In vivo ibogaine blockade and in vitro PKC action of cocaine.
Ibogaine may have antiaddiction potential against alcohol, psychostimulant and opiate abuse, but its mechanism of action is unclear. Ibogaine, however, has been demonstrated in numerous studies to have effects in multiple central nervous system (CNS) neurotransmitters systems. We are using in vitro and in vivo systems to study the effects of cocaine and whether these effects can be blocked by ibogaine. For the in vivo studies, we first determined the acute and subacute effects of ibogaine (1-5.0 mg/kg) in mice using the plus-maze test. Acutely increasing doses of ibogaine produced a reduced aversion to the open arms. The subacute administration provoked a variable response which was characterized by fluctuations in aversive and antiaversive behavior of the animals to the open arms of the plus-maze during the 14-day treatment period. A separate group of mice received 1.0 mg/kg cocaine for 14 days, and upon abrupt cessation from cocaine treatment, ibogaine 2.5 mg/kg was administered to a subgroup of these mice. Ibogaine reversed the withdrawal aversions produced by the abrupt cessation from cocaine administration. For the in vitro studies, the expression and activity of protein kinase C (PKC) isoforms and Ca2+ levels were examined following the incubation of PC 12 cells with cocaine. This is because PKC plays a key role in a number of cellular and neuronal functions. We report that cocaine disrupts signal transduction in PC 12 cells by altering the expression and activity of PKC isoforms and Ca2+ levels. The data obtained suggest (1) that the PC 12 cells may be useful in studying the neurobiology of abused drugs, like cocaine in vitro, (2) that if anxiety is a factor in drug dependency, then the antiaddictive property of ibogaine in vivo may be associated with modifying the CNS neurotransmission that may be involved in anxiety. It remains to be determined whether the signaling involving PKC is important in the antiaddictive properties of ibogaine.
Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. Emmanvel.S.Onaivi@Vanderbilt.edu
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Onaivi
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Ali
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Chakrabarti
D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D006801:Humans; D007050:Ibogaine / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D016716:PC12 Cells; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats
D007527:Isoenzymes; D007050:Ibogaine; D011493:Protein Kinase C; D003042:Cocaine