Training rats to recognize the smells of banana and orange may not seem too exciting to most people, but for alcoholics trying to remain abstinent from alcohol, it could mean the difference between relapse and recovery. Researchers have discovered that "alcohol-related cues" like smell can induce a neurochemical response in the brain that may "reinstate alcohol-seeking behavior" after withdrawal and abstinence. In other words, smells may trigger craving for alcohol, which could lead to relapse.
"Addiction is essentially a chronic relapsing disease of the brain," said Friedbert Weiss, Associate Professor in the Department of Neuropharmacology at the Scripps Research Institute and senior author of the study. "Addiction is a relapsing disorder that, even after successful short-term treatments, has a strong tendency to reoccur." Weiss said there are both biological and ‘situational’ factors involved in relapse; situational factors that include stress, a particular neighborhood, a piece of music, the sight of a liquor bottle, a bar environment, or the smell of alcohol.
"Evidence suggests that all drugs, including alcohol, increase dopamine levels in a part of the brain known as the nucleus accumbens," said Simon N. Katner, Senior Scientist at the Gallo Clinic, University of California and the study’s first author. "We wanted to examine if alcohol-associated cues like smell could also alter dopamine levels."
In the study, published in the November edition of Alcoholism: Clinical & Experimental Research, rats were trained to self-administer alcohol or quinine in the presence of particular smells: the smell of alcohol or banana was presented to the animals when they consumed alcohol, and the smell of quinine or orange was presented when they consumed quinine. During this "discrimination" phase, the rats quickly learned to distinguish between alcohol and quinine, showing a marked preference for alcohol either "straight up" or smelling of banana. During the next phase of "abstinence," the rats received neither liquid nor smell. During a third phase called "behavioral reinstatement," the rats not only demonstrated a remarkable "recovery of response" to the alcohol-associated smells of alcohol and banana, but also showed changes in forebrain dopamine levels while waiting for, and after being presented with, their cue.
Dopamine is one of the key components of the "pleasure and reward" system in the brain, a complex reward and reinforcement system. Several decades of research on the biological basis of chemical dependency have demonstrated a common underlying set of biochemical mechanisms. Although different substances of abuse seem to act on different parts of the brain’s neuronal circuitry, the result is the same: dopamine is released in the nucleus accumbens. Dopamine appears to be one of the primary neurotransmitters of reward at this site.
"This is an extremely important and timely study," said Rueben Gonzales, Associate Professor of Pharmacology at The University of Texas at Austin. "I don’t think we really know that much about the factors that lead to relapse in humans. This study, one of the first of its kind using an animal model, at least gives us a handle on it." Gonzales explained that until very recently, people were predominantly interested in the behavior of drinking itself, what Gonzales called "self-administration." Now the field of study has shifted, and researchers are showing greater interest in environmental stimuli and problems of relapse.
According to the National Institute on Alcohol Abuse and Alcoholism, which also funded this study, approximately 90 percent of alcoholics are likely to experience at least one relapse during the four-year period following treatment. Similar relapse rates for alcohol, nicotine and heroin addiction suggest that the relapse mechanisms for several addictive disorders may share common biochemical, behavioral or cognitive components. Yet no controlled studies have definitively shown any single or combined intervention that prevents relapse in a fairly predictable manner. Part of that has to do with confusion about the very definition of craving, despite its predominant role in several theories of relapse. Although many clinicians and researchers in the addictions’ field agree that craving is a hallmark of alcohol dependence, that it may precede drinking, and that it is a measurable construct, it is not clear what craving means. Still, one area of agreement seems to be an acceptance of the relationship between environmental stimuli - cues like smell or sound - and relapse.
"This is one of the first preclinical studies to look at the neurochemical mechanisms involved in alcohol craving and relapse," said Katner. "If we can understand the processes involved in relapse, then we can ‘tease’ things apart more and screen for possible therapeutic agents."
Katner and Weiss believe that more research is needed to better understand the neurobiology of alcohol- or drug-seeking behavior which, when combined with behavior modification and appropriate therapeutic agents, can greatly advance the prevention and treatment of craving and relapse.
Weiss elaborated. "Once we understand what neural and molecular mechanisms become activated by exposure to alcohol-related cues, we will have a rational basis to guide us in the development of medications that target specific critical neural systems. This is our study’s significance: it provides a reliable tool that allows us to investigate brain mechanisms and neurochemical systems so that we can embark on a more educated approach to find effective medications."
Funding for this Addiction Science Made Easy project is provided by the Addiction Technology Transfer Center National Office, under the cooperative agreement from the Center for Substance Abuse Treatment of SAMHSA.
Articles were written based on the following published research:
Katner, S.N., & Weiss, F. (1999, November). Ethanol-associated olfactory stimuli reinstate ethanol-seeking behavior after extinction and modify extracellular dopamine levels in the nucleus accumbens. Alcoholism: Clinical and Experimental Research, 23(11), 1751.