- Alcoholics may drink because they get a "bigger bang" each time they drink.
- This phenomenon is known as "behavioral sensitization."
- Behavioral sensitization is the opposite of tolerance; it is even known as "reverse tolerance."
- A neurochemical called MK-801 may block alcohol's sensitizing effects.
"What we've tried to show in this study," said Rosana Camarini, the study's lead author who is conducting post-doctoral research in neurology at the University of California San Francisco, "is that it may be possible to block behavioral sensitization to alcohol by using NMDA receptor antagonists. The specific one we studied is called MK-801."
Alcohol affects virtually every organ system in the body and alters the activity of most major neurochemicals. Alcohol's effects on the glutamate system are of particular interest to researchers. Glutamate acts as one of the brain's endogenous (made within the body) excitatory systems. A subtype of glutamate receptors, the n-methyl-d-aspartate (NMDA) receptor, is highly sensitive to low doses of alcohol. Evidence indicates that alcohol may interact directly with the NMDA receptor complex. Indeed, NMDA receptors may be involved in sensitization to, tolerance of, and physical dependence on a variety of drugs, including opiates, nicotine, antidepressants and alcohol. NMDA receptor antagonists - in this case, MK-801 - appear to be able to "block" some of the pleasing effects of alcohol. In other words, MK-801 may lend itself to treatment possibilities by helping make alcohol less appealing to someone who has lost control of their drinking.
"All basic, biomedical research that addresses drug abuse," said Clyde W. Hodge, assistant professor of neurology at the University of California San Francisco, "whether that abuse is about alcohol, cocaine, or any drug, is directed toward understanding the neurobiological mechanisms that lead to addiction. Once we understand the neurobiology, hopefully we can design medications to alter some aspect of addiction.
"This study provides evidence," he continued, "that MK-801 blocks one of the addictive properties of alcohol, its sensitizing effects. From a perspective of therapeutics, it means that NMDA receptors could be a valid target for treatment."
To those familiar with the concept of tolerance, the phenomenon known as behavioral sensitization is intuitively confusing. Yet many aspects of the processes that underlie the transition from initial drinking to uncontrolled drinking remain unknown and under research. For example, studies of amphetamine and cocaine have shown that, with repeated and intermittent administration, both behavioral and neurochemical responses are progressively enhanced. This phenomenon, behavioral sensitization, contrasts with the well-known observation that repeated, frequent or continuous drug administration can lead to many diminished responses (tolerance). Indeed, behavioral sensitization is also called "reverse tolerance." Despite the potential confusion, behavioral sensitization may help explain how substances of abuse can become addicting.
"We believe that people may drink more and more because of the pleasurable and euphoric effects of alcohol," said Camarini, "and these effects increase with time. In fact, there are theories that, after time, once this phenomenon is very well established in a person, it may actually change the responses in their gene expression. That is why behavioral sensitization is difficult to reverse."
The method this study used to study alcohol's effects was to measure locomotor activity; researchers measured the distance that laboratory animals traveled following alcohol ingestion. Given independently, MK-801 stimulated locomotor activity, as did alcohol. When given together, however, the two substances diminished locomotor activity. This is how researchers determined that MK-801 might block the development of behavioral sensitization to alcohol as measured by locomotor activity.
"The results are not entirely anomalous," said Hodge. "But it is a curious finding that a drug that increases locomotor behavior, and acts like alcohol, would block the locomotor-activating effect of alcohol." Hodge said that a similar case of this phenomenon is the use of Ritalin for treating hyperactivity in children. "Ritalin is a stimulant," he said. "Yet it is a general finding that stimulants will decrease behavior occurring at high rates."
Both Camarini and Hodge admit that it's difficult to distinguish when, in the continuum of addiction development, sensitization and tolerance may develop and/or co-exist. Hodge speculated that sensitization might occur early on in an individual's exposure to a drug like alcohol, but noted that several ethical and practical considerations would impede testing that theory. A more procurable group would be alcoholics at risk of relapse.
"Sensitization may occur in relation to recent cessation of drinking," said Hodge. "An alcoholic who has been alcohol-free for some time may start drinking again. MK-801 could be useful, in this case, to diminish the effects of drinking."
Camarini and Hodge affirm the need for further research in this area, both to explore how something that acts like alcohol can block alcohol's effects, and also how this finding can be turned into a drug that can help alcoholics.
"We don't know if MK-801 can be used in the future as a prevention tool or as a reversal of alcoholism," said Camarini, "but we do know that it makes alcohol less appealing to someone when they drink it."
Co-authors of the Alcoholism: Clinical & Experimental Research paper included: Roberto Frussa-Filho, Department of Pharmacology, Universidade Federal de São Paulo, Brazil; and Maristela Goldnadel Monteiro and Helena Maria Calil, Department of Psychobiology, Universidade Federal de São Paulo, Brazil. The study was funded in part by the Conselho Nacional de Desenvolvimento Científico e Tecnológico and the Associação Fundo de Pesquisa à Psicofarmacologia.