The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

Lieben, C.K.J.; Blokland, Arjan; Şık, Ayhan; Sung, Eric; Nieuwenhuizen, Petra van; Schreiber, Rudy

doi:10.1038/sj.npp.1300777

Cited by 135 publications

(68 citation statements)

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“…More recent studies with the currently prescribed AD drugs rivastigmine, donepezil, and galantamine have reported similar scopolamine-reversal properties in the rat (Bejar et al 1999;Takahata et al 2005;van der Staay and Bouger 2005;de Bruin and Pouzet 2006;Lindner et al 2006). However, cholinomimetic drugs are not the only pharmacological class to reverse scopolamine-induced memory deficits (Misane and Ogren 2003;Van Kampen et al 2004;Lieben et al 2005) attesting perhaps to the greater than expected versatility of the model.…”

Section: Introductionmentioning

confidence: 99%

The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates

et al. 2007

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Rationale The scopolamine-reversal model is enjoying a resurgence of interest in clinical studies as a reversible pharmacological model for Alzheimer's disease (AD). The cognitive impairment associated with scopolamine is similar to that in AD. The scopolamine model is not simply a cholinergic model, as it can be reversed by drugs that are noncholinergic cognition-enhancing agents. Objectives The objective of the study was to determine relevance of computer-assisted operant-conditioning tasks in the scopolamine-reversal model in rats and monkeys. Materials and methods Rats were evaluated for their acquisition of a spatial reference memory task in the Morris water maze. A separate cohort was proficient in performance of an automated delayed stimulus discrimination task (DSDT). Rhesus monkeys were proficient in the performance of an automated delayed matching-to-sample task (DMTS). Results The AD drug donepezil was evaluated for its ability to reverse the decrements in accuracy induced by scopolamine administration in all three tasks. In the DSDT and DMTS tasks, the effects of donepezil were delay (retention interval)-dependent, affecting primarily short delay trials. Donepezil produced significant but partial reversals of the scopolamine-induced impairment in task accuracies after 2 mg/kg in the water maze, after 1 mg/kg in the DSDT, and after 50 μg/kg in the DMTS task. Conclusions The two operant-conditioning tasks (DSDT and DMTS) provided data most in keeping with those reported in clinical studies with these drugs. The model applied to nonhuman primates provides an excellent transitional model for new cognition-enhancing drugs before clinical trials.

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Section: Introductionmentioning

confidence: 99%

The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates

et al. 2007

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“…impairments, which typically use 100 μg/kg to 3 mg/kg doses of scopolamine (31)(32)(33). Second, the antidepressant-like effects were observed 24 hours after the final 25 μg/kg dose of scopolamine, at a time when the drug had largely been cleared.…”

Section: Figure 6 M1-achr Mediates Cholinergic Stimulation Of Sst Inmentioning

confidence: 99%

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

Wohleb¹,

Wu²,

Gerhard³

et al. 2016

Journal of Clinical Investigation

129

112

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R e s e a R c h a R t i c l e2 4 8 2 jci.org Volume 126 Number 7 July 2016 IntroductionMajor depressive disorder (MDD) is a recurring neuropsychiatric illness that affects up to 17% of the population and causes substantial social and economic burdens (1-4). While some patients respond to existing medications, currently available antidepressants take weeks to months to have an effect, and many patients are considered treatment resistant because they fail to respond to 2 or more antidepressants (5). Recent studies demonstrate that scopolamine, a nonselective muscarinic acetylcholine (ACh) receptor (mAChR) antagonist, and ketamine, an NMDA receptor antagonist, produce rapid antidepressant actions (within hours) and are effective even in treatment-resistant MDD patients (6-8). The rapid antidepressant actions of scopolamine and ketamine are dependent on glutamate release and induction of new spine synapses in the medial prefrontal cortex (mPFC) (9-11), effects that directly target the synaptic pathophysiology of MDD and chronic stress (12-19). However, a major question in the field is, what are the initial cellular targets that mediate the increase in glutamate transmission, leading to increased synapse formation and rapid antidepressant behavior (10, 20, 21)? One hypothesis is that scopolamine blocks muscarinic receptors on GABAergic interneurons, resulting in disinhibition of pyramidal neurons and increased glutamate transmission. Alternatively, scopolamine may act directly on pyramidal neurons to enhance synaptic plasticity and produce antidepressant behavioral responses. Recent studies suggest that the M1-type muscarinic ACh receptor (M1-AChR) subtype may mediate the antidepressant actions of scopolamine (9, 22, 23).M1-AChRs are expressed on both GABAergic interneurons and glutamatergic pyramidal neurons in the mPFC and regulate the activity of both cell types (24)(25)(26).In the present study, we used transgenic mice and viralmediated gene transfer to drive Cre-dependent expression of M1-AChR shRNA in different subtypes of GABA interneurons or glutamate neurons in the mPFC. The results demonstrate that M1-AChR knockdown in GABA interneurons, but not pyramidal neurons, blocks the antidepressant-like response to scopolamine in mouse behavioral models. In addition, we show that knockdown of M1-AChR in somatostatin (SST), but not parvalbumin (PV), interneurons, blocks the actions of scopolamine. These findings reveal that M1-AChRs on SST interneurons in the mPFC are a critical cellular target underlying the rapid antidepressant effects of scopolamine. Results CaMKII+ and GAD + cell type-specific knockdown of M1-AChR in the mPFC. To determine whether glutamatergic pyramidal neurons and GABAergic interneurons in the mPFC express M1-AChR, double immunohistology was conducted with an M1-AChR antibody and Ca 2+ /calmodulin-dependent kinase II (CaMKII; pyramidal cell) or glutamate decarboxylase-67 (GAD67; GABA interneuron) (25). The results show that CaMKII + pyramidal neurons display punctate M1-AChR labeling in the mPF...

