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  • Carmustine Although effects of low concentrations of agonist

    2023-09-18

    Although effects of low concentrations of agonist were not as thoroughly documented for heteromeric receptors such as the major Carmustine α4β2 nAChR, a similar mechanism of action was described to explain the potentiation of these receptors with low concentrations of acetylcholine-esterase-inhibiting drugs [52].
    Reconciling experiments and drug exposure time Data from the literature have indicated that continuous exposure to nicotine, such as experienced by smokers, causes long lasting modifications of receptor expression as initially observed, for example, in autoradiography studies [53]. Subsequently, it was proposed that nicotine, or other agonist exposures can trigger an upregulation of the receptors that is associated with a series of mechanisms, including stabilization of the receptors inserted in the membrane, increased synthesis and trafficking, etc. A further complexity is that such biological equilibria (e.g., receptor upregulation) can be altered by chronic drug treatment such as in the case of antipsychotic treatment in schizophrenia patients [54].
    Multiple nAChR expressed in the brain In recombinant receptors α4 and β2 can associate in a 2:3 or 3:2 ratio and these complexes differ in affinity for ACh and for their sensitivity to exogenous compounds as, for example, sazetidine. While it would be beyond the scope of this document to discuss in more details the receptor composition, this argument must be kept in mind both for the comprehension of nAChR function and the design of novel compounds. Nonetheless, the importance of heteromeric nAChRs was illustrated by the reports of associations between genome variants and genetically transmissible epilepsies [55]. The predominant role of the β2 containing receptors in the prefrontal cortex is further supported by the correlation observed between genetically associated epilepsies and cognitive deficits observed in several members of the affected families. While it is currently difficult to dissociate the pure cholinergic influence here from the epileptiform activity, these results provide additional support for the role of nAChRs in brain function.
    nAChR pharmacological actions: agonist, antagonist, or PAM? In addition to the receptor selectivity issue, another interesting contemporary question in the nAChR-drug discovery field is: Which pharmacologic approach to modulating nAChRs may actually be the best pro-cognitive strategy, agonist, antagonist, or positive allosteric modulator? While the long-held classical view was that stimulation of nAChRs is the key action responsible for nicotine-induced cognitive improvements, as noted above, nAChRs are easily desensitized by nicotine and other nicotinic agonists, thus the relative roles of nAChR activation versus desensitization and net antagonist actions in the pro-cognitive effects are unclear [56]. Other reviews of the literature have concluded that both nAChR activation and desensitization play important roles in nicotine’s effects on reinforcement, affective behavior, as well as cognitive function [57], [58]. Interestingly, pro-cognitive effects of the nAChR antagonist mecamylamine have reported in working memory tasks in both rodents [59] and monkeys [60], [61] as well as a recognition memory task in humans with attention deficit hyperactivity disorder (ADHD) [62]. Moreover, in a signal detection task in rats, the α4β2 antagonist DHβE improved attentional function either alone or in reversing the attentional impairment caused by the NMDA glutamate antagonist dizocilpine (MK-801) [56]. Other data indicate that direct infusions of nAChR antagonists into discrete brain regions can enhance memory function. For example, infusions of the α4β2 nicotinic antagonist DHβE into the mediodorsal thalamic nucleus (which has direct connections with the frontal cortex area) either acutely or chronically significantly improved memory-related behaviors in rats [63]. In contrast, acute and chronic DHβE induced memory impairments when infused into the ventral hippocampus of rats [64], [65]. Similar to antagonist drugs, compounds known to selectively desensitize nAChRs have also been shown to improve cognitive function in some conditions. For example, the α4β2 receptor desensitizing agent sazetidine-A, significantly improved attentional function by reversing impairments induced by the NMDA glutamate antagonist dizocilpine (MK-801) and the muscarinic cholinergic antagonist scopolamine [66], [67].