Reversal of a vigilance decrement in the aged rat by subtype-selective nicotinic ligands.
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 alpha(4)beta(2) and alpha(7) receptor sites, respectively. We then attempted to block this effect of nicotine using the high affinity, competitive nicotinic antagonist DHbetaE (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 DHbetaE 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 alpha(4)beta(2) nicotinic receptor in mediating the attention-enhancing properties of nicotine.
Grottick
Andrew J
AJ
PRBN-B, F Hoffmann-La Roche AG, Basel, Switzerland. agrottick@arenapharm.com
Haman
Marie
M
Wyler
Rene
R
Higgins
Guy A
GA
D000375:Aging / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001143:Arousal / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000031:analogs & derivatives / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000502:physiology*
D018733:Nicotinic Antagonists; D011725:Pyridines; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine; C100989:altinicline maleate