For centuries human behavior has been dictated by contextual cues, like nonverbal behavior that we observe from another, the context of the environment we are in, or specific stimuli which force us to behave in a certain way. In his study with rats, Siegel was the first to introduce the link between classical conditioning, the recognition of environmental cues, and drug tolerance. This work was important because it gave us an idea of why overdoses occurred when drug users were outside their normal injection areas, in addition to understanding how they established subconscious tolerance to the amount of drug injected. Later studies proved that tolerance and environment go hand and hand, but they are not dependent upon each other to exist.
One of the biological mechanisms of addiction and drug tolerance is the reward circuit of the brain. This circuit creates cravings and motivation to obtain a rewarding substance and is essential for survival. As a result, food and drugs share the same pathway through the cortical regions of the brain, which is why there is such a motivation to obtain either rewarding stimuli. Neurotransmitters are essential to the activation of the reward pathway. In essence, these circuits create a drive to obtain rewards that produce the neurotransmitters that activate it. This is evident in sacrificed animals whose brains are examined for genes directly linked to learning and changes in synaptic strength due to the plasticity of the brain. These changes and the expression of specific genes are correlated to learning, altered by cravings and sensory memory. Evidence shows that the prefrontal cortex is one of the main areas in the brain associated with understanding cues in the environment and pairing them with the biological excitement that occurs when receiving a reward. (Kelly, Craig, Landry, 2005).
Former experiences can determine the strength of drug tolerance and ultimately influence the behavior that goes with it. For drug users, the ritual of injection can be just as important as the administration of the drug. The ritual establishes a memory through the senses, which is renewed in the brain every time the same environment or stimulus is present in a similar way it was during the past experience. This past memory is ultimately a precursor for the brain and five senses for predicting a reward. The importance of the ritual has been expressed in various animal studies. Specifically, rats subjected to routine rituals before being injected established a stronger tolerance at a quicker pace in addition to expressing the understanding the connection between ritual, environment and the injection of a drug. The importance of the ritual is evident in animals who were still able to establish tolerance independently of environmental cues, and injections (Cepeda-Benito & Tiffany 1995).
Siegel was the first to connect classical conditioning with the establishment of drug tolerance in rats. Repeated exposure to both drug and another stimulus (such as environment) are essential for creating tolerance, but there are other elements that influence tolerance. Previous exposures to drugs (or learned stimuli) lessen the effect since there is not a surprise from a new stimulus being introduced. Short-term memory and sensory experience are important in the establishment of associative tolerance, where a stimulus is associated with a memory of an event. Changes in drug dosing and the frequency of dosing is a determining factor if tolerance is established through memories. Lower dosages produced a tolerance based on memories of prior exposure, while higher dosages created a greater association between the environment and a quicker establishment of tolerance. Both dosages created different types of tolerance, but only one was established by past experience. (Dafters & Odber 1989).
Contextual cues may not always be the base for establishing tolerance, but drastic changes in behavior can also be an indicator of tolerance. Behavior changes are one of the many ways that tolerance can be expressed in the system. In studies testing antipsychotics and their behavioral effects on rats, animals expressed two different behavioral expressions of clozapine tolerance, avoidance or increase locomotive activity through the administration of PCP. Clozapine creates drastic withdrawal symptoms in humans and triggers the mesolimbic reward pathway in the brain. Rats who had previous experience with clozapine would exhibit higher levels and in the PCP testing, these rats had an increase in activity ( hyperlocomotion) compared to animals who had not received prior exposure to the drug. Contextual cues and changes in behavior are a unique attribute to psychotropic drugs in concern to the development of tolerance. This suggests that different drugs produce different types of reactions and tolerance and that there is not a universal signal for the establishment of tolerance. (Feng, Sui, & Li 2013)
Tolerance from environmental cues is common but is not present in every type of drug that is in existence. As mentioned in studies before, drug tolerance can happen with or without environmental cues. If this is assumed, tolerance should be greater when drug-related cues are present, then when they are not, but this is not the case for all drugs. Benzodiazepine studies have failed to discover tolerance based on the environmental stimulus. Rats were able to obtain tolerance, but it was not context specific like morphine trials, instead, it was only physical tolerance with no presence of environmental stimuli having any impact on it. Perhaps context specific tolerance only occurs with drugs that trigger the reward center of the brain and creates cravings, rather than drugs that sedate and calm the body. Other suggestions for why benzodiazepine was not able to create the same tolerance as morphine was a lack of pre-exposure, changing the measurement of tolerance instead of observing the hypothermic effects of the drug. No studies have been conducted to see why some drugs are more likely to trigger the association of cues in the brain with a reward, while others do not.(Griffiths & Goudie 1986).
There is no doubt that the relationship between tolerance and classical conditioning exists. Classical conditioning is the main force behind the creation of tolerance since there is a repeated behavior paired with a stimulus. Occasionally environmental cues can aid in the conditioning of expectation of rewards based on specific stimuli present. These three aspects are not the only influences on tolerance, biological mechanisms like the reward circuits that exist in the brain help influence the cycle of drug use, and produces a motivation to survive. Each type of drug has its own tolerance, further studies were encouraged to gain more information and explain why associative tolerance (from environmental cues) is not present in the drug like sedatives, but fully present in morphine studies. The importance of understanding drug tolerance and all the mechanisms behind it, could really shine a light on addiction and give us a way to prevent it by understanding the mechanisms that are behind drug tolerance.
Bibliography
Cepeda-Benito, A., and S. T. Tiffany. Role of Drug-Administration Cues in the Associative Control of Morphine Tolerance in the Rat. Psychopharmacology, vol.122, no. 3Ω 1995, pp. 312–316., doi:10.1007/bf02246554.
Dafters, Richard, and Josephine Odber. Effects of Dose, Interdose Interval, and Drug-Signal Parameters on Morphine Analgesic Tolerance: Implications for Current Theories of Tolerance. Behavioral Neuroscience, vol. 103, no. 5, 1989, pp. 1082–1090., doi:10.1037/0735-7044.103.5.1082.
Griffiths, J.w., and A.j. Goudie. Analysis of the Role of Drug-Predictive Environmental Stimuli in Tolerance to the Hypothermic Effects of the Benzodiazepine Midazolam. Psychopharmacology, vol. 90, no. 4, 1986, doi:10.1007/bf00174071.
Kelley, Ann E., et al. Neural Systems Recruited by Drug- and Food-Related Cues: Studies of Gene Activation in Corticolimbic Regions.†Physiology & Behavior, vol. 86, no. 1-2, 2005, pp. 11“14., doi:10.1016/j.physbeh.2005.06.018.
Sun, Tao, et al. Effect of Environmental Cues on the Behavioral Efficacy of Haloperidol, Olanzapine, and Clozapine in Rats.†Behavioral Pharmacology, vol. 25, no. 4, 2014, pp. 277286., doi:10.1097/fbp.0000000000000047.