Grant: Operating Grant

Metabolism of drugs by liver enzymes is the principal mechanism the body has for removal of drugs, including nicotine and ethanol. For drugs that enter the brain and have their actions in the brain, such as nicotine and alcohol, many effects on brain function have been demonstrated after both one-time and long term use. Recently we have shown that the liver enzymes that inactivate nicotine and ethanol are also made in the brain in very specific regions and cells. We have also shown that they are increased after even very low doses of nicotine or ethanol (or in the brains of human smokers or alcoholics). The increased activity of these enzymes can have a number of consequences. 1) Increased levels of these enzymes can increase the speed of inactivation (or activation) of drugs in the brain as a safeguard or this may provide an incentive for increased use, for example for drinking more alcohol or lighting up the next cigarette to replenish the drug that is removed by metabolism. 2) Increased levels may alter the activation/inactivation of other drugs which also use this enzyme, for example smokers may require more sedative than nonsmokers. 3) The higher levels of activity could increase the metabolism of other chemicals in the brain, both chemicals that are required for normal brain function, and other pharmaceutical drugs. We will investigate the consequences of the presence and induction of these enzymes in the brain in animal drug-induced behavioural models. This information will improve our understanding of the brain and its response to drugs and will also provide opportunities for altering this process to decrease the harm done by these drugs.