Heroin neuroteratogenicity: targeting adenylyl cyclase as an underlying biochemical mechanism.
Prenatal heroin exposure evokes neurochemical and behavioral deficits that in part, reflect disruption of septohippocampal cholinergic function. In earlier studies, we found that cholinergic synaptic defects involve changes in proteins, like protein kinase C, that are essential to receptor-mediated signaling. In the current study, we determined whether heroin targets another signaling protein, adenylyl cyclase (AC), which regulates the production of cAMP. Mice exposed to prenatal heroin showed subsequent postnatal elevations of AC activity that lasted into adulthood. The effect was most robust with stimulants that activate AC directly (forskolin, Mn(2+)), indicating increased expression of AC itself; we also identified shifts in catalytic properties suggestive of a change in the AC isoform. Superimposed on the overall induction of AC, there were transient deficits in the responses to stimulants working through G-proteins (NaF) or G-protein coupled receptors (isoproterenol, a beta-adrenoceptor agonist), indicating alterations at other steps in the signaling pathway. Effects on the regulation of AC activity were seen in brain regions with widely disparate maturational timetables and also occurred in regions, like the cerebellum, that are sparse in cholinergic input. These results suggest that the expression and/or function of signaling proteins distal to neurotransmitter receptors represent a major target for neurobehavioral teratogenesis by heroin; the fact that these targets are shared by otherwise unrelated neuroteratogens may account for a common set of neurochemical and behavioral anomalies in response to prenatal exposure to drugs or environmental chemicals.
Slotkin
T A
TA
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Seidler
F J
FJ
Yanai
J
J
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000196:embryology* / Q000201:enzymology*; D002531:Cerebellum / Q000196:embryology / Q000201:enzymology; D002540:Cerebral Cortex / Q000196:embryology / Q000201:enzymology; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D003932:Heroin / Q000494:pharmacology*; D006624:Hippocampus / Q000196:embryology / Q000201:enzymology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D013723:Teratogens / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D000701:Analgesics, Opioid; D013723:Teratogens; D003932:Heroin; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; D007545:Isoproterenol