The value of maintaining cognition in patients with mild cognitive impairment: The innovation headroom and potential cost-effectiveness of roflumilast.

INTRODUCTION: Early health-technology assessment can support discussing scarce resource allocation among stakeholders. We explored the value of maintaining cognition in patients with mild cognitive impairment (MCI) by estimating: (1) the innovation headroom and (2) the potential cost effectiveness of roflumilast treatment in this population. METHODS: The innovation headroom was operationalized by a fictive 100% efficacious treatment effect, and the roflumilast effect on memory word learning test was assumed to be associated with 7% relative risk reduction of dementia onset. Both were compared to Dutch setting usual care using the adapted International Pharmaco-Economic Collaboration on Alzheimer's Disease (IPECAD) open-source model. RESULTS: The total innovation headroom expressed as net health benefit was 4.2 (95% bootstrap interval: 2.9-5.7) quality-adjusted life years (QALYs). The potential cost effectiveness of roflumilast was k€34 per QALY. DISCUSSION: The innovation headroom in MCI is substantial. Although the potential cost effectiveness of roflumilast treatment is uncertain, further research on its effect on dementia onset is likely valuable.

The antimuscarinic agent biperiden selectively impairs recognition of abstract figures without affecting the processing of non-words.

OBJECTIVES: The present study investigated the effects of biperiden, a muscarinic type 1 antagonist, on the recognition performance of pre-experimentally unfamiliar abstract figures and non-words in healthy young volunteers. The aim was to examine whether 4 mg biperiden could model the recognition memory impairment seen in healthy aging. METHODS: A double-blind, placebo-controlled, two-way crossover study was conducted. We used a three-phase (deep memorization, shallow memorization, and recognition) old/new discrimination paradigm in which memory strength was manipulated. Strong memories were induced by deep encoding and repetition. Deep encoding was encouraged by redrawing the abstract figures and mentioning existing rhyme words for the non-words (semantic processing). Weak memories were created by merely instructing the participants to study the stimuli (shallow memorization). RESULTS: Biperiden impaired recognition accuracy and prolonged reaction times of the drawn and the studied abstract figures. However, participants were biased towards "old" responses in the placebo condition. The recognition of the new abstract figures was unaffected by the drug. Biperiden did not affect the recognition of the non-words. CONCLUSIONS: Although biperiden may model age-related deficits in episodic memory, the current findings indicate that biperiden does not mimic age-related deficits in recognition performance.

Biperiden Selectively Impairs Verbal Episodic Memory in a Dose- and Time-Dependent Manner in Healthy Subjects.

PURPOSE/BACKGROUND: Biperiden is a muscarinic antagonist that produces memory impairments without impairing attention or motor functions in healthy subjects. It has been suggested that a biperiden-induced memory deficit could model age- and dementia-related memory impairments. The goal of the current study was to determine the dose- and time-dependent effects of biperiden on cognition in healthy volunteers. METHODS/PROCEDURES: Twenty-one healthy volunteers participated in a placebo-controlled, 3-way, crossover study. After a baseline test, cognitive performance was tested at 3 time points after a single dose of biperiden 2 or 4 mg, or placebo. Episodic memory was measured using a 15-word verbal learning task (VLT). Furthermore, n-back tasks, a sustained attention to response task and a reaction time task were used, as well as subjective alertness and a side effects questionnaire. In addition, blood serum values and physiological measures were taken. FINDINGS/RESULTS: Biperiden decreased the number of words recalled in immediate and delayed recall of the VLT 90 minutes after drug intake. A dose-dependent impairment was found for the delayed recall, whereas the immediate recall was equally impaired by the 2 doses. Biperiden did not affect the performance on the VLT 4 hours after administration. Performance in the n-back task and the sustained attention to response task were not affected by biperiden at any time point. Both doses were well tolerated as reported side effects were mild at Tmax and were minimal at the other time points. IMPLICATIONS/CONCLUSIONS: Biperiden exerts effects on episodic memory without negatively affecting other cognitive performance and behavioral measures that were assessed in this study. The data provide further evidence that biperiden has selective effects on cognition, even after a high dose.

Learning-induced neural plasticity of speech processing before birth.

