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 o f 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 (BDN F) or phorbol-12-myristate-13-acetate (PMA) was used as a functional c riterion. A 5 day exposure to cocaine did not affect basal or stimulat ed (BDNF or PMA) production of NPY but it markedly suppressed BDNF- or PMA-stimulated production of SRIF. Exposure to CE led to a drastic su ppression of basal as well as stimulated (BDNF or PMA) production of b oth NPY and SRIF. These effects of cocaine and CE were concentration d ependent (1-100 mu M). BZE did not alter any of these functional param eters. Next, we evaluated the fate of cocaine, CE, and BZE in the cult ure medium. Cocaine was converted to BZE, whereas BZE was not converte d to cocaine. CE was converted to cocaine and BZE, with substantial am ounts of cocaine and CE remaining in the medium after 72 hr (approxima te to 20% each). In summary, cocaine, CE, and BZE exhibited differenti al potencies in suppressing the expression of cultured NPY and SRIF ne urons: CE was more potent than cocaine and BZE was inactive. SRIF neur ons 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 cocai ne by the brain cells themselves. (C) 1997 Elsevier Science Inc.