Procognitive profiling of a serotonin 5-HT6 receptor antagonist in a complex model system in rats: A novel translational approach for clinical prediction

• Published in: Brain research bulletin 2020-12, Vol.165, p.238-245
• Main Authors: Gyertyán, István, Kassai, Ferenc, Kozma, Kata, Kitka, Tamás, Ernyey, Aliz Judit
• Format: Article
• Language: English
• Subjects: Clinical trial-like design; Cognitive enhancer; Increased task difficulty; Pattern-based target validation; RO4368554
• ISSN: 0361-9230; 1873-2747
• DOI: 10.1016/j.brainresbull.2020.10.014

•A novel approach for validating cognitive enhancer targets in rodents is described.•Rats with a ‘widespread knowledge’ (long and diverse learning history) were used.•Their performance was impaired by increasing task difficulty (‘patient population’).•Procognitive action of a 5-HT6 antagonist was tested in a clinical trial-like design.•Its activity pattern highlighted social cognition as the most sensitive domain. The serial clinical failures of novel cognitive enhancer candidates point out the lack of predictive power in the preceding animal experimentation. For a more predictive profiling of putative procognitive drugs in rodents, we recently elaborated a methodical approach which consists of three fundamental steps: 1. teaching various learning tasks representing different cognitive domains to the same cohort of animals with the aim to create a population with ‘widespread knowledge’. 2. Applying a cognitive deficit-inducing intervention to transform this cohort of animals to a ‘patient population’. 3. Testing putative procognitive drugs with a ‘clinical trial-like’ design on the wide spectrum of cognitive (dys)functions in the actual ‘patient population’. The present study has been the first trial to test the feasibility and utility of the proposed system. The population with ‘widespread knowledge’ consisted of 2 year old male Long-Evans rats with a learning history in five-choice serial reaction time task (5-CSRTT, attentional paradigm), Morris water maze (MWM, spatial learning), a cooperative task carried out in pairs (social learning), and a skill-learning task, „pot-jumping”. For inducing cognitive deficit, thus creating a ‘patient population’ we increased the difficulty of the tasks. For the cognitive enhancer mechanism to test in the system we chose a serotonin 5-HT6 receptor antagonist compound, RO4368554. Animals were randomly assigned to vehicle- and drug treated groups based on their baseline learning performance and their response in a pilot test of increase in task difficulty. During the 13-day long treatment with 3 mg/kg ip. RO4368554 all the learning paradigms were repeatedly run with increased difficulty supplemented with a novel object recognition test (NOR, episodic memory). In the 5-CSRTT, reducing the stimulus duration from 1 s to 0.25 s caused a significant decrease in the percentage of correct responses (from 52 % to 31 % in the control group) which was not affected by the 5-HT6 receptor antagonist treatment (correct responses decre