The 5-hydroxytryptamine2 agonist, (±)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane stimulates the hypothalamic-pituitary-adrenal (HPA) axis. II. Biochemical and physiological evidence for the development of tolerance after chronic administration

M. J. Owens, D. L. Knight, J. C. Ritchie, Charles Nemeroff

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Abstract

In order to investigate the long term effects of the 5-hydroxytryptamine2 (5-HT2) receptor agonist, (±)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB), on hypothalamic-pituitary-adrenal (HPA) axis activity, DOB (0.35 mg/kg/day) was administered via osmotic minipumps to rats for 7 days at which time plasma adrenocorticotrophic hormone (ACTH), corticosterone and regional brain corticotropin-releasing factor (CRF) concentrations were measured. In addition, anterior pituitary CRF and frontal cortical 5-HT2 receptor binding was measured. Seven-day infusion of DOB resulted in tolerance to the stimulatory actions of the drug on the HPA axis as evidenced by the return of plasma ACTH and corticosterone concentrations to base-line values. Moreover, rats treated chronically with DOB exhibited decreased numbers of both anterior pituitary CRF and cortical and hypothalamic 5-HT2 receptor. These receptor changes were physiologically significant as challenge doses of DOB or CRF resulted in blunted ACTH responses. Chronic DOB infusion was without effect on CRF concentrations in all hypothalamic and extrahypothalamic brain regions studied. A series of time course experiments revealed that DOB-induced increases in plasma corticosterone returned to base-line by 2-days postimplantation. This effect was apparently associated with down-regulation of the 5-HT2 receptor because high-affinity cortical [3H]DOB and hypothalamic (±)-[125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane binding were decreased at this time as well. Although median eminence CRF content was unchanged at all time points, anterior pituitary CRF receptor binding was significantly decreased 7 days postimplantation. These results suggest that tolerance of the HPA axis to the stimulatory actions of DOB initially results from down-regulation of 5-HT2 receptors. Additionally, by 7 days postimplantation, down-regulation of anterior pituitary CRF receptors may also contribute to the observed tolerance.

Original languageEnglish
Pages (from-to)795-800
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume256
Issue number2
StatePublished - Jan 1 1991
Externally publishedYes

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Corticotropin-Releasing Hormone
Corticosterone
Adrenocorticotropic Hormone
Corticotropin-Releasing Hormone Receptors
Down-Regulation
Propane
Median Eminence
Brain
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "The 5-hydroxytryptamine2 agonist, (±)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane stimulates the hypothalamic-pituitary-adrenal (HPA) axis. II. Biochemical and physiological evidence for the development of tolerance after chronic administration",
abstract = "In order to investigate the long term effects of the 5-hydroxytryptamine2 (5-HT2) receptor agonist, (±)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB), on hypothalamic-pituitary-adrenal (HPA) axis activity, DOB (0.35 mg/kg/day) was administered via osmotic minipumps to rats for 7 days at which time plasma adrenocorticotrophic hormone (ACTH), corticosterone and regional brain corticotropin-releasing factor (CRF) concentrations were measured. In addition, anterior pituitary CRF and frontal cortical 5-HT2 receptor binding was measured. Seven-day infusion of DOB resulted in tolerance to the stimulatory actions of the drug on the HPA axis as evidenced by the return of plasma ACTH and corticosterone concentrations to base-line values. Moreover, rats treated chronically with DOB exhibited decreased numbers of both anterior pituitary CRF and cortical and hypothalamic 5-HT2 receptor. These receptor changes were physiologically significant as challenge doses of DOB or CRF resulted in blunted ACTH responses. Chronic DOB infusion was without effect on CRF concentrations in all hypothalamic and extrahypothalamic brain regions studied. A series of time course experiments revealed that DOB-induced increases in plasma corticosterone returned to base-line by 2-days postimplantation. This effect was apparently associated with down-regulation of the 5-HT2 receptor because high-affinity cortical [3H]DOB and hypothalamic (±)-[125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane binding were decreased at this time as well. Although median eminence CRF content was unchanged at all time points, anterior pituitary CRF receptor binding was significantly decreased 7 days postimplantation. These results suggest that tolerance of the HPA axis to the stimulatory actions of DOB initially results from down-regulation of 5-HT2 receptors. Additionally, by 7 days postimplantation, down-regulation of anterior pituitary CRF receptors may also contribute to the observed tolerance.",
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T1 - The 5-hydroxytryptamine2 agonist, (±)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane stimulates the hypothalamic-pituitary-adrenal (HPA) axis. II. Biochemical and physiological evidence for the development of tolerance after chronic administration

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