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Biology 202
2003 First Web Paper
On Serendip

The Coorelation between Drug Tolerance and the Environment

C. Richards

When considering the dynamics of brain and behavior, another component that enters the equation is environment. If brain equals behavior then changes to either should result in an altercation to the other component. The question that arises is whether a change in the environment produces change in brain chemistry and therefore, behavior. A connection between brain, behavior and environment may be observed in the context of drug tolerance. There are a collection of questions that seem essential to consider when attempting to correlate the brain's development of an observable drug tolerance and the environment.

Does the environment affect drug tolerance? How?

What observations correlate environmental cues and a tolerance to drugs?

How can an understanding of the correlation between environment and tolerance be applied to medical care and treatments?

Tolerance is caused by the brain's ability to adapt to or compensate for the presence of a chemical (1). Tolerance developed after a repeated exposure to a drug is due to two possible biological processes. One process involves a decrease in the concentration of the drug at the effector site due to changes in the absorption, distribution, metabolism or excretion of the drug. The other process involves changes in the sensitivity towards a drug due to adaptive changes that diminish the initial effects of a drug. The nervous system is able to adapt and thereby reduce the initial effects of a drug by using two methods. The first method involves a change in the number or properties of drug-sensitive receptors. The second method provides a coordinated compensatory response to counteract or oppose the effects of a drug (2).

In terms of drug administration, various observations indicate that the nervous system adapts through a compensatory response. A delayed recovery to the initial stimuli would be expected if the receptors were numerically or physically altered. However, after terminating a drug treatment, a delayed recovery to the initial stimuli has not been observed. Instead, the body readapts to the drug-free state (2). Furthermore, reactions that are almost directly opposite to the desired effect of the drug are observed. These reactions are termed withdrawal symptoms and are observed when no drugs are administered and compensatory processes operate unopposed (2). If the nervous system provides compensatory responses, then the question arises as to whether environmental cues initiate the response.

Environmental cues that initiate responses were observed by the Russian physiologist, Ivan Pavlov (1849-1936). Pavlov made initial observations pertaining to 'classical conditioning'. Pavlov correlated environmental cues and physiological changes as he observed dogs salivating in response to a collection of cues that signaled feeding time. Without the stimulus of food present, there was an observable response to the anticipated stimuli as the dogs salivated in preparation for the emanate arrival of food (3).

Siegel et al. (1982) applied Pavlov's model of 'classical conditioning' to the administration of drugs (4). Siegel et al. observed that the anticipated stimuli signaled by environmental cues provided an additional drug tolerance. An experiment was designed with three groups of rats. For thirty days, one group received injections of heroin in the Colony room (normal living conditions) and placebo (dextrose) in the Noisy room the next day while the second group, received placebo in the Colony room and heroin in the Noisy room. The third group received placebo in both the Colony room and Noisy room. After 30 days, the rats were injected with a potentially lethal dose of heroin. Of the rats that had never been previously injected with heroin, there was a 96% mortality rate. There was a 64% mortality rate with rats that were administered heroin in an alternative room to where they had previously been injected with the drug. Of the group of rats that received heroin injections in the same environment, there was only a 30% mortality rate. (5)
These observations show that while there is a tolerance to the drug itself through repeated exposure, environmental cues result in an additional tolerance.

As the nervous system attempts to maintain homeostasis, disturbances created by a drug trigger compensatory reactions. If environmental cues were coordinating the brain to engage in specific reactions and develop a drug tolerance, then differences within the brain would be expected. The neurons in the hippocampus and amygdala are postulated to participate in a mechanism of learning and memory necessary for processing and assigning value to drug-associated cues (6). Indeed, Mitchell et al. (2000) observed that a tolerance induced by environmental cues compared to a tolerance without consistent contextual pairing involved different patterns of neuronal activity in both the amygdala and the hippocampus (6).

The conclusions that are drawn from the previously mentioned observations suggest an additional tolerance caused by environmental cues. Such results can be applied to medical care and treatment. Within medical terminology, "drug overdose" may be a misnomer in many cases. An overdose may not only be the result of an alteration of the dosage. When ten drug addicts who had experienced near-death overdoses were questioned about their environment while injecting heroin, seven out of the ten claimed to have been shooting up in a new and unfamiliar setting (7).

Changing the environment where a drug is administered may be advantageous for those patients suffering from chronic illnesses and limitations to treatments, due to developing tolerances. Typically, the development of a drug tolerance results in either an increase in the dosage, which often involves toxic side effects or a change in the prescription if the option is available. Considering the role environment plays in drug tolerance offers an alternative. That is, a patient may limit the progression of developing a tolerance by changing the environment. Astonishing medical professional, a patient suffering from cancer endured a treatment that was expected to become ineffective within two years, yet continued to be effective after almost five years (8). The lack of tolerance was attributed to the fact that the patient moved twice during the previous years of treatment and therefore changed the environmental cues (8).

The treatment of patients in rehabilitation centers may also be based on observations made pertaining to environmental cues and physiological adaptations. Since an addict's response to drug-paired stimuli reflects a learned compensatory response, clinicians may weaken the response and onset of a craving through a repeated, controlled exposure to the drug-paired environmental cues, without the administration of the full drug dose (9).

Due to the observations mentioned, the model for drug tolerance within the nervous system can be modified. Traditionally, drug tolerance was a direct consequence of prolonged and repeated input of a drug resulting in a change within the nervous system. Instead however, in addition to the drug, there are numerous additional inputs pertaining to the environment in which the drug is administered. The collection of additional inputs causes conditioned responses within the nervous system. The inputs provided by environmental cues contribute to the observable drug tolerance and explain the increased level of tolerance that is conditional to a consistent setting.


1)Tolerance Definition Information

2)The American College of Neuropsychopharmacology Descriptive account for the adaptive processed that regulate tolerance to behavioral effects of drugs

3) Biography of Ivan Pavlov

4) Siegel, S., Hinson, R.E., Krank, M.D. and McCully, J. Heroin "overdose" death: contribution of drug-associated environmental cues. Science 216, 436-437 (1982)

5)University of Plymouth, Department of Psycology page clear outline of experiment

6) Nature Neuroscience

7) Siegel, S. Pavlovian conditioning and heroin overdose: reposts by overdose victims. Bull. Psychonomic Soc. 22, 428-430

8)A Practical Application of Environmentally-Induced Tolerance Theory

9) American Psychological Association

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