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Persuasion research in the 1950s found that providing two sides of an issue seemed to create greater resistance to later arguments. To explain this phenomenon, William McGuire and his colleagues a decade later began to explore ways in which messages might inoculate recipients against belief attacks. By 1964, he proposed the original inoculation theory. This theory says that persuasive message recipients become resistant to attitudinal attacks in the same way that bodies become immunized from viral attacks. A weak dose of the virus activates the immune system. Likewise, challenges to attitudes, beliefs, and behaviors make them more resistant to change if the exposure to counterviews is given in weakened, small doses. The theory is relevant because unchallenged beliefs can be swayed if the holder is not used to defending them. A weak dose of a counterargument will cause the belief to become more resistant. In the medical venue, the approach has been more effective than the supportive treatment in producing resistance. In the persuasive venue, presenting arguments supporting beliefs is less effective than exposing the receiver to a weak attack on the belief.

In his first experiments, McGuire selected cultural truisms, or beliefs rarely challenged, such as brushing teeth. When considering expanding the boundaries of inoculation theory, he reasoned that because people tend to avoid arguments that oppose their views on controversial issues, almost all beliefs are protected from counterattack. John B. Pryor and Thomas M. Steinfatt offered an opposing view for extending inoculation's boundaries beyond cultural truisms in observing that almost no beliefs are completely protected. If one rarely exposed one's beliefs to threats, those beliefs could be changed if attacked by a particular virus, as it were. Pryor and Steinfatt's rationale propelled the investigation of inoculation into controversial topics.

McGuire found that a passive reception of a message (requiring participants to read a section in which counterarguments were mentioned and rebuked) had a greater effect in making attitudes resistant to persuasion than did active reception (a writing assignment in which subjects explained their responses to the counterarguments). Participants in the reading conditions had more independent action in their immunizing treatments; that is, they had to work harder in the reading treatment than in the writing treatment and generate their own independent arguments in support of the original beliefs.

Subsequent research has shown that active, passive, and mixed refutational conditions can be effective in inoculation, but their effects are not necessarily the same and depend on other variables. Exposing a person to weakened, defense-stimulating forms of argument seems to be more effective in inoculation than exposing an individual to arguments supporting the individual's belief. This happens because threat provides an explicit forewarning of a challenge, enabling the recipient to prepare counterarguments. People prefer, however, to inoculate the beliefs of others by using bolstering strategies, even though these have been shown to be less effective than counterarguing strategies.

Inoculation is often used in courtrooms. An attorney says, “You're going to hear the prosecution call Mrs. Smith mean, evil, a terrible mother, and a poor member of society, but this is not true, as I will show you over the next couple of weeks.” When the prosecutor stands up and states anything close to what the defense attorney has claimed he will, the jury is prepared, thinking he is acting exactly the way the defense said he would. This gives the jurors a way to ignore or even discount the prosecutor's arguments.

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