Neural adaptation is "...a change over time in the responsiveness of the sensory system to a constant stimulus". The example given is placing your hand on the surface of a table. Eventually, you no longer sense your hand touching the table because your neurons have adapted to the stimulus.

Drug tolerance is "...reduced reaction to a drug following its repeated use". This means that increased dosages are required to produce the same effect. I've been careful to state that the drugs I'm considering are psychoactive drugs, so their mechanism of action of is mostly within the brain.

The missing link between these two concepts seems to be acclimatization. Acclimatization is "the process by which the nervous system fails to respond to a stimulus, as a result of the repeated stimulation of a transmission across a synapse". The article on neural adaptation states that acclimatization is the process by which neural adaptation is usually believed to occur.

So is drug tolerance a form of neural adaption with the stimulus being whatever substance a subject repeatedly consumes? It's worth noticing that adaptation does not specify a direction of change in responsiveness. Therefore, assuming drug tolerance is a form of neural adaption, and if the effects of exposure to drugs become amplified rather than diminished, it too would be a form of neural adaptation.

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Drug tolerance can be generally defined as

A condition that occurs when the body gets used to a medicine so that either more medicine is needed or different medicine is needed.

Tolerance to drugs can be produced by several different mechanisms.

  • In the case of morphine or heroin, tolerance develops at the level of the cellular targets. Activation of opiate receptors triggers the inhibition of the enzyme adenylate cyclase. After repeated receptor activation, adenylate cyclase adapts so that the morphine can no longer cause changes in cell firing (source: NIH).

However, stating that a single target is involved is definitely an oversimplification.

Another NIH report on ethanol dependence gives an awesome comprehensive overview of the bewildering complexity behind this phenomenon, and I will only shortly sum up the different mechanisms stated there:

  • Functional Tolerance develops due to brain adaptations that compensate for the alcohol. Chronic heavy drinkers show few obvious signs of intoxication even at blood alcohol concentrations (BAC's) that would otherwise be considered fatal. Examples of functional tolerance are the following:
  • Acute tolerance can be observed within a single drinking session. Alcohol-induced impairment is greater when measured soon after beginning alcohol consumption than when measured later in the drinking session.
  • Environment-dependent tolerance develops over several drinking sessions and is accelerated if alcohol administration is always in the same environment, for instance in the local pub.
  • Learned tolerance develops by practicing a task while under the influence of alcohol. Rats develop tolerance faster in the context of maze walking when they have been when walking in a maze under influence for instance that practiced the task while under the influence of alcohol than rats practicing without prior alcohol administration. Likewise, people develop tolerance more rapidly if they practice a task while under influence, for instance on an eye-hand coordination task. w
  • Environment-independent tolerance needs larger doses.
  • Metabolic tolerance results from a more rapid elimination of alcohol from the body and is caused by the upregulation of liver enzymes that metabolize alcohol. Enzyme activation increases alcohol degradation and reduces the time during which alcohol is active in the body, thereby reducing the duration of alcohol's intoxicating effects.

The metabolic tolerance is the easiest to comprehend, but the environmentally-dependent tolerance and learned tolerance, for instance, are definitely centrally mediated, but not just by one simple molecular mechanism, but by the interplay of complex neural networks governing complete and complex associations and tasks.

- National Institute on Alcohol Abuse and Alcoholism

  • $\begingroup$ Do you know of tolerance studies done on SSRIs? I keep up to date with the literature, but have not seen tolerance studies on SSRIs. $\endgroup$
    – OhBeeHive
    Jun 22, 2019 at 10:45
  • $\begingroup$ @OhBeeHive, nope, I'm unaware, but haven't looked either. $\endgroup$
    – AliceD
    Sep 13, 2022 at 6:59

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