Learning, the foundation of adaptive and intelligent behavior, is based on plastic changes in neural assemblies, reflected by the modulation of electric brain responses. In infancy, auditory learning implicates the formation and strengthening of neural long-term memory traces, improving discrimination skills, in particular those forming the prerequisites for speech perception and understanding. Although previous behavioral observations show that newborns react differentially to unfamiliar sounds vs. familiar sound material that they were exposed to as fetuses, the neural basis of fetal learning has not thus far been investigated. Here we demonstrate direct neural correlates of human fetal learning of speech-like auditory stimuli. We presented variants of words to fetuses; unlike infants with no exposure to these stimuli, the exposed fetuses showed enhanced brain activity (mismatch responses) in response to pitch changes for the trained variants after birth. Furthermore, a significant correlation existed between the amount of prenatal exposure and brain activity, with greater activity being associated with a higher amount of prenatal speech exposure. Moreover, the learning effect was generalized to other types of similar speech sounds not included in the training material. Consequently, our results indicate neural commitment specifically tuned to the speech features heard before birth and their memory representations.

Human electrophysiological correlates of learned irrelevance: effects of the muscarinic M1 antagonist biperiden.

Learned irrelevance (LIrr) refers to a reduction in associative learning after pre-exposure of the conditioned and unconditioned stimulus in a non-contingent fashion. This paradigm might serve as a translational model for (pre)attentive information processing deficits in schizophrenia. This is the first study to investigate the event-related potentials (ERPs) of a within-subject LIrr paradigm in humans. Furthermore, the effects of the muscarinic M1 antagonist biperiden on LIrr were assessed. As expected, LIrr was found to be intact in young healthy volunteers after placebo. Furthermore, in the placebo condition P3b latency was decreased for target stimuli, which were pre-cued. This suggests that the predictability of the occurrence of these stimuli is mainly reflected by this ERP component. Biperiden had no effect on the behavioural LIrr measures, although prolonged reaction times were evident. Biperiden increased the N1 amplitude of the pre-exposed predictor letters, suggesting an effect of this drug on early perceptual processing. In conclusion, the within-subject paradigm used in the current study in combination with electroencephalography can reveal brain mechanisms involved in LIrr. M1 antagonism did not affect LIrr performance but seemed to influence early information processing.

Age Effects on Old/New Recognition Memory Involving Abstract Figures and Non-words.

Age-related memory problems posit a growing concern in our society. This study investigated the impact of age and memory strength on recognition memory of pre-experimentally unfamiliar abstract figures and non-words. We applied a three-phase old/new recognition memory paradigm and manipulated memory strength as a function of the Levels of Processing (deep vs. shallow) and repetition. Older adults relative to the young showed impairment in the correct identification of new items. As indicated by the lower discriminability indexes, the older adults also had difficulties discriminating the strongly (drawn/semantically processed) and the weakly (studied) embedded abstract figures but not the non-words. Age-related differences in reaction times were only evident with the abstract figures. Finally, our results revealed that the recognition performance was equally affected by memory strength in both age groups. The current findings agree with previous research on age-related impairment in new item recognition, which can be attributed to misrecollection and decreased sensitivity to novelty in the older adults than the young. The detected age effects on the discriminability of the drawn and studied abstract figures agree with the age-related impairment in the perceptual encoding hypothesis and support the notion related to the need for environmental support to reduce age effects. The lack of age effects with the non-words indicates that age effects on discriminability are stimulus-dependent. The current results support the notion that recognition memory in aging is only impaired under certain conditions and depends on the stimuli used.

EEG Correlates of Old/New Discrimination Performance Involving Abstract Figures and Non-Words.

The processing of pre-experimentally unfamiliar stimuli such as abstract figures and non-words is poorly understood. Here, we considered the role of memory strength in the discrimination process of such stimuli using a three-phase old/new recognition memory paradigm. Memory strength was manipulated as a function of the levels of processing (deep vs. shallow) and repetition. Behavioral results were matched to brain responses using EEG. We found that correct identification of the new abstract figures and non-words was superior to old item recognition when they were merely studied without repetition, but not when they were semantically processed or drawn. EEG results indicated that successful new item identification was marked by a combination of the absence of familiarity (N400) and recollection (P600) for the studied figures. For both the abstract figures and the non-words, the parietal P600 was found to differentiate between the old and new items (late old/new effects). The present study extends current knowledge on the processing of pre-experimentally unfamiliar figurative and verbal stimuli by showing that their discrimination depends on experimentally induced memory strength and that the underlying brain processes differ. Nevertheless, the P600, similar to pre-experimentally familiar figures and words, likely reflects improved recognition memory of meaningless pictorial and verbal items.

