Exley_2012_J.Neurosci_32_2352

Polymorphisms in the gene for the alpha5 nicotinic acetylcholine receptor (nAChR) subunit are associated with vulnerability to nicotine addiction. However, the underlying normal functions of alpha5-containing nAChRs in the brain are poorly understood. Striatal dopamine (DA) transmission is critical to the acquisition and maintenance of drug addiction and is modulated strongly by nicotine acting at heteromeric beta2-containing (beta2*) nAChRs. We explored whether alpha5 subunits, as well as alpha4, alpha6, and beta3 subunits, participate in the powerful regulation of DA release probability by beta2* nAChRs in nucleus accumbens (NAc) core and in dorsal striatum [caudatoputamen (CPu)]. We detected evoked dopamine release using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in striatal slices from mice with deletions of alpha4, alpha5, alpha6, or beta3 subunits. We show that the nAChR subtypes that dominantly regulate dopamine transmission depend critically upon alpha5 subunits in the dorsal CPu in alpha4alpha5(non-alpha6)beta2-nAChRs but not in NAc core, where alpha4alpha6beta2beta3-nAChRs are required. These data reveal the distinct populations of nAChRs that govern DA transmission in NAc core versus dorsal CPu. Furthermore, they indicate that alpha5 subunits are critical to the regulation of DA transmission by alpha4beta2* nAChRs in regions of striatum associated with habitual and instrumental responses (dorsal CPu) rather than pavlovian associations (NAc).