Paroxetine is effective in desensitizing 5-HT1A receptor function in adult offspring exposed prenatally to cocaine.
BACKGROUND
Desensitization of postsynaptic 5-HT(1A) receptors may be responsible for the therapeutic effectiveness of serotonin selective uptake inhibitors (SSRIs). As prenatal cocaine exposure produces long-term deficits in 5-HT neurons in offspring, it may alter the ability of postsynaptic 5-HT(1A) receptors to be desensitized by chronic paroxetine.


OBJECTIVE
The aim of the study is to determine (1) prenatal cocaine-induced changes in 5-HT(1A) receptor function and (2) the effectiveness of chronic treatment with paroxetine to produce 5-HT(1A) receptor desensitization in adult offspring exposed to cocaine in utero.


METHODS
Pregnant rats received saline or (-)cocaine (15 mg/kg, s.c.) twice daily from gestational days 13 through 20. Adult male offspring from each of prenatal groups were treated with saline or paroxetine (10 mg/kg/day; i.p.) for 14 days. Eighteen hours post-treatment, rats were challenged with saline or the 5-HT(1A) receptor agonist (+)8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.04 or 0.2 mg/kg, s.c.). Plasma oxytocin, adrenocorticotropic hormone (ACTH), corticosterone, renin and prolactin were determined.


RESULTS
Prenatal cocaine exposure did not alter 5-HT(1A) receptor-mediated neuroendocrine responses. Paroxetine treatment desensitized 5-HT(1A) receptor-mediated increases in oxytocin, ACTH and corticosterone to a comparable extent in all offspring and reduced the E(max) for ACTH only in prenatal cocaine-exposed offspring. Cortical [(3)H]-8-OH-DPAT- or [(3)H]-WAY100635-labeled 5-HT(1A) receptors were unaltered by prenatal cocaine or subsequent paroxetine treatment.


CONCLUSIONS
Postsynaptic 5-HT(1A) receptor function is unaltered by prenatal cocaine exposure and paroxetine can effectively desensitize 5-HT(1A) receptor function in adult cocaine-exposed offspring. These data suggest that paroxetine may be clinically effective in treating mood disorders in adults exposed in utero to cocaine.
Chen
Zhuo
Z
Department of Pharmacology and Center for Serotonin Disorders Research, Stritch School of Medicine, Loyola University of Chicago, 2160 South First Avenue, Maywood, IL 60153, USA.
Tetzlaff
Julie
J
Sripathirathan
Kumar
K
Carrasco
Gonzalo A
GA
Shankaran
Mahalakshmi
M
Van De Kar
Louis D
LD
Muma
Nancy A
NA
Battaglia
George
G
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D003042:Cocaine / Q000633:toxicity*; D003345:Corticosterone / Q000097:blood; D005260:Female; D005333:Fetus / Q000187:drug effects*; D006128:Growth / Q000187:drug effects; D010121:Oxytocin / Q000097:blood; D017374:Paroxetine / Q000494:pharmacology*; D010879:Piperazines / Q000378:metabolism; D011247:Pregnancy; D011388:Prolactin / Q000097:blood; D011725:Pyridines / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects* / Q000502:physiology; D012083:Renin / Q000097:blood; D015430:Weight Gain / Q000187:drug effects
D010879:Piperazines; D011725:Pyridines; D044282:Receptor, Serotonin, 5-HT1A; D017374:Paroxetine; D010121:Oxytocin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D012083:Renin; D003042:Cocaine; D003345:Corticosterone