Effects of alpha sub(4)/ beta sub(2)- and alpha sub(7)-nicotine acetylcholine receptor agonists on prepulse inhibition of the acoustic startle response in rats and mice

Rationale: Nicotine and agonists at subtypes of the nicotine acetylcholine receptor (nAChR) affect auditory gating, but the magnitude and direction of such effects appear highly variable. This variability may be due to differences in the tested dose range, selectivity of the test compound, species and strain, and suggests that nAChR subtypes are differentially involved in the control of auditory gating. Objectives and methods: This study aimed to characterise the effects of nicotine and agonists with preferential activity at alpha sub(4)/ beta sub(2)- and alpha sub(7)-nAChRs on auditory sensorimotor gating using a prepulse inhibition (PPI) paradigm. Similar experimental conditions were employed in rats and two strains of mice. The paradigm used startle stimuli of 120 dB and prepulse intensities of 3, 6 and 12 dB above a background of 70 dB. Results: In Sprague-Dawley rats, nicotine disrupted PPI [minimal effective dose (MED): 1 mg/kg, SC] and this effect was mimicked by the potent nAChR agonist, epibatidine, (MED: less than or equal to 0.001 mg /kg, IP) and the potent, and relatively selective, alpha sub(4) / beta sub(2)-nAChR agonist A-85380 (MED: less than or equal to 0.1 mg/kg, IP). The effects of epibatidine, A-85380 and, to a lesser extent, nicotine were blocked by the non-selective nAChR antagonist mecamylamine. The relatively selective alpha sub(7)-nAChR agonists, GTS-21 and AR-R-17779, did not affect PPI in a consistent manner, both in rats and in DBA /2 mice, a strain expressing a disrupted gating phenotype, presumably due to altered activity of hippocampal alpha sub(7)-nAChRs. In BALB/c mice, a strain expressing a normal gating phenotype, nicotine (MED: 10 mg/kg, SC), epibatidine (MED: 0.03 mg/kg, IP) and A-85380 (MED: 0.3 mg/kg, IP) predominantly augmented PPI and mecamylamine attenuated these effects. Conclusions: The present results confirm that the effects of nAChR agonists on PPI are species dependent and suggest that stimulation of heteromeric nAChRs containing both alpha and beta subunits, and possibly of the alpha sub(4)/ beta sub(2) type, affect sensorimotor gating. Evidence supporting a role for alpha sub(7)-nAChRs in the control of PPI of the acoustic startle response was not obtained.