Dr. Koek's laboratory uses animal models aimed at aiding the development of medications for substance abuse. The models involve behavioral effects that range from directly observable (e.g., drug-induced motor impairment) to effects examined by operant conditioning procedures (e.g., discriminative stimulus effects, which are related to subjective drug effects in humans). The models are used mainly to examine the effects of alcohol and the club drug gamma-hydroxybutyrate (GHB), because alcohol abuse is a major public health problem, and because recreational use of GHB is increasing dramatically. One of the difficulties with treating alcohol abuse is that alcoholism is not a homogeneous disease entity: early onset alcoholism differs from late onset alcoholism by its association with greater serotonergic abnormality and antisocial behaviors, but also by being more effectively treated with the 5-HT3 antagonist ondansetron than with serotonin reuptake inhibitors. Thus, an important therapeutic goal is to match subtypes of alcoholics to effective treatment medications based on their different biologies. Animal models sharing neurobiological and behavioral features with these subtypes will contribute to the development of better medications to aid in treating alcoholism. The laboratory focuses on early onset alcoholism, the subtype posing the most severe problems. Early onset alcoholism is often associated with poor inhibitory control, evidenced by increased impulsivity and aggression that is exacerbated further by an increased sensitivity to the activating, disinhibiting effects of alcohol and by a decreased sensitivity to its motor impairing effects. These features, which result from interactions of genetic and environmental factors, involve decreased serotonin levels, increased neurosteroid levels, and altered functioning of GABA-ergic systems. Increased understanding of these underlying mechanisms will contribute to better treatment efforts. The pharmacological mechanisms by which GHB produces its abuse-related effects are poorly understood. GHB abuse is likely related to its subjective effects, and subjective effects of drugs in humans can often be predicted from drug discrimination experiments in animals. The discriminative stimulus effects of GHB are likely to involve several different receptor mechanisms. Some of these mechanisms may be unique to GHB (i.e., those involving specific GHB receptors), whereas others may be in common with other compounds (i.e., those involving GABAA and GABAB receptors). The laboratory examines the involvement of these mechanisms in the discriminative stimulus effects of GHB under various conditions (e.g., training dose, alternative training condition). By identifying the role of specific receptors in abuse-related effects of GHB, future studies may be better able to develop specific, pharmacologically targeted therapies for GHB abuse.

Selected Publications

Koek W, Chen W, Mercer SL, Coop A, France CP. Discriminative stimulus effects of gamma-hydroxybutyrate: role of training dose. J Pharmacol Exp Ther 317:409-17, 2006.

Koek W, Carter LP, Lamb RJ, Chen W, Wu H, Coop A, France CP. Discriminative stimulus effects of gamma-hydroxybutyrate (GHB) in rats discriminating GHB from baclofen and diazepam. J Pharmacol Exp Ther 314:170-9, 2005.

Bergman J, France CP, Holtzman SG, Katz JL, Koek W, Stephens DN. Agonist efficacy, drug dependence, and medications development: preclinical evaluation of opioid, dopaminergic, and GABAA-ergic ligands. Psychopharmacology 153:67-84, 2000.