Optimizing Behavioral Paradigms to Facilitate Development of New Treatments for Anhedonia and Reward Processing Deficits in Schizophrenia and Major Depressive Disorder: Study Protocol.

Background: Behavioral tasks focusing on different subdomains of reward processing may provide more objective and quantifiable measures of anhedonia and impaired motivation compared with clinical scales. Typically, single tasks are used in relatively small studies to compare cases and controls in one indication, but they are rarely included in larger multisite trials. This is due to limited systematic standardization as well as the challenges of deployment in international studies and stringent adherence to the high regulatory requirements for data integrity. The Reward Task Optimization Consortium (RTOC) was formed to facilitate operational implementation of reward processing tasks, making them suitable for use in future large-scale, international, multisite drug development studies across multiple indications. The RTOC clinical study aims to conduct initial optimization of a set of tasks in patients with major depressive disorder (MDD) or schizophrenia (SZ). Methods: We will conduct a multicenter study across four EU countries. Participants (MDD = 37, SZ = 37, with ≤80 age- and gender-matched healthy volunteers) will attend a study visit comprising screening, self-report and clinically rated assessments of anhedonia and symptom severity, and three reward processing tasks; specifically, the Grip Strength Effort task, the Doors task, and the Reinforcement Learning Working Memory task. The Grip Strength Effort and Doors tasks include simultaneous electroencephalography/event-related potential recordings. Outcomes will be compared using a two-way group design of MDD and SZ with matched controls, respectively. Further analyses will include anhedonia assessment scores as covariates. Planned analyses will assess whether our findings replicate previously published data, and multisite deployment will be evaluated through assessments of quality and conduct. A subset of participants will complete a second visit, to assess test-retest reliability of the task battery. Discussion: This study will evaluate the operational deployment of three reward processing tasks to the regulatory standards required for use in drug development trials. We will explore the potential of these tasks to differentiate patients from controls and to provide a quantitative marker of anhedonia and/or impaired motivation, establishing their usefulness as endpoints in multisite clinical trials. This study should demonstrate where multifaceted reward deficits are similar or divergent across patient populations. Registration: ClinicalTrials.gov (NCT04024371).

Acute treatment with the PDE4 inhibitor roflumilast improves verbal word memory in healthy old individuals: a double-blind placebo-controlled study.

There is ample evidence that phosphodiesterase 4 (PDE4) inhibition can improve memory performance in animal studies. In the present study, we examined the acute effects of the PDE4 inhibitor roflumilast on memory performance in healthy individuals (60-80 years of age). We tested the effects of acute roflumilast administration (100, 250, 1000 µg) in a double-blind, placebo-controlled, 4-way crossover design. Participants were first screened for their verbal word memory performance to ensure normal memory performance (within 0.5 standard deviation from norm score; n = 20) Drug effects on memory performance were tested in a verbal memory test and a spatial memory test. Reported side effects of drug treatment were registered. Roflumilast (100 µg) improved the delayed recall performance of the participants (Cohen's d, 0.69). No effects were observed in the spatial memory task. Roflumilast was well tolerated at this low dose. Although no clear adverse side effects were reported at the low dose, mild adverse events (including headache, dizziness, insomnia, and diarrhea) were reported after the 1000 µg dose. The present study provides first evidence that the PDE4 inhibitor roflumilast improves verbal memory performance in old participants. The current data encourage further development of PDE4 inhibitors for improving memory.

Sleeping newborns extract prosody from continuous speech.

OBJECTIVE: Behavioral experiments show that infants use both prosodic and statistical cues in acquiring language. However, it is not yet clear whether these prosodic and statistical tools are already present at birth. METHODS: We recorded brain responses of sleeping newborns to natural sounds rich in prosody, namely singing and continuous speech, and to two impoverished manipulations of speech. A total of 11 newborns were presented with continuous speech, singing, and degraded speech, while MEG was recorded. RESULTS: We found that a brain response elicited to the prosodically rich singing and continuous natural speech conditions decreased dramatically when the prosody in the speech was impoverished. CONCLUSIONS: We claim that this response is the indicator of the infants' sensitivity to prosodic cues in language, which is already present at birth during natural sleep. SIGNIFICANCE: The indicators of detection of prosody may be crucial in assessing the normal and abnormal cortical function in newborns, especially of those infants at-risk for language problems.

