HT2 Receptor Agonist Challenge

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m-Chlorophenylpiperazine (mCPP) is an increasingly widely used 5-HT challenge which increases body temperature, stimulates PRL and ACTH/cortisol secretion and causes anxiety with GH stimulation occurring after intravenous but not oral administration.61,62 It is non-selective in its binding to 5-HT receptors,63,64 but animal studies suggest that many of its agonist effects are mediated by 5-HT2C receptors.65 mCPP's postsynaptic site of action has been challenged in animals by an in vivo microdialysis finding that it releases 5-HT and that the 5-HT reuptake inhibitor, fluoxetine, blocks this effect and partially attenuates mCPP-mediated PRL release.66 There are however contradictory reports about mCPP's affinity for the human brain 5-HT transporter,64,67 possibly related to different methodologies. In humans, the PRL, cortisol and anxiety responses are antagonized by non-selective 5-HT antagonists68,69 and by ritanserin70 as well as clozapine,71,72 but not by the 5-HT3 antagonist, endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3yl)-2,3-dihydro-3,3-dimethyl-indole-1-carboxamide HCl (BRL 46470)73 However, ondansetron is reported to attenuate cortisol and behavioral responses without affecting the PRL response in another study74 raising the possibility that 5-HT3 receptors may be involved in some responses. GH stimulation is not blocked by ritanserin70 raising doubts about the role of 5-HT2 receptors in this response. In summary the situation with regard to mCPP-mediated responses is complex with the strongest evidence linking PRL, cortisol and behavioral responses with 5HT2 receptors. Animal evidence further suggests that it is the 5-HT2C receptor subtype that is involved. However the assumption that responses purely reflect postsynaptic receptor function must be treated with caution.

6-Chloro-2-(l-piperazinyl)pyrazine (MK-212) binds to a variety of 5-HT receptors including 5-HT2A, 5-HT2C and 5-HT1A receptors.63 Animal studies show dose-related stimulation of PRL and ACTH/cortisol with antagonism by 5-HT2A/2C, but not 5-HT1A receptor antagonists.75-77 It stimulates PRL and cortisol secretion after oral administration in humans75,78 with pindolol pretreatment partially antagonizing PRL but not cortisol responses.79 Overall therefore the evidence is supportive of 5-HT2A/2C mediation of cortisol stimulation in humans with less certainty about the PRL response (reminiscent of 5-HTP, see above).

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