Atypical antipsychotics as noncompetitive inhibitors of α4β2 and α7 neuronal nicotinic receptors

Abstract

It has been suggested that the interaction of antipsychotic medications with neuronal nicotinic receptors may increase the cognitive dysfunction associated with schizophrenia and may explain why current therapies only partially address this core feature of the illness. In the present studies we compared the effects of the atypical antipsychotics quetiapine, clozapine and N-desmethylclozapine to those of the typical antipsychotics haloperidol and chlorpromazine on the α4β2 and α7 nicotinic receptor subtypes. The binding of [3H]-nicotine to rat cortical α4β2 receptors and [3H]-methyllycaconitine to rat hippocampal α7 receptors was not affected by any of the compounds tested. However, Rb+ efflux evoked either by nicotine or the selective α4β2 agonist TC-1827 from α4β2 receptors expressed in SH-EP1 cells and nicotine-evoked [3H]-dopamine release from rat striatal synaptosomes were non-competitively inhibited by all of the antipsychotics. Similarly, α-bungarotoxin-sensitive epibatidine-evoked [3H]-norepinephrine release from rat hippocampal slices and acetylcholine-activated currents of α7 nicotinic receptors expressed in oocytes were inhibited by haloperidol, chlorpromazine, clozapine and N-desmethylclozapine. The inhibitory effects on nicotinic receptor function produced by the antipsychotics tested occurred at concentrations similar to plasma levels achieved in schizophrenia patients, suggesting that they may lead to clinically relevant effects on cognition.

Negative Allosteric Modulators That Target Human α4β2 Neuronal Nicotinic Receptors

“…The potencies for our NAMs are similar to potencies of other established nAChR antagonists including dihydro-␤-erythroidine, D-tubocurarine, tetracaine, buproprion, and mecamylamine (McKay and Sanchez, 1990;McKay and Burkman, 1993;Jensen et al, 2005). In addition, the potency of these NAMs is similar to atypical antipsychotics that act as noncompetitive inhibitors of ␣4␤2 and ␣7 nAChRs (Grinevich et al, 2009). A significant finding in this study is that several of these NAMs do not inhibit H␣3␤4 nAChRs.…”

Smoking, nicotine and neuropsychiatric disorders

“…Another possible link between nicotinic cholinergic systems and antipsychotic treatment is that some antipsychotics, such as clozapine, chlorpromazine, haloperidol and quetiapine were shown to inhibit the function of nAChRs (Grinevich et al, 2009;Xu et al, 2006;Singhal et al, 2007).…”

Alpha7 Neuronal Nicotinic Receptors as Targets for Novel Therapies to Treat Multiple Domains of Schizophrenia

“…Another challenge to the development of alpha7 ligands as therapies is that their positive effects could potentially be nullified by concomitant medications such as antipsychotics, some of which have been shown to inhibit the activity of alpha7 NNRs [137,138]. For this reason the inclusion of patients taking clozapine may have obscured the effects of DMXB in an initial Phase 2 trial in schizophrenia [132].…”

“…Nicotine also improves haloperidol-related cognitive impairments in tests assessing memory and reaction time [20]. On the other hand, typical and atypical antipsychotics act as noncompetitive inhibitors of 4 2 and alpha7 NNRs, providing a physiological rationale for the failure of these drugs to alleviate cognitive deficits [138]. It has been shown in rats that clozapine improves reference memory but makes working memory worse; however, co-administration of nicotine attenuates this deficit [140].…”