Galantamine and donepezil attenuate pharmacologically induced deficits in prepulse inhibition in rats

Abstract

Acetylcholinesterase inhibitors (AChEIs) are currently being evaluated as adjunctive therapy for the cognitive dysfunction of schizophrenia. This core symptom of schizophrenia has often been attributed to impaired attention and abnormal sensory motor gating, features that are also found in Huntington's Disease, autism, and several other psychiatric and neurological disorders. The ability to improve prepulse inhibition (PPI) of the acoustic startle response may predict the efficacy of compounds as cognitive enhancers. In this study, PPI was disrupted in Wistar rats in three pharmacologic models: dopamine receptor agonism by apomorphine, NMDA receptor antagonism by MK801, or muscarinic acetylcholine receptor antagonism by scopolamine. We then evaluated the commonly used AChEIs, donepezil (0.5, 1.0, or 2.0mg/kg) and galantamine (0.3, 1.0, or 3.0mg/kg) for the capacity to improve PPI in each model. Under vehicle conditions, the prepulse stimuli (75, 80 and 85dB) inhibited the startle response to a 120dB auditory stimulus in a graded fashion. Galantamine (depending on dose) improved PPI deficits in all three PPI disruption models, whereas donepezil ameliorated PPI deficits induced by scopolamine and apomorphine, but was not effective in the MK801 model. These results indicate that some AChEIs may have the potential to improve cognition in schizophrenia by improving auditory sensory gating.

Fig 1

Effects of repeated exposures to the PPI testing method in rats. (A) Level of prepulse inhibition associated with three prepulse intensities (75, 80, and 85 dB). (B) Startle amplitude. (C) Level of prepulse inhibition averaged across prepulse level. Bars represent mean ± S.E.M. for each session (N=10).

Fig 2

(A) Effects of apomorphine (0.5 mg/kg) and several doses of galantamine on apomorphine-induced deficits in prepulse inhibition in rats associated with three prepulse intensities (75, 80, and 85 dB). (B) Effects of apomorphine and galantamine combined with apomorphine on startle amplitude. (C) Effects of apomorphine (0.5 mg/kg) and several doses of galantamine on apomorphine-induced deficits in prepulse inhibition averaged across prepulse level. Bars represent mean ± S.E.M. for each treatment (N=8-10). VEH = vehicle; GAL = galantamine; APO = apomorphine. * = significantly different (p<0.05) than the vehicle associated response. + = significantly different (p<0.05) than the apomorphine-associated response.

Fig 3

(A) Effects of MK801 (0.1 mg/kg) and several doses of galantamine on MK-801-induced deficits in prepulse inhibition in rats associated with three prepulse intensities (75, 80, and 85 dB). (B) Effects of MK801 and galantamine combined with MK801 on startle amplitude. (C) Effects of galantamine on MK801-induced deficits in prepulse inhibition averaged across prepulse level. Bars represent mean ± S.E.M. for each treatment (N=10). VEH = vehicle; GAL = galantamine. * = significantly different (p<0.05) than the vehicle associated response. + = significantly different (p<0.05) than the MK801-associated response.

Fig 4

(A) Effects of scopolamine (0.33 mg/kg) and several doses of galantamine on scopolamine-induced deficits in prepulse inhibition in rats associated with three prepulse intensities (75, 80, and 85 dB). (B) Effects of scopolamine and galantamine combined with scopolamine on startle amplitude. (C) Effects of galantamine on scopolamine-induced deficits in prepulse inhibition across prepulse level. Bars represent mean ± S.E.M. for each treatment (N=8-10). VEH = vehicle; SCOP = scopolamine; DON= donepezil. * = significantly different (p<0.05) than the vehicle associated response. + = significantly different (p<0.05) than the scopolamine-associated response.

Fig 5

(A) Effects of apomorphine (0.5 mg/kg) and several doses of donepezil on apomorphine-induced deficits in prepulse inhibition in rats associated with three prepulse intensities (75, 80, and 85 dB). (B) Effects of apomorphine and donepezil combined with apomorphine on startle amplitude. (C) Effects of apomorphine (0.5 mg/kg) and several doses of donepezil on apomorphine-induced deficits in prepulse inhibition averaged across prepulse level. Bars represent mean ± S.E.M. for each treatment (N=8-10). VEH = vehicle; DON = donepezil; APO = apomorphine. * = significantly different (p<0.05) than the vehicle associated response. + = significantly different (p<0.05) than the apomorphine-associated response.

Fig 6

(A) Effects of MK801 (0.1 mg/kg) and several doses of donepeizil on MK-801-induced deficits in prepulse inhibition in rats associated with three prepulse intensities (75, 80, and 85 dB). (B) Effects of MK801 and donepezil combined with MK801 on startle amplitude. (C) Effects of donepezil on MK801-induced deficits in prepulse inhibition averaged across prepulse level. Bars represent mean ± S.E.M. for each treatment (N=9-10). VEH = vehicle; DON = donepezil. * = significantly different (p<0.05) than the vehicle associated response. + = significantly different (p<0.05) than the MK801-associated response.

Fig 7

(A) Effects of scopolamine (0.33 mg/kg) and several doses of donepezil on scopolamine-induced deficits in prepulse inhibition in rats associated with three prepulse intensities (75, 80, and 85 dB). (B) Effects of scopolamine and donepezil combined with scopolamine on startle amplitude. (C) Effects of donepezil on scopolamine-induced deficits in prepulse inhibition across prepulse level. Bars represent mean ± S.E.M. for each treatment (N=8-10). VEH = vehicle; SCOP = scopolamine; DON= donepezil. * = significantly different (p<0.05) than the vehicle associated response. + = significantly different (p<0.05) than the scopolamine-associated response.