HT Precursor Challenge

Beta Switch Program

The Beta Switch Program by Sue Heintze

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The best characterized precursor challenge is intravenous administration of the amino acid, /-tryptophan (TRP), which reliably stimulates prolactin (PRL) and growth hormone (GH) secretion. Both responses are enhanced by acute 5-HT reuptake blockade with clomipramine15 although only the PRL response is inhibited by the non-selective 5-HT receptor antagonist, metergoline.16 However both responses are inhibited by pindolol which has 5-HT1A receptor antagonist properties.17 Neither response is blocked by the 5-HT2A/2C receptor antagonists, ritanserin and ketanserin,18,19 or by granisetron, a 5-HT3 receptor antagonist.20 These data suggest that the hormonal responses are mediated by 5-HT1A receptors although there is less certainty about the GH than the PRL response.

5-Hydroxytryptophan (5-HTP) is the immediate precursor of 5-HT. Parenteral administration results in unacceptable side-effects so it is generally given orally and, probably because of this, hormone responses tend to be unreliable. An interesting difference from TRP challenge is the stimulation of cortisol secretion. Animal studies suggest 5-HT2 receptor-mediation of hormonal responses.21 In humans the GH response is antagonized by cyproheptidine, a more potent 5-HT2 than 5-HT1 receptor antagonist22 while the cortisol response is antagonized by ritanserin in one study23 but not another.24 Pindolol lacks effect on the cortisol response,25 but PRL stimulation appears to be antagonized by both ritanserin23 and pindolol.25 Therefore the mediation of 5-HTP-induced hormone responses in humans are not entirely certain although the involvement of 5-HT2 receptors seems most

Table 8.1. 5-HT drugs used in human pharmacological challenge tests: Hormonal responses and putative receptor mediation

Hormone (putative receptor mediation)

Drug

5-HT action

Prolactin

Growth hormone

ACTH/cortisol

5-HTP*

precursor

(*) (5-HT2/ 5-HT-ia

(*) (5-HT2)

(*) (?5-HT2)

Tryptophan

precursor

* (5-HTia) * (?)

^ (5-HT1a)

(*)

Clomipramine

reuptake inhibitor

* (?)

-

* (?)

Fenfluramine

reuptake inhibitor/releaser

* (5-HT2)

-

* (5-HT2)

Buspirone

5-HT1A agonist

* (D2/5-HTm)

^ (5-HT1a)

* (5-HTia)

Ipsapirone

5-HT1A agonist

(*) (5-HTia)

^ (5-HT1a)

* (5-HTia)

Gepirone

5-HT1A agonist

* (5-HT1A)

^ (5-HT1a)

* (5-HTia)

Sumatriptan

5-HT1D agonist

(^)(5-HT|d)

^ (5-HT1d)

-

mCPP

5-HT2C agonist ?5-HT releaser

* (5-HT2c)

^ (?)**

* (5-HT2c)

MK-212

5-HT1a/5-HT2c agonist

* (5-HTia/ 5-HT2)

-

* (5-HT2)

^ , increase in plasma hormone; weak/inconsistent increase in plasma hormone;

inconsistent decrease in plasma hormone; -, no response; *, oral administration; **, increases GH after intravenous but not oral administration.

^ , increase in plasma hormone; weak/inconsistent increase in plasma hormone;

inconsistent decrease in plasma hormone; -, no response; *, oral administration; **, increases GH after intravenous but not oral administration.

likely and there may be a 5-HT1A/5HT2 receptor interaction involved in the PRL response. It is unclear why TRP and 5-HTP apparently probe different 5-HT receptors.

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