The smoking cessation drug varenicline improves deficient P20–N40 inhibition in DBA/2 mice

Abstract

Varenicline, an FDA approved smoking cessation pharmacotherapy, is an α4β2* nicotinic acetylcholine receptor (nAChR) partial agonist and an α7* nAChR full agonist. Both subtypes of nAChR are involved in modulating auditory evoked responses in rodents. In DBA/2 mice, an inbred strain, auditory evoked responses to paired auditory stimuli fail to inhibit to the second stimulus. This mouse strain replicates the auditory evoked response inhibition deficit experienced by the majority of schizophrenia patients. In this current study, we examined the effects of five different doses of varenicline (0.06, 0.3, 0.6, 3 and 6 mg/kg) on auditory evoked responses in anesthetized DBA/2 mice. We also examined α4β2* and α7* nAChR selective antagonist pre-administration prior to varenicline administration in order to determine the impact of these two nAChR subtypes in the effects produced by varenicline. Four of the five doses of varenicline produced improvements in auditory evoked response inhibition deficits. Selective blockade of either the α4β2* or α7* nAChR in competition with 0.6 mg/kg varenicline prevented varenicline induced improvements. In competition with a higher dose of varenicline (3 mg/kg) only blockade of the α4β2* nAChR prevented varenicline induced improvement in auditory evoked response inhibition. These data indicate the importance of α4β2* nAChRs and the potential involvement of the α7* subtype in varenicline’s effects on auditory evoked responses in DBA/2 mice.

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…Consistent results obtained in different animal species ranging from rodent to nonhuman primates further strengthened the role of a7 nAChRs in cholinergic system functioning. Preclinical studies have demonstrated the efficacy of several a7 nAChR agonists in an N40 sensory gating model (Hashimoto et al, 2005;Simosky et al, 2008;Wildeboer-Andrud and Stevens, 2011), in particular ABT-107 (Radek et al, 2012). Other molecules such as TC-5619, SSR-180711, A-582941, or encenicline also demonstrated efficacy in cognitive models (Pichat et al, 2007;Tietje et al, 2008;Mazurov et al, 2012;Prickaerts et al, 2012).…”

Translational utility of rodent hippocampal auditory gating in schizophrenia research: a review and evaluation

“…In DBA/2 mice, the drug improves gating by decreasing S2 amplitude at low doses and increasing S1 amplitude at higher doses. 50 The dose dependence of varenicline may be due to the observation that α7 receptors desensitize as a function of increasing agonist concentration, 97 reducing S2-mediated effects at high doses of drug. A pilot human study using a ‘low' dose (0.012 mg kg −1 ), however, showed no significant effects of acute varenicline administration on gating.…”

Evaluating the role of the alpha-7 nicotinic acetylcholine receptor in the pathophysiology and treatment of schizophrenia

“…Accordingly, the gating of the P20/N40 in various mouse strains correlated with their hippocampal α7 nAChR expression [63]. After administration of nicotine or other α7 nAChR agonists the P20/N40 gating of each strain was improved [63–66], providing converging support for the α7 nAChR as a viable therapeutic target in schizophrenia [43, 67, 68]. …”