Differential potencies of cocaine and its metabolites, cocaethylene and benzoylecgonine, in suppressing the functional expression of somatostatin and neuropeptide Y producing neurons in cultures of fetal cortical cells.
Using aggregate cultures derived from 17-day-old fetal rat cortex, we addressed the question: Does cocaine alter the functional expression of neuropeptide Y (NPY) and somatostatin (SRIF) neurons and, if so, are cocaethylene (CE) and benzoylecgonine (BZE) as active as cocaine? NPY/SRIF production in response to brain-derived neurotrophic factor (BDNF) or phorbol-12-myristate-13-acetate (PMA) was used as a functional criterion. A 5-day exposure to cocaine did not affect basal or stimulated (BDNF or PMA) production of NPY but it markedly suppressed BDNF- or PMA-stimulated production of SRIF. Exposure to CE led to a drastic suppression of basal as well as stimulated (BDNF or PMA) production of both NPY and SRIF. These effects of cocaine and CE were concentration dependent (1-100 microM). BZE did not alter any of these functional parameters. Next, we evaluated the fate of cocaine, CE, and BZE in the culture medium. Cocaine was converted to BZE, whereas BZE was not converted to cocaine. CE was converted to cocaine and BZE, with substantial amounts of cocaine and CE remaining in the medium after 72 hr (approximately 20% each). In summary, cocaine, CE, and BZE exhibited differential potencies in suppressing the expression of cultured NPY and SRIF neurons: CE was more potent than cocaine and BZE was inactive. SRIF neurons were more susceptible than NPY neurons to the effects of cocaine. The higher potency of CE may be due to a property of the compound and/or to CE serving as a source for a slow, continuous formation of cocaine by the brain cells themselves.
Aguila-Mansilla
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Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas 75235-9032, USA.
Little
B B
BB
Ho
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RH
Barnea
A
A
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D009478:Neuropeptide Y / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013004:Somatostatin / Q000096:biosynthesis*
D019208:Brain-Derived Neurotrophic Factor; D009478:Neuropeptide Y; D013004:Somatostatin; C005618:benzoylecgonine; C066444:cocaethylene; D003042:Cocaine