Subtypes of the 5-HT receptor mediating the behavioural responses to 5-methoxy-N,N-dimethyltryptamine in the rat

The 5-HT1A receptor subtype mediates forepaw treading behavior in rats given the serotonin agonist 5-MeODMT. In intact rats, the 5-HT2 antagonist ketanserin blocked forepaw treading only at high doses that also blocked dopamine receptors, suggesting its effect was not via 5-HT2 receptors. In rats depleted of monoamines with reserpine, neither ketanserin, haloperidol, nor beta-adrenoceptor antagonists altered forepaw treading or flat body posture, ruling out key roles for 5-HT2, dopamine, and beta receptors. Pindolol and spiperone, which interact with 5-HT1A sites, stereoselectively antagonized forepaw treading in both conditions, supporting mediation by 5-HT1A receptors. Flat body posture antagonism by pindolol occurred only in non-reserpinised rats, leaving its mechanism unclear.

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Abstract

The 5-HT receptor subtypes involved in the mediation of reciprocal forepaw treading and the flat body posture induced by the central 5-HT receptor agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), were examined in intact rats and in rats depleted of monoamines with reserpine. Forepaw treading in non-reserpinised rats was antagonised by the 5-HT2 receptor antagonist, ketanserin, only at doses in excess of those required for occupation of a large proportion of 5-HT2 receptors in brain, and at which there was significant inhibition of stereotyped sniffing induced by the dopamine receptor agonist, apomorphine. Since forepaw treading induced by 5-MeODMT was also blocked in intact rats by haloperidol, blockade of the behaviour by ketanserin may more accurately reflect antagonism at dopamine receptors than at 5-HT2 receptors. In reserpinised rats, i.e. with minimised contributions from other monoamine systems, neither forepaw treading nor the flat body posture were significantly altered by ketanserin, haloperidol or the beta 1- and beta 2-selective adrenoceptor antagonists, betaxolol and ICI 118.551, making a key role for 5-HT2 receptors, dopamine receptors and beta-adrenoceptors unlikely. In contrast, forepaw treading in both reserpinised and non-reserpinised rats was antagonised stereoselectively by pindolol and by spiperone, which interact with 5-HT1 and 5-HT1A recognition sites. The results are consistent with the hypothesis that forepaw treading induced by 5-MeODMT arises by activation of the putative 5-HT1A receptor. Antagonism of the flat body posture by pindolol could be demonstrated only in non-reserpinised rats and the mechanism of induction of this behaviour remains to be established.