, 1993; Crawford et al., 2002; Domino, 2003; Domino & Kishimoto, 2002). Therefore, our paradigm may have been more sensitive to effects of smoking and abstinence compared with studies with a shorter duration of abstinence. In vivo radiotracer experiments suggest that nicotine can take several selleck chemical Nintedanib days to clear high-affinity binding sites (i.e., ��4��2 nAChRs) in humans and nonhuman primates (Staley et al., 2006). Therefore, the effects of abstinence may follow a protracted time course. One potential drawback of our approach is that each subject started from a different level of baseline smoking. We controlled for this possibility by including self-reported baseline cigarette consumption as a covariate in our analyses. Auditory habituation depends on the responses to S1 and S2, and frequently, these amplitudes are condensed into a single ratio.
This approach can obscure the mechanism of habituation enhancements, which may depend on an increased response to S1, decreased response to S2, or both. It has been proposed that nicotine inhibits the response to S2 by activating ��7 nAChRs interneurons in the CA3 region of the hippocampus (Adler et al., 1998; Stevens et al., 1998). However, this mechanism alone is not sufficient to explain our data because nicotine and smoking increased the amplitude of the S1 response without significantly affecting the amplitude of the S2 response. Previous studies in rodents and humans show similar changes in the response to S1 but not S2 (Crawford et al., 2002; Cromwell & Woodward, 2007; Metzger et al., 2007; Phillips et al., 2007).
Varenicline, a relatively selective ��4��2 nAChRs partial agonist (Mihalak et al., 2006), increased amplitude but not habituation of auditory ERPs. Therefore, it is likely that brain regions rich in ��4��2 nAChRs, the target of varenicline, contribute to the amplifying effect of nicotine on the S1 response. Consistent with this hypothesis, nicotine enhances action potential propagation and synaptic release in thalamocortical circuits via DH��E-sensitive nAChRs (Kawai et al., 2007; Lambe, Picciotto, & Aghajanian, 2003). These circuits are an obligate stage of auditory processing and participate in generation of the midlatency ERP components (Hinman & Buchwald, 1983; McGee, Kraus, Comperatore, & Nicol, 1991).
Even if nicotine increases the response to S1 by enhancing thalamic transmission, it must also activate inhibitory networks in order to prevent the response to S2 from increasing in amplitude as well. Therefore, it is likely that both ��7 nAChRs- and ��4��2 nAChRs-expressing brain regions are involved in auditory habituation. Our initial hypothesis was that varenicline would attenuate the effects of nicotine in the presence of nicotine but mimic the effects of a full agonist AV-951 when given alone, consistent with activity as a partial agonist.
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