Two splice isoforms of DRD2 are known to exist: the short (D2S) and long (D2L) isoforms. These isoforms arise from the alternative splicing of exon 6. The D2S isoform is located presynaptically whereas the D2L is found mainly post-synaptically (Khan et al., 1998). These two receptor isoforms are functionally distinct. Studies of D2L-knockout mice have demonstrated that the D2S acts as an autoreceptor, inhibiting the function of the D1 receptors (Usiello et al., 2000). In humans, two intronic single nucleotide polymorphisms (SNPs) that influence D2S/D2L splicing have been discovered: rs1076560 and rs2283265 (Zhang et al., 2007). These two SNPs are in high LD (D’=1) and the minor alleles of both SNPs are associated with decreased expression of D2S relative to D2L in the pre-frontal cortex (PFC) and caudate putamen (Moyer et al., 2011). Furthermore, these SNPs have been found to be associated with cocaine abuse, as the minor alleles were significantly over-represented in cocaine abusers (n=119) compared to controls (n=95) (Moyer et al., 2011).
