Nicotine responses in hypersensitive and knockout alpha 4 mice account for tolerance to both hypothermia and locomotor suppression in wild-type mice.
Nicotinic receptors containing the alpha 4 subunit (alpha 4* nAChRs) have high sensitivity and are widely expressed in the central nervous system, yet their contributions to behavioral tolerance, a hallmark of nicotine dependence, are unclear. To evaluate the contribution of alpha 4* and non-alpha 4 nAChRs in the development of tolerance to hypothermia and locomotor suppression, alpha 4 knockout (KO), hypersensitive Leu9'Ala alpha 4 knock-in, and wild-type (WT) mice received daily nicotine injections, and their behaviors were compared. Repeated selective activation of alpha 4* nAChRs in Leu9'Ala mice produced profound tolerance to hypothermia over 7 days, whereas no tolerance was observed in alpha 4 KO animals. The summed time course and temperature response (after appropriate normalizations) from these two mutant mouse strains resembled the time course of WT tolerance. In addition, daily selective activation of alpha 4* nAChRs elicited locomotor activation in Leu9'Ala mice, but nicotine suppressed activity in alpha 4 KO mice and this did not change with daily drug exposure. Again, appropriately combined responses from the two mutant strains resembled the biphasic nicotine-induced activity in WT animals. Thus, by analyzing nicotinic responses in two complementary mouse lines, one lacking alpha 4* nAChRs, the other expressing hypersensitive alpha 4* nAChRs, one can accurately separate non-alpha 4 nAChR responses from alpha 4 nAChR responses, and one can also account for WT tolerance to both hypothermia and locomotor suppression. Our study suggests a new paradigm for bridging the gap between genetic manipulation of a single receptor and whole animal behavioral studies and shows that activation of alpha 4* nAChRs is both necessary and sufficient for the expression of tolerance.
Tapper
Andrew R
AR
Division of Biology, California Institute of Technology, Pasadena, California, USA.
McKinney
Sheri L
SL
Marks
Michael J
MJ
Lester
Henry A
HA
D000222:Adaptation, Physiological / Q000235:genetics*; D000818:Animals; D007035:Hypothermia / Q000503:physiopathology*; D008124:Locomotion / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009538:Nicotine / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000502:physiology*
D011978:Receptors, Nicotinic; D009538:Nicotine