In the present series of studies, we have investigated the effects of antagonists selective for the 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors on motor and 'impulsive'-type behaviours elicited by the non-competitive N-methyl- d-aspartate (NMDA) antagonist dizocilpine. The selective 5-HT(2A) receptor antagonist M100,907 (0.5 mg/kg) attenuated the hyperlocomotion and stereotypy produced by dizocilpine (0.1-0.3 mg/kg). The selective 5-HT(2B) receptor antagonist SB215,505 (3 mg/kg) and the selective 5-HT(2C) receptor antagonist SB242,084 (0.5 mg/kg) had no effect against either measure, except that SB242,084 produced a small potentiation of the hyperactivity response. Dizocilpine (0.03 mg/kg) increased premature responding in rats performing the 5-choice serial reaction time task (5-CSRTT), and increased response frequency consequently reducing the mean inter-response time (IRT) and efficiency of responding in a DRL24 task. M100,907 (0.5 mg/kg) attenuated each of these effects, as well as the increased premature responding produced by the NMDA NR2B selective antagonist Ro 63-1908 (1 mg/kg) in the 5-CSRTT. In contrast SB242,084 (0.5 mg/kg) did not attenuate the dizocilpine-induced premature responding or increased responding in the DRL24 task. Rather, SB242,084 (0.05-0.5 mg/kg) produced qualitatively similar effects to dizocilpine, increasing premature responding and reducing IRT. The results suggest that 5-HT(2A) receptor antagonists may normalise certain 'impulsive' behaviours produced by NMDA receptor hypofunction. The 5-HT(2C) receptor antagonist SB242,084 failed to exert equivalent effects, rather a trend toward exacerbation of the behavioural changes produced by dizocilpine was apparent.

In humans, nicotine has been demonstrated to improve both normal and disordered attention, suggesting potential clinical utility for nicotinic ligands. However, attempts to replicate these findings in the rodent have met with some difficulty, thus hampering the search for specific receptor mechanisms underlying these effects. In the present studies, we sought to characterize the effects of nicotine and subtype-selective ligands in a group of aged rats, which show consistent deficits in sustained attention over prolonged sessions of responding in the five-choice serial reaction time task (5-CSRTT). Following the establishment of a replicable performance improvement with nicotine (0.4 mg/kg), we assessed the effects of both SIB 1765F (1-5 mg/kg) and AR-R17779 (20 mg/kg), agonist ligands with selective affinities for the a 4 b 2 and a 7 receptor sites, respectively. We then attempted to block this effect of nicotine using the high affinity, competitive nicotinic antagonist DHbE (3 mg/kg). Finally, in an attempt to determine whether the psychostimulant profile of nicotinic agonists could be dissociated from their effects on attention, we compared the (R)-and (S)-enantiomers of SIB 1765F in the 5-CSRTT, and in their ability to increase locomotor activity. Reversal of a within-session decline in performance speed and accuracy by nicotine was mimicked by SIB 1765F, but not by AR-R17779, whereas DHbE antagonized all of the performance changes induced by nicotine. Finally, the (S)-but not the (R)-enantiomer increased locomotor activity and improved performance in the 5-CSRTT. These results support a critical involvement for the a 4 b 2 nicotinic receptor in mediating the attention-enhancing properties of nicotine.

The present studies support the view that selective NR2B NMDA antagonists promote impulsive-type responding in the 5-CSRTT; however, under certain test conditions, drugs of this class-notably traxoprodil-may also improve task performance.

The multi-site study confirmed that scPCP impaired NOR and ASST only and demonstrated the reproducibility and usefulness of the touchscreen approach. Our recommendation, prior to testing novel therapeutics in the scPCP model, is to be aware that further work is required to understand the neurochemical changes and specificity of the cognitive deficits.

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