**5.2 Desensitization of nAChRs and effect on mAChRs**

Chronic nicotine exposure is associated with a long-lasting desensitization of nAChRs, which is both time- and concentration-dependent. In desensitization state, an intrinsic property of brain nAChRs, the receptor does not respond to nicotine or ACh. Although desensitization may lead to upregulation of nAChRs (an increase in the number of receptors), the overall response is diminished. This desensitization of nAChRs results in hypersensitization of mAChRs, stimulation of which by a muscarinic agonist can lead to electroencephalogram seizures, behavioral convulsions,

tremors and inhibition of spontaneous locomotor activity [20]. Moreover, hypersensitivity of mAChRs does not occur after nAChR recovery from desensitization. In addition to affecting mAChRs, desensitization of nAChRs also affects the activities of other systems. For example, desensitized nAChRs reduce GABA release from interneurons leading to disinhibition of pyramidal cells in hippocampus and cerebral cortex [21]. Conversely, activation of interneuron nAChRs enhances GABA release which inhibits pyramidal cells in these areas.

Interestingly, chronic administration of a mAChR antagonist such as scopolamine results in upregulation of cortical nAChRs [22]. Thus, it appears that inhibition of one receptor class such as nAChRs via desensitization, or inhibition of the other receptor class such as mAChRs via administration of an antagonist, results in upregulation or hypersensitization of the second receptor class, possibly as a compensatory mechanism. This fits with the findings that show administration of nAChRs and mAChRs antagonists together significantly decreases the development of kindled seizures in the amygdala, whereas either drug alone is ineffective [23].
