Nicotine responses in hypersensitive and knockout α4 mice account for tolerance to both hypothermia and locomotor suppression in wild-type mice

Abstract

Nicotinic receptors containing the α4 subunit (α4* 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 α4* and non-α4 nAChRs in the development of tolerance to hypothermia and locomotor suppression, α4 knockout (KO), hypersensitive Leu9′Ala α4 knock-in, and wild-type (WT) mice received daily nicotine injections, and their behaviors were compared. Repeated selective activation of α4* nAChRs in Leu9′Ala mice produced profound tolerance to hypothermia over 7 days, whereas no tolerance was observed in α4 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 α4* nAChRs elicited locomotor activation in Leu9′Ala mice, but nicotine suppressed activity in α4 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 α4* nAChRs, the other expressing hypersensitive α4* nAChRs, one can accurately separate non-α4 nAChR responses from α4 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 α4* nAChRs is both necessary and sufficient for the expression of tolerance.

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