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  • Writer's pictureRyan Allen

Tolerance: programmed to protect, potential to harm

We hear the phrase thrown around, often in reference to alcohol, that someone has a “high tolerance.” The truth is that this phenomenon applies to countless molecules, such as drugs or nutritional components, as well as certain habits or experiences. But, what does tolerance actually imply? How do we develop tolerance, and what might result from it?


For the purposes of this post, we can think of tolerance as a neurological phenomenon, although parallel processes occur at the cellular level elsewhere in the body. Neurons are unique, however, in that they can be “excited” to produce and/or relay an electrical signal in response to a stimulus. Like any other cell, each neuron has many receptors at its surface, embedded in the cell membrane. When the molecule specific for the receptor binds, some sort of response is stimulated inside the cell as a result. Typically, receptor binding triggers a signaling pathway. Take the example of insulin signaling. The hormone insulin binds and activates its receptor, which activates downstream signaling molecules by phosphorylation, eventually leading to insulin’s intended response: a transporter protein moves to the surface to let glucose into the cell.


Many of the significant examples of tolerance in neurons are mediated by the molecule dopamine. Contrary to common perception, dopamine levels do not just fluctuate in response to the use of certain drugs. Rather, generally speaking, this molecule is responsible for modifying behaviors (beyond the scope of this post, it is also critical for processes such as voluntary muscular movements, and therefore insufficient dopamine is implicated in conditions such as Parkinson’s disease). Dopamine responses can be seen across a wide range of scenarios: listening to music, using cocaine, scrolling through social media, exercising, eating sugar-packed foods, shopping, telling the blackjack dealer to hit you with another card. In all of these cases, dopamine signaling (via its receptor) stimulates particular neurons involved in “reward” processes in the brain.


As these neurons are stimulated more and more via this signaling, they start to become desensitized to it, doing so in part by decreasing the number of dopamine receptors on the cell surface. This is not a case of damage or dysfunction from increased signaling. Rather, receptor downregulation is actually our neurons’ way of protecting themselves from the overstimulation of the signaling. Because it is unsustainable for any neuron to constantly fire, we’ve evolved such tolerance mechanisms to prevent overwhelming amounts of signaling.


At the macro level, the result of dopamine receptor downregulation is that it takes a higher dose of the molecule, experience, etc. to yield the same effect. One requires far more of the stimulus to acquire the “rewarding” feedback, or the same sensation to which they’re accustomed. You always hear people say with certain experiences that “the first time’s always the best,” and to an extent that is true. In many cases, such events are associated with these tolerance mechanisms, and if performed with regularity will be subject to desensitization.


Evidently, tolerance has been favorable from an evolutionary standpoint, which makes sense due to its remarkable ability to prevent acute neuronal death. Such is the case with many evolutionary forms of acute danger prevention, the issue with this process under current circumstances is a chronic one. In modern times, relative to our evolutionary history, we have an incredibly low barrier of access to large quantities of anything we want: drugs, sugar, gambling, etc. With far less restricted stimulation from these things, we find tolerance mechanisms being employed far more often and on a much larger scale.


Take the example of sugar consumption (and yes, there’s a reason we harp on this topic time and time again). If we eat sugar frequently and in large quantities (i.e. that show up in many packaged foods), we will develop a tolerance to the sweet taste, and the feeling of reward that it provides. For our ancestors, if they ever came across a bunch of fruit and consumed it, they might occasionally get this happening to prevent acute neuronal overstimulation and death from all the sugar. This was beneficial because it helped them get through transient periods of high sugar doses, but they likely never had an unfathomable excess of sugar. The difference today is that, when one acquires a high tolerance to sugar, they will not be nearly as satisfied with normal, natural, physiological doses. In response, they will just go back to the pantry and consume more sugar to satisfy their craving for this reward. Suddenly, with the widespread availability of sugar and other addictive substances and behaviors in our environment, tolerance mechanisms go from preventing overstimulation to encouraging it.


As we throw more and more of the stimulus at ourselves to achieve the outcome we desire, we subject the neuron to incredible chronic overstimulation. Eventually, even such a high degree of tolerance cannot prevent death of the neuron from this kind of abuse. When many neurons responsive to a particular stimulus start to die, one can start to lose the ability to experience the feeling of reward at all, and could find themselves on the path to a medical diagnosis of addiction. In my next post, I’ll discuss ways to address such situations largely through a preventive lens. As always, if you feel you may be suffering from any degree of addiction to a certain substance or behavior, please consult your doctor as soon as possible for professional medical advice and treatment.


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