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“…In the object discrimination task, Ro 04-6790 and SB-271046 increased the acquisition and consolidation of recognition memory in adult rats King et al, 2004), whereas BGC20-761, another 5-HT6R antagonist improved the consolidation of recognition memory in mature rats (Mitchell et al, 2006). Furthermore, Ro 04-6790, SB-271046, Ro4368554, and SB-399885 were all found to reverse the scopolamine-induced deficits in both the long-term memory passive avoidance task (Foley et al, 2004), the novel object discrimination task (recognition memory) (Lieben et al, 2005;Woolley et al, 2003) and the autoshaping learning task (Perez-Garcia and Meneses, 2005) in adult rats. Moreover, reversal of the delay-dependent deficits exerted by Ro 04-6790 and SB-271046 in the rat novel object discrimination task has been shown to be blocked by the NMDA receptor antagonist MK-801 (King et al, 2004).…”

Section: Introductionmentioning

confidence: 97%

“…The mechanisms by which 5-HT6R antagonists can counteract age-related deficits in memory processes are yet unknown. One can however hypothesize a withdrawal of the inhibition exerted by serotonin onto the cholinergic system, notably in the 5-HT6R blockade improves memory V Da Silva Costa et al hippocampus (Foley et al, 2004;Lieben et al, 2005;PerezGarcia and Meneses, 2005;Riemer et al, 2003;ShiraziSouthall et al, 2002)Fthis latter being largely altered during aging (Buhot et al, 2000;Decker and McGaugh, 1991;McEntee and Crook, 1992)Fand/or an interaction with the hippocampal glutamatergic system, leading to an increase in synaptic plasticity (eg long-term potentiation; Bliss and Collingridge, 1993;Dawson et al, 2000Dawson et al, , 2001Foster, 1999;Lynch et al, 2006;Morris, 2006), which is altered during aging (see for review Lynch et al, 2006). Other concepts have been recently proposed (see Perez-Garcia and Meneses, 2008).…”

Section: -Ht6r Blockade Improves Memory V Da Silva Costa Et Almentioning

confidence: 99%

Selective 5-HT6 Receptor Blockade Improves Spatial Recognition Memory and Reverses Age-Related Deficits in Spatial Recognition Memory in the Mouse

Costa

Duchatelle²,

Boulouard³

et al. 2008

Neuropsychopharmacol

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Studies have recently suggested that blockade of 5-HT6 receptors (5-HT6R) improves memory processes. As episodic memory alteration is one of the first deficits observed during normal aging and in neurological and neuropsychiatric disorders (Alzheimer's disease, schizophrenia), the present study sought to characterize the effects of 5-HT6R blockade on spatial recognition memory, which can be considered as 'episodic-like' memory, in rodents. We quantified the effects of the selective 5-HT6R antagonist SB-271046 (10 mg/kg, i.p.), using the two-trial place recognition task in the Y-maze, on acquisition, consolidation, and retrieval of spatial recognition memory in young adult mice (6-week-old; intertrial intervals (ITIs) 30, 60, 120, 240, and 360 min) and on the consolidation of spatial recognition memory in aged mice (3-, 12-, 18-, and 21-month-old; ITI 60 and 240 min). SB-271046-treated young adult mice explored the new arm more after a 240-min (pre-acquisition) and 360-min (post-acquisition) ITI, whereas vehicle-treated animals failed to discriminate the new arm when the ITI exceeded 120 min (pre-acquisition) or 240 min (post-acquisition). Aged mice, which expressed spatial memory deficits, explored the new arm more after a 60-min ITI (21-month-old) and a 240-min ITI (18-and 21-month-old) when treated with SB-271046. Consequently, 5-HT6R blockade improves spatial recognition memory in adult mice and reverses age-related consolidation deficits of episodic-like memory. This study provides further support for the use of 5-HT6R antagonists in the treatment of episodic memory disorders related to aging as well as neurological disorders such as Alzheimer's disease and schizophrenia.

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The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

Cited by 135 publications

References 67 publications

The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates

The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

Selective 5-HT6 Receptor Blockade Improves Spatial Recognition Memory and Reverses Age-Related Deficits in Spatial Recognition Memory in the Mouse

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