PROFESSOR of Psychology G. Daniel Weese and colleagues at the Duke University Medical Center have been working on the hypothesis that reactivating the circuits associated with methamphetamine or cocaine and then disrupting that reconsolidation process would have the effect of eliminating the craving that leads to relapse. The results of their research have appeared in an article, “Reduction in methamphetamine induced sensitization and reinstatement after combined pergolide plus ondansetron treatment during withdrawal,” in
the European Journal of Pharmacology 565 (2007, pp. 113-118), with three others submitted to journals.

Memories of all types are recorded by the physical changes in brain circuits that process our experiences. Th e biological mechanisms appear to be similar regardless of the circuits involved. One experience that has a profound impact on memory pathways is the taking of recreational drugs because they directly influence the communication of the neurons or nerve cells involved. In essence, drug abuse can be attributed to the long-term modification of brain pathways that are involved in determining the importance of events, the aspects of the environment that foretell these events, and the behaviors that promote the reoccurrence of these events.

Once addiction has occurred, individuals are compelled to engage in drug-seeking behavior whenever they are in a situation that has been associated with the drug. That memory-based contributor to the continuation of drug-taking is commonly called craving and can persist for several years after an addict has been abstinent. Craving is also a major contributor to relapse, which occurs in about ninety percent of those who have sought some form of treatment. If the drug-induced changes in the brain are the result of memory processes, new experiences might be able to reverse the modifications. It has been documented that memories are changeable and that the act of recalling a memory makes it susceptible to alteration. The concept of reconsolidation suggests that activating a memory circuit through recollection permits that memory to be erased or new information to be added to the memory.

The researchers’ experiments involved rats. After cocaine abuse was simulated by a few cycles of binge-crash self-administration of cocaine, the rats were withdrawn from the cocaine for ten days and then tested for relapse of cocaine-seeking behavior following a single dose of cocaine. Half of the rats were given a placebo treatment during the withdrawal period, and half were given the experimental treatment. Pergolide, an agonist of dopamine used in the treatment of Parkinson’s disease, was administered to stimulate the circuits (memory) activated by cocaine, and ondansetron, an antagonist of serotonin used to treat nausea, was given to modify the activity in the same circuits. The prediction was that this combination therapy would alter the memories associated with cocaine such that future exposure to cocaine would not trigger cocaine-seeking behavior responsible for relapse.

Th e results of this study support the hypothesis. Relapse behavior was significantly reduced in treated rats when compared with the placebo controls and rats that received pergolide or ondansetron alone. In addition, certain longterm changes in the brain that are associated with addiction were normalized. Specifically, the increases in two types of glutamate receptors that are involved in memory formation and the decrease in dopamine release that are a result of cocaine abuse were either returned or nearly returned to normal levels.

Another study has replicated those findings by substituting methamphetamine for cocaine. Two psychiatrists at Duke University who collaborated on the latter study are currently conducting clinical trials to examine the eff ectiveness of this combination drug therapy for the prevention of relapse in methamphetamine abusers.

If cocaine or pergolide can trigger relapse, it is possible that other drugs that can activate the same circuits in the brain can also trigger relapse. As it happens, a common antidepressant, bupropion, does have similar actions in the brain. Weese and his colleagues sought to examine the possibility that this treatment might have the unintended consequence of reinstating cocaine-taking when given to someone who is abstinent. Giving bupropion to an abstinent cocaine abuser is a distinct possibility because one of the symptoms of withdrawal that responds to treatment is depression. Bupropion was given to rats during abstinence from cocaine and compared with two other antidepressants with different actions, cocaine, and a placebo. Of the antidepressants, only bupropion restarted cocaine-seeking behavior, and it did so to an extent that was equal to that of cocaine. The findings were presented at the meeting of the Society for Neuroscience in 2006. The conclusion was that bupropion poses a potential risk to abstinent cocaine abusers and its use by this population should be monitored.

As tragic as the damage to relationships, careers, and finances that results from methamphetamine abuse are, the neurotoxicity produced by this drug may be even more serious. Not only does this drug alter brain circuits, but it kills the nerve cells that make up the circuits, especially those in the frontal lobes. Th e investigators have adapted a well-established test of human frontal lobe function to rats in an attempt to provide an animal model to examine treatments that could reverse this neurotoxicity. Essentially, the test measures compulsive behavior and has been shown to distinguish people with frontal head injuries or a history of methamphetamine abuse from the normal population. The findings were that rats that had been withdrawn from methamphetamine exhibited compulsive behavior on this test.

Future studies will employ the test to investigate drugs that could either protect the brain from further damage by methamphetamine or promote the replacement of nerve cells that have been killed.

At the College Weese has been working with students on their honors research that is related to the neural basis of compulsive behavior. Jonathan T. Schaaf ’07 and J. Parker Tims ’08 have been examining the role of two neurotransmitters found in a deep-brain structure known as the thalamic reticular nucleus (TRN) in the selection and persistence of behavior. Earlier work that Weese conducted at the University of St. Andrews in Scotland demonstrated that the TRN acts as a filter for attention by inhibiting the transmission of distracting or competing information. Both students have surgically implanted stainless steel tubes known as cannulas above the TRN through which they have infused either a drug that activates these inhibitory mechanisms or other drugs that block them. The line of research will continue until there are enough data to evaluate the normal role of the TRN in controlling the persistence of behavior and how it might become hijacked by drugs of abuse to produce compulsive behavior.

Weese has been at the College since 1989 and was promoted to the rank of professor in 1999. He holds the A.B. from Washington University and the Ph.D. from Indiana University.

BEYOND THE Classroom FOR THE Classroom
Hampden-Sydney College Faculty Scholarship 2005-2008
A report by the Office of the Dean of the Faculty