Isabelle M. Maisonneuve
Albany Medical College
|The mission of our laboratory is||The methodological approaches used are|
|to enhance our understanding of the neurobiology of addictive drugs |
to investigate mechanisms mediating behavioral (e.g., craving) and physiological (e.g., withdrawal) aspects of addiction and dependence to develop novel therapeutic agents that will be useful in treating addictive disorders
|intravenous drug self-administration and other behavioral assays, such as motor activity testing, rotorod, Porsolt test, elevated plus-mazein vivo microdialysis coupled to high performance liquid chromatography multiple receptor binding protocols|
18-Methoxycoronaridine, a novel anti-addictive agent?Although many people regard addiction as a kind of moral failure, there is clear evidence that it is a biological problem. It is, in fact, a chronic disease. Investigators have found there is a pathway in the brain that controls addiction and that in addicted persons there are major problems in the chemistry of this pathway (the mesolimbic dopamine pathway). In this regard, addiction is very much like other metabolic disorders, like diabetes. This suggests that if you could restore brain chemistry to its correct balance, you could cure or at least treat addiction. With this goal in mind, the major research emphasis in the Glick-Maisonneuve laboratory is the development of a new class of anti-addictive agents. These potential pharmacotherapies are structurally related to the naturally occurring agent ibogaine, an alkaloid extracted from the West African shrub Tabernanthe iboga. Anecdotal reports in people, and laboratory studies in rats, suggest that ibogaine can profoundly reduce addiction to many drugs. However, ibogaine has several adverse effects (e.g., cerebellar neurotoxicity, hallucinations, and slow heart rate), and because of this, we have collaborated with medicinal chemists to develop novel, synthetic iboga alkaloid congeners that are safe but yet still likely to be efficacious in the treatment of multiple forms of drug addiction. The lead agent is 18-methoxycoronaridine (18-MC). 18-MC reduces cocaine, methamphetamine, morphine, nicotine and alcohol self-administration in rats and decreases extracellular levels of dopamine in the nucleus accumbens; an increase in dopamine is thought to be a critical determinant of the abuse liability of most or all addictive drugs. Recent research indicates that 18-MC blocks a particular type of nicotinic receptor (alpha3beta4). This action, occurring in other brain areas (medial habenula and interpeduncular nucleus) that modulate the dopamine pathways, appears to be the primary event that leads to both decreases in dopamine release and decreases in drug self-administration. Consistent with this mechanism, we have found that other drugs (e.g., dextromethorphan, mecamylamine) blocking this site also decrease drug self-administration. This research should result in several novel treatments for addictive disorders in humans. Currently, a pharmaceutical partner is being sought to help get 18-MC into clinical testing.
- Glick, S.D., Ramirez, R.L., Livi, J.M. and Maisonneuve, I.M. 18-Methoxycoronaridine acts in the medial habenula and/or interpeduncular nucleus to decrease morphine self-administration in rats. Europ. J. Pharmacol., 2006, 537:94-98.
- Panchal, V., Taraschenko, O.D., Maisonneuve, I.M. and Glick, S.D. Attenuation of morphine withdrawal signs by intracerebral administration of 18-methoxycoronaridine. Europ. J. Pharmacol., 2005, 525: 98-104.
- Pace, C.J., Glick, S.D., Maisonneuve,I.M., He, L.W., Jokiel, P.A., Kuehne, M.E. and Fleck, M.W. Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration. Europ. J. Pharmacol., 2004, 492: 159-167.
- Maisonneuve, I.M. and Glick, S.D. Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment. Pharmacol. Biochem. Behav., 2003, 75: 607-618.
- Glick, S.D., Maisonneuve, I.M., Kitchen, B.A., and Fleck, M.W. Antagonism of alpha3beta4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration. Eur. J. Pharmacol. 2002, 438: 99-105.