Dopamine D2L Receptor Knockout Mouse Provides a Unique Model System for Studying the Functions of D2L and D2S

Abstract

Dopamine receptors are classified into two categories: D1-like receptors (including the D1 and D5 subtypes), and D2-like receptors (including the D2, D3, and D4 subtypes). These classifications are based on both gene structure and pharmacological criteria.¹ Among D2-like receptors, D2 is the most abundant form in the brain, with expression levels 10- to 100-fold higher than those of D3 or D4. Two isoforms of the D2 receptor, termed D2L (long form) and D2S (short form), have been identified in the brain. Little is known about the distinct functions of either D2 isoform. No selective pharmacological agents are currently available. We have generated mice lacking the D2L receptor (D2L-/-), but expressing a functional D2S receptor. Thus, the mouse expressing purely D2S (D2L-/-) should allow us to identify a D2 ligand relatively selective for D2S, to assess the effects of drugs on neurons expressing only D2S, and to examine the effects of drugs on behaviors mediated by D2S. Because D2L is the predominant D2 isoform expressed in wild-type (WT) mice, the comparisons made between D2L-/- and WT mice will reveal novel information regarding the functions of D2L. Here, we attempted to investigate the distinct functional roles of D2L and D2S, using D2L-/- mouse as a model system and a combination of approaches.