The most significant variant in this study (rs1996371) was also found to be associated with CHRNB4 mRNA expression in human brain (p = 0.01) [34]. There are a few functional studies that have reported the possible involvement of the CHRNB4 gene with drugs of abuse. Bruschweiler-Li et al. demonstrated that a 2.3-kb fragment of the CHRNB4 promoter region containing the CA box is capable of directing cell-type specific and developmentally regulated expression of a reporter gene in vivo [35]. There is also some indication that blockade of α3β4 nAChRs results in a reduction of opioid and stimulant self-administration, suggesting that nAChRs that contain the β4 subunit are involved in mediating withdrawal syndromes elicited by some drugs of abuse [36]. In a study using transgenic mice, Frahm and colleagues [37] showed that targeted overexpression of β4 leads to strong aversion to nicotine. This study further provided evidence that the medial habenula acts as a gate-keeper in the control of nicotine consumption and that the balanced contribution of β4 and α5 subunits is critical for this function. Thus, further studies elucidating the
