Can neurotransmitter depletion cause short-term drug tolerance?

Question

**I'm curious to know if neurotransmitter degradation factors into drug tolerance and neural conduction and, if so, to what extent.** As I recall from textbooks I read as an undergrad, one mechanism of drug tolerance works by increasing the necessary thresh-hold at a synapse such that larger concentrations of neurotransmitter or more-frequent action potentials in the upstream axon were required to depolarize the membrane and propagate the signal. It seems to me that the same effect would occur if there were fewer available molecules of the required neurotransmitter.Does over-stimulation of a neural pathway (through the use of a drug or other stimuli that up-regulates a given neurotransmitter) shorten the half-life of the neurotransmitters it uses? Could a diet which is poor for necessary precursor nutrients cause a person's neurotransmitter concentrations to drop and reduce signaling along specific neural pathways? Could lack of sleep or other physiological stressors have a similar effect? I am not a neuroscientist so please correct (and forgive) me if I'm using any terms incorrectly or am flat-out wrong in any of my assumptions.

Answer 1

You have a lot of questions that broach many different topics but I'll try to answer them succinctly. Yes, tolerance is when for a given stimulus the response is muted or depressed due to over stimulation. This can happen with drugs and one prime example is with type two diabetes mellitus where patients that have this condition have what is called "Insulin insensitivity" meaning that they aren't as sensitive to insulin as they once were because their body, in response to chronically elevated glucose due to diet, is producing and secreting chronically large amounts of insulin. This has the effect of resetting the threshold, so to speak. If fewer neurotransmitters were available it could definitely cause the signal to NOT be transmitted. This is seen with sub threshold stimuli, also referred to as end plate potentials. These sub threshold end plate potentials can potentiate with one another either temporally or spatially to actually reach threshold.

In terms of the life span of a neurotransmitter, I don't believe that over stimulation of a pathway would shorten the lifespan of the NT being used, rather less of the NT would be available for use. A couple of things that WOULD shorten the "lifespan" of a NT is the activity or quantity of the enzyme that breaks down the NT. Also changing the internal milieu of the synaptic cleft could MAYBE alter the stability of the NT and cause it to perhaps degrade faster. That being said since the majority of the NT is broken down via enzymes at the level of the synaptic cleft, environmental changes would most likely have little effect.

You also asked if diet could affect neuronal signaling and the answer is a definite yes. In one regard, we are what we eat and what we eat affects us at the cellular level. BUT, remember that our bodies are amazingly adaptive and if someone switches from a diet of 50% carbs to a diet of 25% carbs, it's not going to totally alter someones mind that they are a different person. Sleep deprivation can affect ones ability to think effectively. Chronic sleep deprivation could have longer lasting effects.

I'm sure there is a lot here that I didn't cover so feel free to ask a follow up question.