Clinical and pharmacological evidence suggests that several neurotransmitters are involved in the control of the esophageal motility; in fact, besides the well known cholinergic and sympathetic innervation, Vasoactive Intestinal Polypeptide (VIP)-containing fibers as well as dopamine (DA)-containing nerve endings have been identified within the esophageal wall. Lower Esophageal Sphincter (LES) achalasia is a neuromuscular disorder characterized by the absence of peristalsis in the body of the esophagus and by the failure of the LES to relax in response to swallowing. Stimulation of both VIP receptors and D-2 DA receptors induce a decrease in LES pressure, while D-1 receptors mediates LES contractions. In the present study we show that both VIP and DA system is disregulated in LES achalasia. In particular, this disease is associated not only with the lack of VIP nerves in the LES, but also with a failure in the responsiveness of postsynaptic receptors to VIP stimulation. Furthermore, we demonstrate a selective functional loss of the D-2 DA receptor component, without changes in the D-1 DA receptor mediated responses.