Acute administration of roflumilast enhances sensory gating in healthy young humans in a randomized trial.

INTRODUCTION: Sensory gating is a process involved in early information processing which prevents overstimulation of higher cortical areas by filtering sensory information. Research has shown that the process of sensory gating is disrupted in patients suffering from clinical disorders including attention deficit hyper activity disorder, schizophrenia, and Alzheimer's disease. Phosphodiesterase (PDE) inhibitors have received an increased interest as a tool to improve cognitive performance in both animals and man, including sensory gating. METHODS: The current study investigated the effects of the PDE4 inhibitor roflumilast in a sensory gating paradigm in 20 healthy young human volunteers (age range 18-30 years). We applied a placebo-controlled randomized cross-over design and tested three doses (100, 300, 1000 µg). RESULTS: Results show that roflumilast improves sensory gating in healthy young human volunteers only at the 100-µg dose. The effective dose of 100 µg is five times lower than the clinically approved dose for the treatment of acute exacerbations in chronic obstructive pulmonary disease (COPD). No side-effects, such as nausea and emesis, were observed at this dose. This means roflumilast shows a beneficial effect on gating at a dose that had no adverse effects reported following single-dose administration in the present study. CONCLUSION: The PDE4 inhibitor roflumilast has a favorable side-effect profile at a cognitively effective dose and could be considered as a treatment in disorders affected by disrupted sensory gating.

The effects of the soluble guanylate cyclase stimulator riociguat on memory performance in healthy volunteers with a biperiden-induced memory impairment.

RATIONALE: After stimulation with nitric oxide, soluble guanylate cyclase (sGC) produces cyclic guanosine monophosphate (cGMP), which stimulates an important signalling pathway for long-term potentiation (LTP). By upregulating cGMP, LTP could be stimulated and thereby enhancing memory processes. The present study investigated the effects of the sGC stimulator riociguat on cognition in healthy volunteers. Participants were pre-treated with and without biperiden, which impairs memory performance, to investigate the memory-enhancing effects of riociguat. METHODS: Twenty volunteers participated in a double-blind placebo-controlled six-way crossover design with a cognitive test battery including the verbal learning task (VLT), n-back task, spatial memory test, the attention network test, and a reaction time task. Treatments were placebo and riociguat 0.5 mg, placebo and riociguat 1.0 mg, biperiden 2.0 mg and placebo, biperiden 2.0 mg and riociguat 0.5 mg and biperiden 2.0 mg and riociguat 1.0 mg. RESULTS: Blood pressure was found to be decreased and heart rate to be increased after administration of riociguat. Cognitive performance was not enhanced after administration of riociguat. Biperiden decreased episodic memory on the VLT, yet this deficit was not reversed by riociguat. CONCLUSION: This supports the notion that biperiden might be a valuable pharmacological model to induce episodic memory impairments as observed in AD/MCI.

Sex differences in the effect of acute tryptophan depletion on declarative episodic memory: a pooled analysis of nine studies.

Acute tryptophan depletion (ATD) studies have shown that serotonin plays a role in learning and memory processes. In this study, we performed a pooled analysis of nine ATD studies in order to examine the nature of the memory-impairing effects of ATD and mediating factors, such as gender, age and vulnerability for disease in which disturbed serotonin was hypothesized to play a role. All studies that were used in this pooled analysis assessed declarative episodic memory using a verbal learning task paradigm. Immediate recall, delayed recall, and delayed recognition scores were examined. A total of 211 participants were included in the analysis. The analysis revealed that ATD impaired not only delayed recall, but also immediate recall. The ATD-induced impairments were larger in females than in males. Furthermore, ATD did not interact with any other serotonergic vulnerability and age. This suggests that the only factor that actually has the properties of a serotonergic vulnerability factor for declarative memory performance is female gender. The findings provide further support for a critical role of serotonin in declarative episodic memory.

Cholinergic drugs affect novel object recognition in rats: relation with hippocampal EEG?

