Decreased withdrawal symptoms but normal tolerance to nicotine in mice null for the α7 nicotinic acetylcholine receptor subunit

Abstract

Withdrawal symptoms are a major deterrent when people try to quit smoking. The α7 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) is highly expressed in the brain, and has been suspected to play a major role in nicotine addiction. We studied the influence of α7-containing nAChRs on nicotine withdrawal and tolerance, in wild type mice and mice null for the α 7 nAChR subunit (α7 −/−). For withdrawal experiments, animals were implanted with osmotic minipumps delivering nicotine for 13 days. A single intraperitoneal injection of the nAChR antagonists mecamylamine (MEC) or methyllycaconitine (MLA) was used to precipitate withdrawal. In wild type mice, both MEC and MLA precipitated somatic signs of withdrawal such as increased grooming, scratching and shaking. In α7 −/− mice, the somatic effects of MEC-precipitated nicotine withdrawal were significantly reduced. Interestingly, the presumed α7-specific antagonist MLA also precipitated withdrawal. Tolerance, which was measured as a decrease in nicotine-induced hypolocomotion after subchronic nicotine treatment, was normal in α7 −/− mice. Finally, because anxiety and withdrawal symptoms are highly correlated in humans, we studied anxiety-like behaviors in α7 −/− mice using a battery of anxiety-related tests. The behavior of α7 −/− mice was indistinguishable from that of control mice. Our results point to the α7 subunit as one of the players in nicotine withdrawal, but not in nicotine tolerance or basal anxiety-like behavior.

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

“…In contrast, the somatic symptoms of nicotine withdrawal are present in both β2 KO and WT mice, suggesting that the somatic symptoms of nicotine withdrawal are mediated by other nAChR subunits [7,77,146]. Research with other nAChR subunit KO mice has demonstrated that the β4 [146], α5 [77], and α7 nAChR subunits [148] likely mediate the somatic symptoms of withdrawal. Thus, these studies provide evidence that the various symptoms of nicotine withdrawal are mediated by different nAChR subunits.…”

“…Investigations of nicotine withdrawal symptoms have demonstrated that α7 nAChRs play a role in withdrawal-related changes in somatic symptoms and hyperalgesia [59,77,148], but do not play a crucial role in other withdrawal symptoms. Salas and colleagues [148] reported that somatic signs during nAChR antagonist-precipitated withdrawal are reduced in α7 KO mice relative to WT littermates.…”

“…Salas and colleagues [148] reported that somatic signs during nAChR antagonist-precipitated withdrawal are reduced in α7 KO mice relative to WT littermates. In addition, studies using two different methods of chronic nicotine administration (either chronic oral nicotine or osmotic mini-pumps) have demonstrated that nicotine withdrawal-induced hyperalgesia is present in α7 WT mice, but not in KO mice [59,77].…”

Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors

“…The α7 nAChRs participate in auditory sensory gating, defects in which contribute to the attention and cognitive problems associated with schizophrenia [8,9]. They are also involved in the mechanism of nicotine addiction [10]. The α7 nAChR subunit, which forms robust functional homomeric receptors, has been proposed as a candidate target for new drugs designed to ameliorate symptoms of Alzheimer's disease and schizophrenia as well as to control pain [11].…”

The effects of aging vs. α7 nAChR subunit deficiency on the mouse brain transcriptome: aging beats the deficiency

“…Despite the importance of the α7 nAChR subunit, its deficiency results in viable, anatomically normal α7-null mice (Orr-Urtreger et al 1997;Paylor et al 1998). The only abnormal CNSrelated phenotypes reported in these mice were mild cognitive deficits (Young et al 2004(Young et al , 2007 and reduced nicotine withdrawal symptoms (Salas et al 2007). It has been suggested that overexpression of other types of nAChRs compensates for the depletion of α7-nAChRs, and in fact, the upregulation of α3 and α4 nAChR subunits was demonstrated in brains of postnatal α7−/− mice (Yu et al 2007).…”