Striatal α5 Nicotinic Receptor Subunit Regulates Dopamine Transmission in Dorsal Striatum

Polymorphisms in the gene for the alpha 5 nicotinic acetylcholine receptor (nAChR) subunit are associated with vulnerability to nicotine addiction. However, the underlying normal functions of alpha 5-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 beta 2-containing (beta 2*) nAChRs. We explored whether alpha 5 subunits, as well as alpha 4, alpha 6, and beta 3 subunits, participate in the powerful regulation of DA release probability by beta 2* 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 alpha 4, alpha 5, alpha 6, or beta 3 subunits. We show that the nAChR subtypes that dominantly regulate dopamine transmission depend critically upon alpha 5 subunits in the dorsal CPu in alpha 4 alpha 5(non-alpha 6)beta 2-nAChRs but not in NAc core, where alpha 4 alpha 6 beta 2 beta 3-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 alpha 5 subunits are critical to the regulation of DA transmission by alpha 4 beta 2* nAChRs in regions of striatum associated with habitual and instrumental responses (dorsal CPu) rather than pavlovian associations (NAc).