This study examined the role of cognitively enhancing cholinergic drugs on both object memory and brain activity in rats, as well as the possible relation between the two measures. A group of twenty-four animals was used for assessing object recognition. In another group of eight rats, an electrode was implanted into the dorsal hippocampus to record an electroencephalogram (EEG) and auditory evoked potentials (AEP). In both groups, animals were treated with saline, 0.1 mg/kg scopolamine, 0.1 mg/kg methylscopolamine, 3 mg/kg donepezil, donepezil combined with scopolamine, 0.1 mg/kg nicotine, and nicotine combined with scopolamine. Scopolamine, but not methylscopolamine, impaired object recognition. Both donepezil and nicotine reversed this impairment. The N1 and N2 components of the AEP became closer to baseline after scopolamine, which was not reversed by donepezil or nicotine. Scopolamine increased the theta frequency in the EEG. When combined with donepezil, theta increased even more. Conversely, nicotine reversed the theta increment to control level. It is suggested that scopolamine caused a decrement in arousal in this study. Furthermore, the current results suggest a relation between EEG and object memory after cholinergic drug treatment. However, there was a clear dissociation between memory performance and EEG after combined treatment with drugs, which makes additional research where EEG and performance measures are co-registered imperative.

Effects of biperiden and acute tryptophan depletion and their combination on verbal word memory and EEG.

BACKGROUND: Research on the neurobiological foundations of memory has shown that multiple neurotransmitters play an important role in memory processing. To study the interaction between neurotransmitters such as acetylcholine and serotonin, pharmacological models can be used. In this study, we tested the effects of the muscarinic M1 antagonist biperiden, acute tryptophan depletion (ATD), and the interaction between the two on episodic memory using the verbal learning task. METHODS: The study was conducted according to a double-blind, placebo-controlled, four-way crossover design. Seventeen participants received biperiden (2.0 mg), ATD (SolugelP), a combination of both, or a placebo in counterbalanced order with a wash out of at least 7 days. A verbal learning task was performed while recording electroencephalography. The task consisted of an immediate and delayed recall as well as a recognition part. RESULTS: Results revealed decreased scores on the delayed recall after biperiden and ATD separately but no significant interaction between the two. However, the event-related potential components P3b, N400, and P600 did show an interaction during encoding. CONCLUSION: These results indicate that both BIP and ATD impair episodic memory. However, an interaction between the serotonergic and cholinergic system on memory performance is not supported.

Newborns discriminate novel from harmonic sounds: a study using magnetoencephalography.

OBJECTIVE: We investigated whether newborns respond differently to novel and deviant sounds during quiet sleep. METHODS: Twelve healthy neonates were presented with a three-stimulus oddball paradigm, consisting of frequent standard (76%), infrequent deviant (12%), and infrequent novel stimuli (12%). The standards and deviants were counterbalanced between the newborns and consisted of 500 and 750 Hz tones with two upper harmonics. The novel stimuli contained animal, human, and mechanical sounds. All stimuli had a duration of 300 ms and the stimulus onset asynchrony was 1s. Evoked magnetic responses during quiet sleep were recorded and averaged offline. RESULTS: Two deflections peaking at 345 and 615 ms after stimulus onset were observed in the evoked responses of most of the newborns. The first deflection was larger to novel and deviant stimuli than to the standard and, furthermore, larger to novel than to deviant stimuli. The second deflection was larger to novel and deviant stimuli than to standards, but did not differ between the novels and deviants. CONCLUSIONS: The two deflections found in the present study reflect different mechanisms of auditory change detection and discriminative processes. SIGNIFICANCE: The early brain indicators of novelty detection may be crucial in assessing the normal and abnormal cortical function in newborns. Further, studying evoked magnetic fields to complex auditory stimulation in healthy newborns is needed for studying the newborns at-risk for cognitive or language problems.

The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses.

