Differential effects of ciproxifan and nicotine on impulsivity and attention measures in the 5-choice serial reaction time test

Abstract

Deficits in attention and response inhibition are apparent across several neurodegenerative and neuropsychiatric disorders for which current pharmacotherapy is inadequate. While it is difficult to model such executive processes in animals, the 5-choice serial reaction time test (5-CSRTT), which originated from the continuous performance test (CPT) in humans, may serve as a useful translational assay for efficacy in these key behavioral domains. At Wyeth and Abbott, we recently investigated the utility of employing the 5-CSRTT in adult rats. This involved training and testing groups of rats over an extended period of several months and required the animals to learn to nose-poke into one of five apertures following presentation of a brief visual stimulus in that aperture in order to obtain a food reward. When the stimulus duration was short, the rat had to pay close attention to make a correct choice--a nose-poke into the aperture with the brief visual stimulus. We evaluated nicotine and the histamine H(3) receptor antagonist, ciproxifan, since compounds targeting both nicotinic and histaminergic neurotransmission are currently under investigation for treating cognitive dysfunction in ADHD, AD and schizophrenia. After approximately 12 weeks of training, rats were tested with drug when they had achieved stable performance. Nicotine (0.2, 0.4 mg/kg s.c.) significantly improved accuracy and reduced errors of omission (reflecting improved attention and vigilance) when baseline performance was <90% correct. In contrast, nicotine tended to worsen accuracy when baseline performance was >90% correct. Using the same test paradigm, ciproxifan (3mg/kg i.p.) reduced premature responding, a measure of impulsivity. Under conditions of variable stimulus duration, ciproxifan also improved accuracy and decreased impulsivity. In summary, we have replicated previous findings by others of positive effects of nicotine on attention, but also showed that this is dependent on baseline performance. We also expanded on previous positive findings by others with ciproxifan on attention and both Wyeth and Abbott demonstrate for the first time decreased impulsivity with this mechanism.