Dopamine D2 receptor-mediated inhibition of dopaminergic neurons in mice lacking D2L receptors

Two isoforms of the dopamine (DA) D2 receptor are generated from the same gene by alternative splicing, D2L and D2S. To identify which isoform is involved in the autoregulation of midbrain DA neuron activity, intracellular electrophysiological recordings were performed from substantia nigra and ventral tegmental area neurons of mice lacking either D2L(D2L-/-) or both D2L and D2S receptors (D2-/-). In midbrain DA neurons from wild-type mice, DA and quinpirole, a DA D2-like receptor agonist, produced a significant somatic membrane hyperpolarization, which led to a reversible inhibition of firing activity. Interestingly, this effect was fully abolished in D2-/- neurons but still present in D2L-/- DA neurons. These data clearly show that D2S receptors are the main somatodendritic autoreceptors of central DA neurons. Thus, pharmacological compounds able to interfere selectively with presynaptic D2S receptors might constitute effective therapeutic strategies in neuropsychiatric disorders, by causing negligible side-effects.