Striatal α5 nicotinic receptor subunit regulates dopamine transmission in dorsal striatum

Abstract

Polymorphisms in the gene for the α5 nicotinic acetylcholine receptor (nAChR) subunit are associated with vulnerability to nicotine addiction. However, the underlying normal functions of α5-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 β2-containing (β2*) nAChRs. We explored whether α5 subunits, as well as α4, α6, and β3 subunits, participate in the powerful regulation of DA release probability by β2* 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 α4, α5, α6, or β3 subunits. We show that the nAChR subtypes that dominantly regulate dopamine transmission depend critically upon α5 subunits in the dorsal CPu in α4α5(non-α6)β2-nAChRs but not in NAc core, where α4α6β2β3-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 α5 subunits are critical to the regulation of DA transmission by α4β2* nAChRs in regions of striatum associated with habitual and instrumental responses (dorsal CPu) rather than pavlovian associations (NAc).

Figure 1.

α6, β3, and α4 subunits required for nAChR regulation of DA release probability in NAc core. a, Mean peak [DA]_o ± SEM versus frequency (four pulses) in control (drug-free) conditions (circles), with α-CtxMII (diamonds) or with α-CtxMII plus DHβE (triangles), n = 9. Three-way ANOVA for drug, frequency, and genotype: significant interactions (p < 0.001). Drug effects within genotypes: *p < 0.05, **p < 0.01, ***p < 0.001 (vs control), two-way ANOVA with Bonferroni post hoc t tests. b, Typical evoked DA voltammograms (unscaled).

Figure 2.

Nicotine modulation of DA release probability lost after deletion of α6, β3, and α4 subunits. a, Mean profiles of [DA]_o ± SEM evoked by 1p or 4p/100 Hz in NAc core in drug-free controls or nicotine (500 nm), n = 16–32. b, Ratios of [DA]_o evoked by 4p/100 Hz versus 1p in controls and nicotine (500 nm). Enhanced 4p/1p release in α6^−/−, β3^−/−, and α4^−/− versus wild type is not modified by nicotine. Two-way ANOVA with Bonferroni post hoc t tests.*p < 0.01 (vs wild type), ⁺⁺⁺p < 0.001 (nicotine vs control).

Figure 3.

Versatility in subunit sufficiency but critical role for α5 subunits in nAChR regulation of DA release in CPu. a, Mean peak [DA]_o ± SEM versus frequency (4p) in control conditions (circles), with α-CtxMII (diamonds) or α-CtxMII with DHβE (triangles), n = 9. Three-way ANOVA for drug, frequency, and genotype: significant interactions (p < 0.001). Symbols indicate drug effects within genotypes: *p < 0.05, **p < 0.01, ***p < 0.001 (vs control); ^†††p < 0.001 (vs α-CtxMII), two-way ANOVA with Bonferroni post hoc t test. b, Typical evoked DA voltammograms (unscaled).

Figure 4.

Nicotine modulation of DA release probability in CPu after subunit deletion. a, Mean profiles of [DA]_o ± SEM evoked by 1p or 4p/100 Hz in CPu. Nicotine-mediated changes in [DA]_o were not affected by subunit deletion, n = 16–32. b, Ratios of [DA]_o evoked by 4p/100 Hz versus 1p in control or nicotine (500 nm) where subunit deletion did not alter the 4p/1p release from wild type. Two-way ANOVA with Bonferroni post hoc t tests. ⁺⁺⁺p < 0.001 (nicotine vs control).