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 MK-801, or muscarinic acetylcholine receptor antagonism by scopolamine. We then evaluated the commonly used AChEIs, donepezil (0.5, 1.0, or 2.0 mg/kg) and galantamine (0.3, 1.0, or 3.0 mg/kg) for the capacity to improve PPI in each model. Under vehicle conditions, the prepulse stimuli (75, 80 and 85 dB) inhibited the startle response to a 120 dB 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.

Chronic, Intermittent Exposure to Chlorpyrifos in Rats: Protracted Effects on Axonal Transport, Neurotrophin Receptors, Cholinergic Markers, and Information Processing

“…To assess the effects of CPF exposure on sensorimotor gating, a PPI procedure was conducted as described in detail previously (Hohnadel et al, 2007). In brief, four startle chambers (San Diego Instruments) were used, the background white noise was set at 70 dB, and the PPI trials consisted of a prepulse (20-ms burst of white noise with intensities of 75, 80, or 85 dB) followed 100 ms later by a startle stimulus (120 dB, 20 ms of white noise).…”

“…at ASPET Journals on May 9, 2018 jpet.aspetjournals.org startle response produced by a low-intensity stimulus presented before a high-intensity, startle-producing stimulus has been widely used as a neurophysiological measure of the early preattentive stages of information processing (Braff and Geyer, 1990), Further, it has been shown in animals to be sensitive to cholinergic manipulations (Hohnadel et al, 2007). PPI impairments are evident in a variety of conditions in which deficits in attention and information processing are observed, such as Asperger's syndrome (McAlonan et al, 2002), Huntington's disease (Swerdlow et al, 1995), and schizophrenia (Braff et al, 2001), leading to the logical question of whether OP exposure might be a risk factor for such illnesses.…”

The Prototypical Ranitidine Analog JWS-USC-75-IX Improves Information Processing and Cognitive Function in Animal Models

“…However, the data do support the premise that cholinergic function is important for optimal OR performance and PPI (and thus a viable target in conditions where it is impaired). We recently reported that the AChEIs galantamine and donepezil can also attenuate scopolamine-related impairments in PPI (Hohnadel et al, 2007). In addition, PPI deficits induced by immunolesions of cholinergic neurons of the nucleus basalis were reversed by the AChEI rivastigmine (Ballmaier et al, 2002).…”

“…To assess the effects of JWS on sensorimotor gating, a PPI procedure was conducted as described in detail previously (Hohnadel et al, 2007). In brief, four startle chambers (San Diego Instruments) were used, the background white noise was set at 70 db, and the PPI trials consisted of a prepulse (20-ms burst of white noise with intensities of 75, 80, or 85 db) followed, 100 ms later, by a startle stimulus (120 db, 20-ms white noise).…”

“…scopolamine hydrobromide was administered 40 min before testing followed by vehicle, JWS, or donepezil (by oral gavage) 20 min before testing. The compounds used to disrupt PPI (and their doses) were based on earlier studies (Mansbach et al, 1988;Mansbach and Geyer, 1989) and recent work in our laboratory (Hohnadel et al, 2007).…”