-The drug’s actions may lead to a depletion of the transmitter either because the
transmitter are used faster than they can be replenished or because the actual
synthesis of the tranismitters is decrease (excess activity of auto-receptor)
-With fewer tranimsitter molecules available, a larger drug dose must be
-If this cycle continues long enough,. This form of tolerance can lead to the drug\s
becoming completely ineffective, regardless of the dose administer.
-A drug\s ability to deplete neurotransmitter can also be a factor in some forms of
-Eg. One drug may act bye enhancing the transmitter’s release, and another may
act by reducing the transmitter reuptake.
-With either drug, depletion of the transmitter will reduce the effect of the drug.
-Finally, depletion of neurotransmitters can lead to the person experiencing
symptoms that are the opposite of those he or she experienced with the drug this
where the drug initially induces its effects by amplifying a neurotransmitters
activity on its target neurons, absence of the drug results in a reduction in the
neurotransmitter’s activity on its target neurons
-Another possible tolerance mechanism involves the drug’s occupation and
saturation of receptor sites, whereby the drug molecules exert their action at the
time of occupation of receptor sites.
-One binding occurs, the drug no longer exerts and effect other than preventing the
initiation of a new response by other drug molecules combining with the receptor.
-Eg. Nicotine dissociates from the Ach receptor rather slowly, the cell remains
depolarized, and a new action potential cannot be initiated until the nicotine is
removed from the receptor.
-Large doses of nicotine may actually exert an antagonistic action at Ach receptors
(after initial agonistic action)
-There appear to be several mechanisms for tolerance involving cellular adaptation
related to homeostasis
-One of the more common homeostatic adaptation observed involving drug-
induced alteration in the receptors in neuronal membranes.
-The alterations may reflect either qualitative changes in the NT’s receptors
configuration or changes in the actual number of receptors, which in turn affect
the transmitter binding or efficacy.
-In most cases, a continuous exposure to drugs that mimic or amplify the action of
neurotransmitters at their receptors tends to decrease receptor activity through
processes referred to as down-regulation and desensitization.
-Down-regulation refers to a decrease in the number of functional receptors
available for activation
-This can occur because the receptors dissociate from the neuronal membrane and
becomes sequestered inside the cytoplasm of the neuron, thus making them
inaccessible for activation by agonists, or it can occur because the receptors are