Lack of cross-tolerance for hypophagia induced by DOI versus m-CPP suggests separate mediation by 5-HT2A and 5-HT2C receptors, respectively.
Intraperitoneal administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) produced significant decreases in the first-hour food intake on day 1 and on day 2 relative to saline-treated animals. Complete tolerance developed to DOI-induced hypophagia by day 3. However, there was no cross-tolerance to m-chlorophenyl-piperazine (m-CPP)-induced hypophagia. Similarly, complete tolerance developed to m-CPP-induced hypophagia by day 3, but again there was no cross-tolerance to DOI-induced hypophagia. These findings suggest that DOI and m-CPP-induced hypophagia are mediated by different mechanisms, most likely by selective stimulation of 5-HT2A receptors by DOI and 5-HT2C receptors by m-CPP. The functional sensitivity changes did not parallel changes in hypothalamic [3H]-mesulergine-labeled 5-HT2C receptors or [3H]-ketanserin-labeled 5-HT2A receptors following chronic m-CPP or DOI treatment, although both treatments significantly reduced 5-HT2A and 5-HT2C receptors in cortex. Thus, future studies investigating the effects of daily m-CPP and DOI administration on phosphoinositide hydrolysis or mRNA for 5-HT2C and 5-HT2A receptors in the hypothalamus might help explain the functional sensitivity changes observed in the present study.
Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD 20892, USA.
C S
CS
Aulakh
P
P
Mazzola-Pomietto
B A
BA
Hulihan-Giblin
D L
DL
Murphy
D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D004361:Drug Tolerance; D004435:Eating / Q000187:drug effects*; D004873:Ergolines / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011407:Propane / Q000031:analogs & derivatives / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013997:Time Factors
D000662:Amphetamines; D004873:Ergolines; D010879:Piperazines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D007650:Ketanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; C015068:1-(3-chlorophenyl)piperazine; C031649:mesulergine; D011407:Propane