Characterization of the 5‐HT receptor subtypes involved in the motor behaviours produced by intrathecal administration of 5‐HT agonists in rats

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Abstract
1 The motor behavioural effects of intrathecal injections of 5-hydroxytryptamine (5-HT) and a variety of 5-HT receptor agonists were examined in adult Wistar rats to establish; (a) which 5-HT receptor subtype/s elicit each behaviour and (b) whether these receptors are located within the spinal cord. 2 Intrathecal injection of 5-methoxy-N,N′-dimethyltryptamine (5-MeODMT), (+)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) or 2,5-dimethoxy-α,4-dimethylbenzene ethamine hydrochloride (DOM) produced dose-related back muscle contractions (BMC) and wet dog shakes (WDS) which were both markedly attenuated by intraperitoneal pretreatment with either ritanserin (1 mg kg−1), ketanserin (0.16 mg kg−1) or mianserin (0.6 mg kg−1) indicating the involvement of 5-HT2 receptors in both these motor behaviours. Both fluoxetine (1–20 mg kg−1, i.p.) and high doses of 5-HT (50 μg) following fluoxetine (5 mg kg−1, i.p.) also elicited BMC, further confirming the involvement of 5-HT in this behaviour. 3 Intrathecal 5-carboxamidotryptamine (5-CT) evoked a marked wet-dog shake response without producing any BMC. Intrathecal pretreatment with 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) enhanced, while in contrast 2-methyl-5-HT pretreatment attenuated, 5-HT agonist-induced BMC without affecting WDS. These data suggest that the spinal 5-HT2 receptors mediating BMC are positively modulated by 5-HT1A but negatively influenced by 5-HT3 receptor activation and may be of a different subtype to the supra-spinal 5-HT2 receptors which elicit WDS. 4 A contrast, reciprocal forepaw treading, lateral head weaving, flat body posture and Straub-tail were evoked by 5-MeODMT, 8-OH-DPAT or 5-CT but not by DOI or DOM indicating that these behaviours were not produced by 5-HT2 receptor activation alone. Ritanserin (1 mg kg−1, i.p.) or ketanserin (0.16 mg kg−1, i.p.) pretreatment reduced the reciprocal forepaw treading induced by high intrathecal doses of either 5-MeODMT (25 μg) or 5-CT (50 μg) suggesting that this behaviour may be facilitated by 5-HT2 receptor activation. 5 Intrathecal injection of 5-HT (0.05–50 μg, after systemic fluoxetine, 5 mg kg−1, i.p.), or 1-(3-chlorophenyl)piperazine (mCPP) produced dose-related forepaw-licking and grooming, neither of which were attenuated by ketanserin (0.16 mg kg−1, i.p.) pretreatment suggesting these behaviours may be mediated by 5-HT1C receptors. In contrast, 2-methyl-5-HT (50 and 100 μg) produced sideward tail-flicks, not evoked by any other 5-HT agonist and could therefore be mediated by spinal 5-HT3 receptor activation. 6 These data provide behavioural evidence for the existence of spinal 5-HT2 receptors which produce a novel motor behaviour, BMC. Ligand binding studies and dose-response studies with a range of selective 5-HT antagonists are required to establish whether BMC and WDS are mediated by different subtypes of 5-HT2 receptors.