Enhancement of central availability of the second messenger cAMP is a promising approach to improve cognitive function. Pharmacological inhibition of phosphodiesterase type 4 (PDE4), a group of cAMP hydrolyzing enzymes in the brain, has been shown to improve cognitive performances in rodents and monkeys. However, inhibition of PDE4 is generally associated with severe emetic side-effects. Roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), is yielding only mild emetic side effects. In the present study we investigate the potential of roflumilast as a cognition enhancer and to determine the potential coinciding emetic response in comparison to rolipram, a classic PDE4 inhibitor with pronounced emetic effects. Cognition enhancement was evaluated in mice and it was found that both roflumilast and rolipram enhanced memory in an object location task (0.03mg/kg), whereas only roflumilast was effective in a spatial Y-maze (0.1mg/kg). Emetic potential was measured using competition of PDE4 inhibition for α2-adrenergic receptor antagonism in which recovery from xylazine/ketamine-mediated anesthesia is used as a surrogate marker. While rolipram displayed emetic properties at a dose 10 times the memory-enhancing dose, roflumilast only showed increased emetic-like properties at a dose 100 times the memory-enhancing dose. Moreover, combining sub-efficacious doses of the approved cognition-enhancer donepezil and roflumilast, which did not improve memory when given alone, fully restored object recognition memory deficit in rats induced by the muscarinic receptor antagonist scopolamine. These findings suggest that roflumilast offers a more favorable window for treatment of cognitive deficits compared to rolipram.

Verbal Memory Impairment in Polydrug Ecstasy Users: A Clinical Perspective.

BACKGROUND: Ecstasy use has been associated with short-term and long-term memory deficits on a standard Word Learning Task (WLT). The clinical relevance of this has been debated and is currently unknown. The present study aimed at evaluating the clinical relevance of verbal memory impairment in Ecstasy users. To that end, clinical memory impairment was defined as decrement in memory performance that exceeded the cut-off value of 1.5 times the standard deviation of the average score in the healthy control sample. The primary question was whether being an Ecstasy user (E-user) was predictive of having clinically deficient memory performance compared to a healthy control group. METHODS: WLT data were pooled from four experimental MDMA studies that compared memory performance during placebo and MDMA intoxication. Control data were taken from healthy volunteers with no drug use history who completed the WLT as part of a placebo-controlled clinical trial. This resulted in a sample size of 65 E-users and 65 age- and gender-matched healthy drug-naïve controls. All participants were recruited by similar means and were tested at the same testing facilities using identical standard operating procedures. Data were analyzed using linear mixed-effects models, Bayes factor, and logistic regressions. RESULTS: Findings were that verbal memory performance of placebo-treated E-users did not differ from that of controls, and there was substantial evidence in favor of the null hypothesis. History of use was not predictive of memory impairment. During MDMA intoxication of E-users, verbal memory was impaired. CONCLUSION: The combination of the acute and long-term findings demonstrates that, while clinically relevant memory impairment is present during intoxication, it is absent during abstinence. This suggests that use of Ecstasy/MDMA does not lead to clinically deficient memory performance in the long term. Additionally, it has to be investigated whether the current findings apply to more complex cognitive measures in diverse 'user categories' using a combination of genetics, imaging techniques and neuropsychological assessments.

Biperiden selectively induces memory impairment in healthy volunteers: no interaction with citalopram.

RATIONALE: Traditionally, the non-selective muscarinic antagonist scopolamine has been used to induce episodic memory impairments as found in Alzheimer's disease (AD). However, it also impairs attention and induces drowsiness. Muscarinic antagonists more selective for the M1 receptor might, therefore, be preferred. OBJECTIVES: We examined the effects of the M1 antagonist biperiden on cognitive functions in order to test the specificity of this drug on memory performance. Additionally, we assessed whether the selective serotonin re-uptake inhibitor citalopram can reverse a possible biperiden-induced impairment. METHODS: The study was conducted according to a double-blind, placebo-controlled, four-way cross-over design. Sixteen volunteers received biperiden (2 mg), citalopram (20 mg), a combination of the two, or a placebo in counterbalanced order with a washout of at least 4 days. Cognitive tests (verbal memory, continuous recognition memory, spatial memory, choice reaction) were performed 4 and 1 h after treatment with citalopram and biperiden, respectively. RESULTS: Biperiden impaired memory performance in the verbal learning task, the continuous recognition memory test, and the spatial memory task. Effects on attention and side effects, as measured using the choice reaction time test and questionnaires respectively, could be neglected. Citalopram did not affect any of the memory or attention measures taken. Most importantly, citalopram was also unable to reverse the biperiden-induced memory impairments. CONCLUSIONS: Our results, thus, show that the M1 antagonist biperiden may serve as a translational model to induce episodic memory deficits as seen in AD. However, the interactive influence of acetylcholine and serotonin on memory could not be confirmed.