NLX-101, a cortical 5-HT 1A receptor biased agonist, reverses scopolamine-induced deficit in the delayed non-matching to position model of cognition.

NLX-101 is a selective, high efficacy, biased agonist at post-synaptic cortical 5-HT _1A receptors. We have previously shown that it opposes deficits produced by blockade of NMDA receptors and has pro-cognitive activity of its own. Based on the strong interaction between 5-HT _1A receptors and the central cholinergic system, we tested NLX-101 on scopolamine-induced impairment of cognition in a delayed non-matching to position (DNMTP) model. The cholinesterase inhibitor, tacrine, was used as a comparator. In operant chambers with two retractable levers, male rats were trained to press one randomly presented lever during a "sample" phase. Following a time delay of either 1, 5 or 10 s, both levers were then presented, the rat being required to press the correct lever (i.e. the one not previously presented) to receive a food pellet reward. Scopolamine (0.16 mg/kg i.p.) significantly impaired accuracy (i.e. choice of correct lever) at 5 and 10 s delays. In contrast, NLX-101 (0.04, 0.16, 0.63 mg/kg i.p.) did not worsen accuracy, except at 0.63 mg/kg. Moreover, NLX-101 (0.04 and 0.16 mg/kg) dose-dependently and significantly opposed scopolamine-induced impairment for 5 and 10 s delays, with near-total reversal at 10 s. The acetylcholinesterase inhibitor, tacrine, also opposed scopolamine-induced impairment but was less potent and efficacious, with a single significant effect at 2.5 mg/kg and 5 s delay only. The present data suggest that biased agonism at post-synaptic, cortical 5-HT _1A receptors could prove useful in neurological or neuropsychiatric pathologies characterized by cognitive deficits consecutive to a reduced central cholinergic tone.
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