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Please critique my theory of drug tolerance


gib65
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Hello everyone,

I have a theory about drug tolerance that I'd like some feedback on (is there support for it? Against it? Can anyone tell me if there's reasons it might to true/false?). It goes a bit deeper than the already widely accepted their of receptor upgrading/downgrading (and note that it's not a competing theory but builds on it). The theory of receptor upgrading/downgrading, as I understand it, is that neurons will shed their receptors (downgrade) if they detect (somehow) that those receptors are overstimulated, and will build more receptors (upgrade) if they detect that those receptors are understimulated. As I understand it, this happens with both drugs and naturally occurring neurotransmitters. If a drug finds its way into the synaptic gap and binds to receptors therein, then after a while those receptors will start downgrading to return the level of activity to normal. If the drug somehow blocks naturally occurring neurotransmitters from stimulating the receptors, then after a while those receptors will start upgrading to return the level of activity to normal. This can happen directly or indirectly. A drug can indirectly increase the amount of stimulation at receptor sites by, for example, increasing the rate at which naturally occurring neurotransmitters are released into the synaptic gap. This is the case with dextroamphetamine. It increasing the amount of stimulation by entering into the synapse and pushing out more dopamine into the synaptic gap than usual, and the dopamine stimulates the receptors directly. Likewise, a drug can indirectly decrease the level of stimulation of receptor sites by, for example, increasing the amount of stimulation at a neuron whose function it is to inhibit the stimulation of the first neuron, thereby causing less naturally occurring neurotransmitters to enter into the synaptic gap of the latter.

But where my theory comes in is to answer the question: how does upgrading/downgrading work? What is the mechanism by which it happens? My theory is this: upgrading is constantly happening all the time. It's a naturally occurring behavior of any neuron. Leave a neuron to its own devices and over time it will produce more and more receptors on its surface until it can't anymore. However, receptors are fragile. Too much stimulation can destroy them. So with enough stimulation, the rate at which receptors are destroyed will balance the rate at which they are produced, thereby keeping the number of receptors in an equilibrium state. Moving above that equilibrium will, therefore, imbalance the rate in the direction of destroying more receptors than are created, thereby resulting in downgrading. Moving below the threshold will imbalance the rate in the direction of allowing more receptors to be created than are destroyed, thereby resulting in upgrading.

That's the theory. Is there anything too this theory? Is there anything in the scientific literature that either supports this or discredits it? Does anyone have any reasons to agree? Reasons to doubt? What are those reasons either way?

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