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Mnemonic and Behavioral Effects of Biperiden, an M1-Selective Antagonist, in the Rat

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Mnemonic and Behavioral Effects of Biperiden, an M1-Selective Antagonist, in the Rat Psychopharmacology https://doi.org/10.1007/s00213-018-4899-3 ORIGINAL INVESTIGATION Mnemonic and behavioral effects of biperiden, an M1-selective antagonist, in the rat Anna Popelíková1 & Štěpán Bahník2 & Veronika Lobellová1 & Jan Svoboda1 & Aleš Stuchlík1 Received: 6 October 2017 /Accepted: 9 April 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Rationale There is a persistent pressing need for valid animal models of cognitive and mnemonic disruptions (such as seen in Alzheimer’s disease and other dementias) usable for preclinical research. Objectives We have set out to test the validity of administration of biperiden, an M1-acetylcholine receptor antagonist with central selectivity, as a potential tool for generating a fast screening model of cognitive impairment, in outbred Wistar rats. Methods We used several variants of the Morris water maze task: (1) reversal learning, to assess cognitive flexibility, with probe trials testing memory retention; (2) delayed matching to position (DMP), to evaluate working memory; and (3) Bcounter-balanced acquisition,^ to test for possible anomalies in acquisition learning. We also included a visible platform paradigm to reveal possible sensorimotor and motivational deficits. Results A significant effect of biperiden on memory acquisition and retention was found in the counter-balanced acquisition and probe trials of the counter-balanced acquisition and reversal tasks. Strikingly, a less pronounced deficit was observed in the DMP. No effects were revealed in the reversal learning task. Conclusions Based on our results, we do not recommend biperiden as a reliable tool for modeling cognitive impairment. Keywords Anticholinergics . Muscarinic receptors . Learning . Memory . Morris water maze . Rat Abbreviations DMSO Dimethyl-sulfoxide Ach Acetylcholine GABA Gamma-amino-butyric acid AChR Acetylcholine receptors GPCRs G-Protein coupled receptors AD Alzheimer’sdisease i.p. Intraperitoneally BBB Blood-brain barrier ITI Inter-trial interval BIP Biperiden mAChR Muscarinic acetylcholine receptors C Control group MWM Morris water maze CA Counter-balanced acquisition NSP Non-spatial pretraining cAMP Cyclic adenosine monophosphate s.c. Subcutaneously CNS Central nervous system SCOP Scopolamine DMP Delayed matching to position VP Visible platform Introduction * Jan Svoboda [email protected] The rapid rise of incidence of neurodegenerative diseases in * Aleš Stuchlík [email protected]; http://memory.biomed.cas.cz the aging population with no effective therapy available to date presses the need for the development of better animal 1 Institute of Physiology of the Czech Academy of Sciences, Videnska models to be used in preclinical research. Here, we investigat- 1083, 142 20 Prague 4, Czech Republic ed the capacity of biperiden, an M1 selective antimuscarinic 2 The Prague College of Psychosocial Studies, Hekrova 805, 149 compound used in treatment of Parkinson’s disease, to impair 00 Prague, Czech Republic memory performance. This drug has been proposed as a Psychopharmacology potentially superior alternative to the non-selective scopol- 2005; Deiana et al. 2011), and many more. It comes as no amine in generating fast screening animal models of neurode- surprise that any abnormalities in function of the cholinergic generation and dementia in rodents (Klinkenberg and system and its components accompany a multitude of pathol- Blokland 2011). ogies such as Parkinson’s disease (Schliebs and Arendt 2011), Klinkenberg and Blokland (2011) published a study which Alzheimer’s disease (Jiang et al. 2014), schizophrenia, bipolar compared the effects of biperiden and scopolamine on various disorder (Carruthers et al. 2015;Pittarasetal.2016), and de- tasks using Skinner boxes, from operational conditioning to pression (Witkin et al. 2014). For these reasons, the choliner- attention tests, and delayed non-matching to sample. Thus, gic system has been extensively studied in the recent years; short-term memory as well as food motivation and sensorimo- however, many mechanisms of its functioning remain mostly tor responsiveness could be evaluated, while enabling the au- unclear. The main focus of this study, i.e., the target of the thors to measure any potential attention deficit. Having tested antimuscarinic biperiden, is the M1 receptor, which is consid- three different doses of both drugs, the authors found short- ered to be the most abundant subtype (50–60% of all mAChR) term memory disruption following biperiden treatment (at of muscarinic receptors in the brain. It plays an essential role doses of 1 and 3 mg/kg), whereas no significant changes in in many cognitive functions