Effects of nornicotine enantiomers on intravenous S(-)-nicotine self-administration and cardiovascular function in rats.
BACKGROUND
Previous neurochemical evidence indicates that R(+)-nornicotine is more potent than S(-)-nornicotine in evoking dopamine release in rat nucleus accumbens slices.


OBJECTIVE
The current study tested the hypothesis that R(+)-nornicotine is also more potent than S(-)-nornicotine in selectively decreasing intravenous S(-)-nicotine self-administration in rats.


RESULTS
After acute pretreatment (1-10 mg/kg for each enantiomer), R(+)-nornicotine was more potent than S(-)-nornicotine in decreasing S(-)-nicotine self-administration; in contrast, within the same dose range, the nornicotine enantiomers were equipotent in decreasing sucrose-maintained responding. This enantioselectivity does not likely reflect a difference in bioavailability, since similar levels of nornicotine were recovered from the brain 60 min after injection (5.6 mg/kg for each enantiomer). With repeated pretreatment, tolerance did not develop to the rate-decreasing effect of either nornicotine enantiomer (3 or 5.6 mg/kg) with respect to the decrease in S(-)-nicotine self-administration, although the enantioselectivity dissipated across repeated pretreatments. While both enantiomers acutely produced a similar increase in blood pressure and heart rate, tolerance developed to the blood pressure effects of R(+)-nornicotine, but not to the effects of S(-)-nornicotine, across repeated treatments.


CONCLUSIONS
Both R(+)- and S(-)-nornicotine may have potential utility as a novel tobacco use cessation agent.
Stairs
D J
DJ
Department of Psychology, University of Kentucky, BBSRB, Room 253, Lexington, KY 40536-0509, USA.
Neugebauer
N M
NM
Wei
X
X
Boustany
C
C
Hojahmat
M
M
Cassis
L A
LA
Crooks
P A
PA
Dwoskin
L P
LP
Bardo
M T
MT
D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects / Q000502:physiology; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D007262:Infusions, Intravenous; D008297:Male; D009042:Motivation; D009538:Nicotine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D012646:Self Administration; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014029:Tobacco Use Disorder / Q000503:physiopathology*
D009538:Nicotine; C005311:nornicotine; D004298:Dopamine