Studying the Pleasure Center of the Brain

by Suzanna Engman
photos José V. Camacho

When drug addicts receive pharmacological and psychiatric therapy in a rehabilitation facility, they often respond quickly to detoxification and begin a drug-free period. However, the home environment is fraught with cues that spur a craving for drugs, and memories of drug use threaten recovery. Now new research at the University of Puerto Rico, Río Piedras has detected two naturally occurring neuropeptide-hormones that can be manipulated to perhaps help prevent drug abuse relapse.

The neuropeptide-hormone vasopressin is needed to form drug/environment associative memories. If it can be blocked, the memories might be avoided. The other neuropeptide-hormone, oxytocin, can reduce the anxiety a recovering addict feels upon return to an environment that provokes drug-use memories. Without the anxiety, a recovering addict would be more likely to resist drug use. These findings are part of the continuing research of Carmen S. Maldonado-Vlaar, Ph.D., a biologist specializing in behavioral neuroscience and the neurobiology of drug addiction.

Intracranial surgery in Carmen Maldonado-Vlaar’s lab to implant two cannulae, tubes that serve to deliver drugs directly to a specific area of the brain. The professor and student researchers are studying the effects of two nuropeptide-hormones on rats’ ability to remember environmental cues associated with drug use. Rats’ brains are analogues to human brains, and rats respond similarly to drugs, drug addiction, and drug addiction relapse.

“To understand addiction, you have to approach it with a bio-psycho-social model. In our laboratory, we focus more on the bio-social approach because we use animal models that mimic drug use scenarios found in our society,” she says. Maldonado-Vlaar’s laboratory researchers experiment with the rat because its brain is a tiny analogue to the human brain. Weighing in at barely two grams, this rodent’s brain has many of the same basic parts with the same functions as the much larger human counterpart, which weighs about 1,500 grams.

The biology of addiction involves several neurotransmitters. Among them the most studied is dopamine. “Every time you experience pleasure, there is a release of dopamine in the brain. It doesn’t matter if it is drug related. Food, sex—anything that makes you feel good, that gives you pleasure—has the potential to become addictive. For example, jogging can be addictive. People become anxious when they can’t do it. And uncontrollable gambling can also be described as an addiction. Shopping is also an addiction. Our whole society is vulnerable to addictive behaviors.”

Pleasure can result from pleasant experiences such as food, friendships, fantasies, or even altruistic behavior. Memories themselves bring pleasure. Scientists have recently observed that the molecule associated with pleasure, dopamine, is released before the pleasurable event rather than afterwards as was previously believed. Instead of being a reward, dopamine is part of a mechanism that focuses our attention on an event we imagine to be pleasurable, and this is based on learning.

Professor Maldonado-Vlaar focuses her research on an area of the brain that is part of the dopamine mesolimbic system. In particular, she examines the nucleus accumbens, a collection of neurons located within both hemispheres of the forebrain. Her studies also take into account the social context, particularly the environmental component, and its relation to drug relapse. She and her student researchers measure neurochemical and neuroanatomical changes that occur when a subject learns to associate an environmental cue with cocaine. They also examine the neurochemistry and neuroanatomy of the rat’s brain during relapse—after a prolonged period of abstinence—to examine what modulates the release of dopamine and other neurotransmitters associated with cocaine addiction.
“Within this mesolimbic system, several neurotransmitters interact with dopamine and regulate its release. In our lab we try to address these other neurochemical candidates, in particular those involved in learning to associate an environment with the drug. Thus far we have found different neuropeptides in the brain that seem to modulate dopamine release in the accumbens when learning affiliated with drugs occurs, in particular cocaine addiction. Specifically, the neuropeptides vasopressin and oxytocin, which also act as hormones in the brain, are crucial for the appropriate functioning of our nervous system,” says Maldonado-Vlaar.

An antidiuretic hormone, vasopressin regulates water balance and is a vasoconstrictor and blood pressure regulating agent. Other researchers have found that vasopressin also has the capacity to help with learning and memory. “However, we are the first to show that vasopressin is needed for learning to associate an environment with cocaine use. This is the first time that a hormone related to peripheral endocrine functions has been observed to be involved in memory processes that trigger cocaine addiction. This finding was part of the doctoral thesis of one of my students, Enrique Rodríguez.”

Maldonado-Vlaar and her students will soon submit a paper on their findings to the Journal of Neuroscience, the premiere journal in the field, and are continuing their investigations with experiments that prevent vasopressin reception. “Our focus will be on using drugs that can perhaps block vasopressin receptors, in this case to avoid the learning affiliated with cocaine and the environment.”

Another line of Maldonado-Vlaar’s research, co-investigated with undergraduate student Janitza Montalvo, looks at the role that oxytocin could play in prevention of addiction relapse. Oxytocin stimulates milk release during lactation, uterine contractions during labor, and genital contractions in both women and men during orgasm. The neuropeptide-hormone also has an anxiolytic effect. In other words, it reduces anxiety. “Two years ago I went to the Society of Neuroscience Annual Convention to look at the role of neuropeptides in drug addiction and other behaviors. Dr. Eric Hollander in psychiatry at Mt. Sinai School of Medicine was giving oxytocin intranasally to autistic patients to help them with social anxiety. It worked, actually, without any severe side effects. We thought, this is interesting. People get anxious when they are exposed to drug cues, what if oxytocin could reduce anxiety affiliated with cocaine use?”

Maldonado-Vlaar and her students designed an animal conditioning model that simulates a recovering cocaine addict’s experience when returning home from a rehabilitation facility. They trained the lab rats to associate an environment with cocaine treatment for several days. Following these training sessions, the rats had a session free of training and then were tested in the cocaine-related environment without the drug present. Animals exposed to cocaine cues were more anxious than the control animals. However, when oxytocin was infused directly into the rats’ brains, they relaxed and showed decreased anxiety.

Several pharmaceutical companies, intrigued by these results, have come to the poster presentation sessions of Maldonado-Vlaar’s work. “It is possible to provide a natural alternative at the clinical level for both men and women who want to deal with the anxiety related to drug abuse,” she says. The researcher believes that vasopressin and oxytocin therapy can be used to treat addictions to a variety of drugs. In the future, her studies will be aimed at further examining the effects of pharmacotherapeutical agents that target these neuropeptide-hormones as possible venues for cocaine abuse treatment.

Scientists view drug addiction as a chronic disease that needs to be continuously monitored and treated. According to the National Institute on Drug Abuse (NIDA), drug addiction is a mental illness. The NIDA Web site states:“[A]ddiction changes the brain in fundamental ways, disturbing a person’s normal hierarchy of needs and desires and substituting new priorities connected with procuring and using the drug. The resulting compulsive behaviors that override the ability to control impulses despite the consequences are similar to hallmarks of other mental illnesses.” www.nida.nih.gov/researchreports/comorbidity/whatis.html

“The director of NIDA, Dr. Nora D. Volkow, is a true believer that drug abuse is a chronic disease,” Maldonado-Vlaar says. “The brain of a person changes dramatically with drug abuse. For example, alcohol disinhibits a person emotionally and increases aggression because it increases levels of serotonin in the brain.

“Alcoholics and drug addicts need to be treated for their entire lives. The question is, how do you avoid being exposed to these things when your body is wired to feel pleasure? Feeling reward and pleasure is related to survival.”

Students Jimena Marino and Nelson E. Caraballo examine thin slices of a rat brain to see if the cannulae were properly aligned when implanted in the nucleus accumbens during intracranial surgery (see photo above).