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Rational: Inhibition of renin-angiotensin system (RAS) improves cognitive functions in hypertensive patients. However, role of AT1 and AT2 receptors in memory impairment due to cholinergic hypofunction is unexplored., Objective: This study investigated the role of AT1 and AT2 receptors in cerebral blood flow (CBF), cholinergic neurotransmission, and cerebral energy metabolism in scopolamine-induced amnesic mice., Methods: Scopolamine was given to male Swiss albino mice to induce memory impairment tested in passive avoidance and Morris water maze tests after a week long administration of blocker of AT1 receptor, candesartan, and AT2 receptor, PD123, 319. CBF was measured by laser Doppler flowmetry. Biochemical and molecular studies were done in cortex and hippocampus of mice brain., Results: Scopolamine caused memory impairment, reduced CBF, acetylcholine (ACh) level, elevated acetylcholinesterase (AChE) activity, and malondialdehyde (MDA). Administration of vehicle had no significant effect on any parameter in comparison to control. Candesartan prevented scopolamine-induced amnesia, restored CBF and ACh level, and decreased AChE activity and MDA level. In contrast, PD123, 319 was not effective. However, the effect of AT1 receptor blocker on memory, CBF, ACh level, and oxidative stress was blunted by concomitant blockade of AT2 receptor. Angiotensin-converting enzyme (ACE) activity, ATP level, and mRNA expression of AT1, AT2, and ACE remained unaltered., Conclusion: The study suggests that activation of AT1 receptors appears to be involved in the scopolamine-induced amnesia and that AT2 receptors contribute to the beneficial effects of candesartan. Theses finding corroborated the number of clinical studies that RAS inhibition in hypertensive patients could be neuroprotective.

Rationale: Drug development is a high-risk and high failure enterprise, and studies that provide an early read on the pharmacodynamic activity of novel compounds could save time and money, increasing the efficiency of the drug development process., Objective: Preclinical and clinical experiments were designed to examine the utility of the scopolamine-induced cognitive impairment model in predicting pharmacodynamic signals of putatively procognitive compounds, utilizing the acetylcholinesterase inhibitor donepezil for illustration., Methods/results: In normal healthy rats, scopolamine (0.3 mg/kg) significantly impaired performance on the two-platform water maze and on the T-maze. The deficits in water maze performance were reversed by donepezil at 0.5 and 1.0 mg/kg. There was a trend towards reversal of scopolamine-induced deficits in performance on the T-maze with 1.0 mg/kg donepezil. In normal healthy humans, scopolamine (0.3 and 0.5 mg) reliably impaired performance on the Cognitive Drug Research test battery composite scores (power of attention, continuity of attention, quality of working memory, quality of episodic secondary memory, and speed of memory) in a dose- and time-dependent manner. Donepezil (10 mg) significantly attenuated the scopolamine-induced impairment in cognition on power of attention, continuity of attention, quality of working memory, and speed of memory., Conclusions: These findings suggest that reversal of scopolamine-induced cognitive impairment is a viable model for predicting pharmacodynamic signals of procognitive compounds in both animals and humans. The utility of the scopolamine-induced cognitive impairment model is discussed and illustrated at various decision points in drug development, with a focus on Go/No Go decisions.

Rationale: The nonselective muscarinic antagonist scopolamine hydrobromide (SCOP) is employed as the gold standard for inducing memory impairments in healthy humans and animals. However, its use remains controversial due to the wide spectrum of behavioral effects of this drug., Objective: The present study investigated whether biperiden (BIP), a muscarinic m1 receptor antagonist, is to be preferred over SCOP as a pharmacological model for cholinergic memory deficits in rats. This was done by comparing the effects of SCOP and BIP using a battery of operant tasks: fixed ratio (FR5) and progressive ratio (PR10) schedules of reinforcement, an attention paradigm and delayed nonmatching to position task., Results: SCOP induced diffuse behavioral disruption, which included sensorimotor responding (FR5, 0.3 and 1 mg/kg), food motivation (PR10, 1 mg/kg), attention (0.3 mg/kg, independent of stimulus duration), and short-term memory (delayed nonmatching to position (DNMTP), 0.1 and 0.3 mg/kg, delay-dependent but also impairment at the zero second delay). BIP induced relatively more selective deficits, as it slowed sensorimotor responding (FR5, 10 mg/kg) and disrupted short-term memory (DNMTP, 3 mg/kg, delay-dependent but no impairment at the zero second delay). BIP had no effect on food motivation (PR10) or attention., Conclusion: Muscarinic m1 antagonists should be considered an interesting alternative for SCOP as a pharmacological model for cholinergic mnemonic deficits in animals.

