a small increase in wet-dog shakes, was significantly altered by intrathecal 5,7-DHT (which reduced thoraco-lumbar spinal cord 5-HT by 84%). Taken together these data suggest that the only 5-HT agonist-induced behaviour mediated by the activation of 5-HT2 receptors located postsynaptic to bulbospinal 5-hydroxytryptaminergic (5-HTergic) neurones was back muscle contractions. 4 The wet-dog shake and forepaw licking behaviors produced by intrathecal CG 3509 (0.5 Mg) were attenuated when ritanserin was administered intrathecally 30 min before, but not when it was given at the same time as CG 3509 and neither behaviour was altered by intrathecal 5,7-DHT. This suggests that bulbospinal 5-HTergic neurones are not involved in the production of these TRH analogue-induced behaviours and that the 5-HT2 receptors which mediate these behaviours are not located in the spinal cord.

Characterization of the head-twitch response induced by hallucinogens in mice

“…Most importantly, selective 5-HT 2A antagonists block the HTR induced by DOI and other hallucinogens (Schreiber et al, 1995; Fantegrossi et al, 2005, 2006, 2008, 2010), and hallucinogens do not induce the HTR in 5-HT 2A knockout mice (Gonzalez-Maeso et al, 2003, 2007; Keiser et al, 2009; Halberstadt et al, 2011). Although phencyclidine (Nabeshima et al, 1987), benzodiazepines (Tadano et al, 2001), the CB 1 antagonist SR 14176A (Darmani and Pandya, 2000), the 5-HT 1A antagonist WAY-100635 (Darmani, 1998), and thyrotropin-releasing hormone analogs (Fone et al, 1989) induce the HTR, these effects are blocked by 5-HT 2A receptor antagonists. Because of this specificity, this behavior has been widely adopted as an animal behavioral assay for 5-HT 2A activation and hallucinogen-like effects.…”

Altered responsiveness of serotonin receptor subtypes following long-term cannabinoid treatment

“…Immediately following injection of DOI or saline, subjects were placed into a Plexiglas testing bin (60 cmr45 cmr 45 cm) lined with Aspen chip bedding. During a 30-min interval in the testing bin, they were scored for the occurrence of wet-dog shakes (defined as a paroxysmal shudder of the head, neck and trunk ; Bedard and Pycock, 1977 ; and back muscle contractions (defined as a clear-cut powerful contraction sweeping from the back of the neck along the back to the tail ; Fone et al, 1989).…”

YM-14673, a thyrotropin-releasing hormone analogue, injected into the nucleus accumbens and the striatum produces repetitive jaw movements in rats

“…The m echanism underlying T R H augm entation of dopam ine-dependent behaviours is still u n d er dis cussion. A p art from th e conflicting reports concerning the ability of T R H to enhance the release of dopam ine (Miyamoto et al, 1981;Sharp et al, 1982;Xu et al, 1990;M éndez et al, 1993), it is also able to inhibit the uptake of dopam ine (Prasad, 1987(Prasad, , 1991 277 (1995) [63][64][65][66][67][68][69] these properties may underlie the ability of T R H to alter dopam ine-dependent effects, it cannot underlie the wet-dog shakes th at are elicited by TR H , since 5-H T2a receptors appear to be involved in this T R H effect (Fone et al, 1989a), Today, there are several T R H analogues th a t are known to produce T R H effects. Previously, we have shown that the T R H analogue, A^a-[{(5)-4-oxo-2-azetidinyI}-carbonyI]-L-histidyl-L-proIinamide dihydrate (YM-14673), elicits dopamine-like behaviours such as sniffing and hyperlocomotion (Yamamoto et al, 1990).…”