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December 01, 1995
Robert Mathias & Neil Swan
Special Report: ARC's 60th Anniversary

The Preclinical Pharmacology Laboratory conducts research with animals to learn how drugs of abuse produce their rewarding effects. The goal is to better understand pharmacological and behavioral mechanisms - how drugs of abuse affect the central nervous system and how those actions translate into the behavior of living animals - to help develop effective drug abuse treatments.

Research is conducted with mice, rats, and rhesus and squirrel monkeys. New drugs are evaluated for abuse potential by studying their ability to reward or punish behavior or to produce internal stimulus effects similar to those of other abused drugs such as cocaine and heroin. Researchers seek pharmacological, environmental, and genetic interventions that can alter the effects of these drugs of abuse.

The laboratory's chief is Dr. Steven R. Goldberg, who also heads its Behavioral Pharmacology and Genetics Section. In his section, animals are used to study drug-induced physiological effects such as analgesia, cardiovascular activity, and toxicity. Other research seeks to determine how drug-seeking behavior becomes stronger and more persistent over time and how it might be halted or reversed by medication or behavioral changes.

Dr. Mohammed ShoaibLaboratory rats are used in a number of studies seeking to learn more about how drugs of abuse produce rewarding effects. In his research, Dr. Mohammed Shoaib is evaluating how rats respond to drug administration.

The section also uses classic experimental procedures in which animals learn to discriminate among drugs and receive drugs of abuse by pushing one of two or three levers to select the drug administered. The animals' responses help evaluate the drug's rewarding effects.

Using genetically selected animals, scientists study inherited traits evident in varying responses to acute and long-term exposure to drugs. These inherited traits may be linked to vulnerability to addiction. The section also correlates changes in brain chemistry in living animals with behavioral effects following drug administration.

The laboratory's Psychobiology Section, headed by Dr. Jonathan Katz, conducts animal studies of the pharmacologic mechanisms of drugs that lead to behavior change, substance abuse, and addiction. Behavioral effects studied include those from psychomotor stimulation, reinforcement, acute toxicity due to overdose, and drug tolerance or sensitization.

Current activities include examining mechanisms responsible for the behavioral effects of cocaine. Scientists hope to find ways to interfere with, or manipulate, cocaine's ability to influence the neurotransmitter dopamine. Cocaine binds to dopa-mine transporters - proteins that facilitate the natural cycling of dopamine release and reuptake among neurons - and blocks the reuptake of dopamine. The resulting flood of dopamine in the gaps between neurons produces cocaine's distinctive euphoric rush.

Section scientists are synthesizing and testing a series of compounds that, like cocaine, bind selectively to dopamine transporters. One of the experimental compounds, known as 4 CBT, has the ability to bind like cocaine but does not have cocaine's reinforcing power to induce animals to self-administer the drug. This finding by DIR researchers - that 4 CBT binds like cocaine but apparently without its accompanying sensations of reward - bears promise for further study of the compound as a potential cocaine treatment, says Dr. Katz.

Studies by scientists in the Behavioral Pharmacology and Genetics Section also are examining interactions and similarities between the dopamine and opioid reward systems. The opioid reward system was the focus of pioneering drug-binding studies by ARC researchers years ago that determined that morphine and heroin act on the brain by binding to various opioid receptors and receptor subtypes, with varying responses. In recent years, researchers have learned that cocaine acts at various dopamine binding sites and that there appear to be interactions between the two reward systems.