Reversal of a Vigilance Decrement in the Aged Rat by Subtype-Selective Nicotinic Ligands

Abstract

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.

Nicotine Improves Sustained Attention in Mice: Evidence for Involvement of the α7 Nicotinic Acetylcholine Receptor

“…The doses of nicotine that improved attention in mice in the present studies are consistent with those reported to improve attention in normal humans Heishman and Henningfield, 2000;Min et al, 2001). In contrast, studies in rats have generally required higher doses of nicotine and the inclusion of lesions or task challenges (Muir et al, 1995;Mirza and Stolerman, 1998;Stolerman et al, 2000;Hahn et al, 2002Hahn et al, , 2003aGrottick et al, 2003). In addition, whereas nicotine reduced omission levels in ostensibly normal mice in the current study, and previously in normal human subjects , in rats, the most consistent manifestation of an improvement in attention was an increase in accuracy (Mirza and Stolerman, 1998;Hahn et al, 2002).…”

“…The 5-CSR task was developed to examine sustained attention in rodents (Carli et al, 1983) and is regarded as being analogous to the CPT (Jones and Higgins, 1995). This task has been used extensively with rats, with nicotine generally showing an improvement in attention, but only when lesions or specific task challenges have been introduced to impair performance (Mirza and Stolerman, 1998;Grottick and Higgins, 2000;Stolerman et al, 2000;Mirza and Bright, 2001;Hahn et al, 2002Hahn et al, , 2003aGrottick et al, 2003). A consistent demonstration of a nicotine-induced facilitation of attention in unimpaired rats, unlike observations in humans , has proven challenging (Mirza and Bright, 2001;Terry et al, 2002).…”

“…Furthermore, both DMXBA (Kem, 2000), and the full a7 nAChR agonist AR-R17779 (Mullen et al, 2000), are able to replicate the beneficial effects observed with nicotine on working memory (Felix and Levin, 1997;Levin and Simon, 1998). In contrast, and perhaps somewhat surprisingly, recent studies in rats showed that AR-R17779 had no effect on attention in the 5-CSR task (Grottick and Higgins, 2000;Grottick et al, 2003;Hahn et al, 2003a). To date, independent evaluation of these agents is not possible as these compounds are not commercially available.…”

“…In rodent brains, the two most predominant nAChRs appear to be the heteromeric a4b2 nAChR, and the homomeric a7 nAChR, accounting for 85 and 10% of neuronal nAChRs respectively (Clarke et al, 1985). In rats, the roles that these receptors play in sustained attention is examined using the 5-choice serial reaction-time (5-CSR) task (Mirza and Stolerman, 1998;Grottick and Higgins, 2000;Stolerman et al, 2000;Mirza and Bright, 2001;Hahn et al, 2002Hahn et al, , 2003aTerry et al, 2002;Grottick et al, 2003). While nicotine-induced improvements in sustained attention have been reported in the rat literature, these studies have generally required the additional complexities afforded by brain lesions, poorly performing subjects, or task challenges (Muir et al, 1995;Grottick and Higgins, 2000;Hahn et al, 2002).…”

Vigilance, alertness, or sustained attention: physiological basis and measurement

“…There is some conflicting data on whether there is a significant cholinergic effect on sustained attention (Dalley et al, 2004;Gill et al, 2000;Grottick et al, 2003). The cholinergic system has a direct impact on EEG, with cholinergic activity in cortex being related to wakefulness and desynchronization of the EEG (Celesia and Jasper, 1966;Vanderwolf and Robinson, 1981).…”