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.
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 challenges 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Owens
M J
MJ
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina.
Knight
D L
DL
Ritchie
J C
JC
Nemeroff
C B
CB
D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D004361:Drug Tolerance; D006213:Hallucinogens / Q000494:pharmacology*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D018019:Receptors, Corticotropin-Releasing Hormone; D017981:Receptors, Neurotransmitter / Q000032:analysis / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000032:analysis / Q000187:drug effects*
D006213:Hallucinogens; D018019:Receptors, Corticotropin-Releasing Hormone; D017981:Receptors, Neurotransmitter; D011985:Receptors, Serotonin; D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine; C003943:2,5-dimethoxy-4-bromoamphetamine; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone