The [alpha]3[beta]4 nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies

Background and Purpose Recent data have indicated that [alpha]3[beta]4* neuronal nicotinic (n) ACh receptors may play a role in morphine dependence. Here we investigated if nACh receptors modulate morphine physical withdrawal. Experimental Approaches To assess the role of [alpha]3[beta]4* nACh receptors in morphine withdrawal, we used a genetic correlation approach using publically available datasets within the GeneNetwork web resource, genetic knockout and pharmacological tools. Male and female European-American (n = 2772) and African-American (n = 1309) subjects from the Study of Addiction: Genetics and Environment dataset were assessed for possible associations of polymorphisms in the 15q25 gene cluster and opioid dependence. Key Results BXD recombinant mouse lines demonstrated an increased expression of [alpha]3, [beta]4 and [alpha]5 nACh receptor mRNA in the forebrain and midbrain, which significantly correlated with increased defecation in mice undergoing morphine withdrawal. Mice overexpressing the gene cluster CHRNA5/A3/B4 exhibited increased somatic signs of withdrawal. Furthermore, [alpha]5 and [beta]4 nACh receptor knockout mice expressed decreased somatic withdrawal signs compared with their wild-type counterparts. Moreover, selective [alpha]3[beta]4* nACh receptor antagonists, [alpha]-conotoxin AuIB and AT-1001, attenuated somatic signs of morphine withdrawal in a dose-related manner. In addition, two human datasets revealed a protective role for variants in the CHRNA3 gene, which codes for the [alpha]3 nACh receptor subunit, in opioid dependence and withdrawal. In contrast, we found that the [alpha]4[beta]2* nACh receptor subtype is not involved in morphine somatic withdrawal signs. Conclusion and Implications Overall, our findings suggest an important role for the [alpha]3[beta]4* nACh receptor subtype in morphine physical dependence.