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

• Published in: British journal of pharmacology Vol. 171; no. 16; pp. 3845 - 3857
• Main Authors: Muldoon, P P, Jackson, K J, Perez, E, Harenza, J L, Molas, S, Rais, B, Anwar, H, Zaveri, N T, Maldonado, R, Maskos, U, McIntosh, J M, Dierssen, M, Miles, M F, Chen, X, De Biasi, M, Damaj, M I
• Format: Journal Article
• Language: English
• Published: 01.08.2014
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.12741

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.