Rationale: Orexins play a key role in the maintenance of alertness and are implicated in the modulation of diverse physiological processes, including cognitive function. Almorexant, a dual orexin receptor antagonist, transiently and reversibly blocks the action of orexin peptides at both OX(1) and OX(2) receptors and increases time spent in rapid eye movement (REM) and non-REM sleep., Objectives: We explored the direct effects on learning and memory of single and repeated administration of almorexant in rats., Methods: Following administration of high doses of almorexant (300 mg/kg, p.o.), scopolamine (0.8 mg/kg, i.p.), combination almorexant-scopolamine, or vehicle alone, rats were trained on a Morris water maze spatial navigation task, or on a passive avoidance task., Results: Rats treated with almorexant learned the spatial navigation task with similar efficacy as vehicle-treated animals. After 4 days, almorexant-but not vehicle-treated rats had established spatial memory; after 8 days, spatial memory had been established in both vehicle-and almorexant-treated rats. Scopolamine-treated rats failed to learn the spatial task. Both vehicle-and almorexant-but not scopolamine-treated rats demonstrated passive avoidance learning. Almorexant did not ameliorate scopolamine-induced impairment of learning in either task., Conclusions: Rats treated with almorexant are fully capable of spatial and avoidance learning.

Rationale: Dimethylaminoethanol pyroglutamate (DMAE p-Glu) is a compound resulting from the reaction between dimethylaminoethanol (an indirect precursor of acetylcholine) and pyroglutamic acid (a cyclic derivative of glutamic acid having procholinergic properties and promnesic effects in both animals and man)., Objectives: The present study undertook preclinical and clinical evaluations to test a potential therapeutic utility for DMAE p-Glu in cognitive impairments related to central cholinergic deficit., Materials and Methods: In preclinical study, DMAE p-Glu was studied in rats by intracerebral microdialysis in conscious freely moving animals, on performance of rats in the Morris water maze test of spatial memory, and on the deficit in passive avoidance behavior induced by scopolamine. The clinical study examined the effect of DMAE p-Glu on cognitive deficits induced by an intravenous injection of scopolamine in healthy young male subjects., Results: In rat experiments, DMAE p-Glu increased the extracellular levels of choline and acetylcholine in the medial prefrontal cortex, as assessed by intracerebral microdialysis, improved performance in a test of spatial memory, and reduced scopolamine-induced memory deficit in passive avoidance behavior. Clinical study results show that scopolamine induced a memory deficit and that DMAE p-Glu produced a significant positive effect on scores in the Buschke test, as well as a slight but significant difference on choice reaction time., Conclusion: These results indicate that DMAE p-Glu reduces the deleterious effect of scopolamine on long-term memory in healthy volunteers and suggest that DMAE p-Glu might be effective in reducing memory deficits in patients with cognitive impairment.

Rationale: Although much research has focused on the effects of ovarian hormones on learning and memory in females, less information is available regarding the effects of testicular hormones on learning and memory in males. Additionally, despite evidence of an interaction of testicular hormones and the cholinergic system in areas of the brain implicated in learning and memory, no information is available regarding the behavioral consequences of that interaction., Objectives: We assessed the effect of castration in male rats on working memory during acquisition of a radial maze. We also assessed the interactive effects of castration and scopolamine, a muscarinic receptor antagonist, as well as mecamylamine, a nicotinic receptor antagonist, on behavior., Methods: Young adult male rats were castrated or underwent sham surgeries. Beginning 10 days after surgeries, performance on a task of working memory was assessed across 24 days of acquisition in an eight-arm radial maze. Following acquisition, scopolamine and mecamylamine dose-effect curves were established., Results: Castration of male rats significantly decreased arm-choice accuracy during acquisition. Castration significantly exacerbated impairments in arm-choice accuracy produced by scopolamine as well as mecamylamine, without altering the disruptive effects of the drugs on the rate at which rats entered the arms of the maze., Conclusions: These results indicate that castration in male rats impairs working memory during acquisition of a spatial maze task. Additionally, these results suggest that the absence of testicular hormones increases the sensitivity of male rats to the impairing effects of scopolamine as well as mecamylamine on working memory.

Rationale: Cholinergic receptor blockade produces memory deficits in animal models. These deficits can be prevented by 5-HT3 receptor antagonists, such as ondansetron, which increases acetylcholine release. We investigated the effects on cognitive performance of combined treatments of ondansetron with either flumazenil, a GABA(A) receptor benzodiazepine site antagonist, or tacrine, a cholinesterase inhibitor, which are also able to prevent scopolamine-induced cognitive impairment., Methods: Spatial learning and memory was assessed by studying the effects of single and combined treatments on acquisition and retention of the Morris water maze task in rats., Results: Scopolamine (0.6 mg/kg) induced significant learning and retention deficits. Both ondansetron (0.1 microg/kg) and tacrine (3 mg/kg) partially prevented the scopolamine-induced learning deficit. A full reversal was only found after the combined treatment of ondansetron with flumazenil (10 mg/kg) and also after tacrine in combination with ondansetron. Likewise, scopolamine-induced retention deficit was fully counteracted by the combined treatment of ondansetron with either flumazenil or tacrine, and only partially by any of the single treatments tested., Conclusions: The scopolamine-induced impairment of learning and retention in the water maze is fully prevented by ondansetron when given in combination with either flumazenil or tacrine, suggesting that both combined treatments result in a potentiated cholinergic function and may constitute the basis of a new therapy for cognitive disorders.