such as learning and memory and food motivation and attention were observed. Sensorimotor thus has become the target of research focusing on developing responding was affected only after the highest dose of therapeutics for neurodegenerative diseases (Foster et al. 10 mg/kg. In contrast, scopolamine-treatment was followed 2014; Jiang et al. 2014; Carruthers et al. 2015). It is generally by attention and sensorimotor deficits and lowered food mo- accepted that anticholinergics disrupt acquisition learning and tivation at both middle and high doses (0.3 and 1 mg/kg). long-term memory processing. As such, antimuscarinic com- Short-term memory was also affected; however, the authors pounds are often employed for inducing memory and cogni- argue the impairment may have been in a larger part of non- tive impairments in laboratory animals in order to simulate mnemonic nature. Thus, the authors conclude by pathological states observed in human diseases such as recommending biperiden for future studies (Klinkenberg and Alzheimer’s disease and other dementias (Robinson et al. Blokland 2011). In 2015, Blokland’s group published another 2011). Detailed information regarding effect of antimuscarinic study assessing the effects of biperiden in human volunteers agents on various kinds of memory can be found in recent and validating biperiden as a translational modeling tool for reviews (Deiana et al. 2011; Svoboda et al. 2017). research of cognition (Sambeth et al. 2015). Biperiden hydrochloride (or lactate) is a proven M1- In contrast, the study of Szczodry et al. (2014)reacheda receptor selective antagonist. Approved for human usage virtually opposite verdict: a cone-field test revealed no signif- and sold under the brand name of Akineton, it is prescribed icant differences between rats treated with biperiden (at both 3 for Parkinsonism (to improve motor abilities such as gait and and 10 mg/kg doses) versus controls, suggesting little or no tremor) and occasionally to suppress the side effects of neu- influence on either working or reference memory. roleptics (AHFS DI Essentials 2017). Due to its selectivity, it Furthermore, side effects were observed following the higher has been proposed as a potential tool for modeling cognitive dose in the form of increased latency to start the task and lower impairment in rodents without sensorimotor side effects, spe- number of food rewards collected, which might indicate pos- cifically as a replacement for scopolamine, the so-called gold- sible xerostomia. Hence, in conclusion, the authors do not en standard in research of cognitive impairment whose valid- support the validity of this model for research of neurodegen- ity as a model has often been questioned on the grounds of its erative diseases (Szczodry et al. 2014). Similarly, Talpos et al. considerable side effects. (2014) found no effect of either scopolamine or biperiden on Scopolamine lacks selectivity for any of the subtypes of performance in a touch screen-based paired-associates learn- muscarinic receptors; apart from memory and cognition, it ing which essentially evaluates spatial working memory. also affects sensorimotor, motivational, attentional, and other Acetylcholine (ACh) counts among one of the major neu- functions of the treated subjects, thus sometimes compromis- rotransmitters and modulators in the nervous system; its re- ing the results of the behavioral tests (Klinkenberg and ceptors are abundantly expressed in a wide variety of tissues, Blokland 2011). On the other hand, Robinson et al. (2004) from neuromuscular junctions and parasympathetic system to reported an impaired performance in the Morris water maze cortical regions involved in cognitive functions such as learn- (MWM) in both rats and mice following scopolamine admin- ing and memory (VanPatten and Al-Abed 2017). The cholin- istration at a dose that exhibited no effect on visual acuity ergic system has been shown to play an important role in (Robinson et al. 2004). Furthermore, Von Linstow Roloff processes such as circadian rhythmicity (Hut and Van der et al. (2007) reported in their study that poor performance Zee 2011), addiction (Leslie et al. 2013), motivation, pain, observed in scopolamine-treated rats in a delayed matching and reward (VanPatten and Al-Abed 2017), as well as cogni- to place task in the MWM is in main part of the result of tive flexibility (Prado et al. 2017), perceptual memory memory impairment, not due to compromised sensorimotor (Robinson et al. 2011), spatial learning (Vales and Stuchlik abilities (von Linstow Roloff et al. 2007). Scopolamine- Psychopharmacology induced cognitive impairment was also shown to possess DMSO per 1 mg BIP) and then sterile saline (NaCl 0.9%) was good validity as a translational model in research by our recent added to reach the final concentration of 3 mg/ml. The solu- study (Laczó et al.
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