Distinct regulation of dopamine D2S and D2L autoreceptor signaling by calcium

Dopamine is an important component of the brain's reward system and is commonly referred to as a ‘feel-good’ chemical. It is mainly released from neurons in the brain in response to natural rewards, such as food or sex, and following exposure to, or in anticipation of, certain drugs of abuse (including cocaine). Dopamine-releasing neurons also sense dopamine, and just like someone can change the volume of their voice by hearing themselves speak, dopamine neurons regulate how much dopamine is released based on how much dopamine they sense. This feedback system is known as autoinhibition. These neurons sense dopamine when it binds to, and activates, so-called ‘dopamine D2 receptors’ on their cell surface. But not all D2 receptors are alike. Instead there are two variants called D2S and D2L. Previous studies have shown that D2 receptor signaling in dopamine neurons is altered by the concentration of calcium ions inside these cells. Furthermore, exposure to cocaine and other drugs is known to change how these calcium ions regulate D2 receptor signaling. Now, Gantz et al. have used mice that produce only a single variant of the D2 receptor (either D2S or D2L) in their dopamine neurons to uncover similarities and differences between the two variants. The experiments show that localized increases in calcium ion concentration make D2S less capable of autoinhibition, like D2 receptors in neurons from wild type mice, without affecting autoinhibition by D2L. In further experiments, some of these mice were given cocaine before D2 receptor signaling was assessed. In dopamine neurons from wild type mice, a single exposure to cocaine eliminates the calcium-dependent regulation; thus, cocaine treatment causes a D2L-like response. In contrast, cocaine treatment did not affect the calcium-dependent regulation when only one variant of the D2 receptor was present. This implies that dopamine neurons must have both D2S and D2L receptors before the drug can induce changes in D2 receptor signaling. These findings also challenge the long-held view that the D2S receptor is the predominant form involved in autoinhibition. The next challenge is to determine how cocaine induces an apparent switch from D2S to D2L and the implications of this switch for the development of cocaine addiction.