We demonstrated the presence of circulating antibodies from Sjögren syndrome (SS) patients enable to interact with rat cerebral frontal cortex by activating muscarinic acetylcholine receptors (mAChRs). IgG from SS and IgG from normal subjects were studied by flow cytometry, enzyme immunoassay (ELISA), and radioligand binding assays. By flow cytometric and ELISA procedures, it was shown that IgG from SS patients reacted to cerebral frontal cortex cell surface. SS IgG was able to interact with mAChR by inhibiting 3H-QNB binding to its specific receptor. Besides, SS IgG displayed an agonistic-like activity associated to specific M1 and M3 mAChR activation, increasing nitric oxide synthase (NOS) isoform activities. Neuronal (n) and endothelial (e) NOS-mRNA gene expression of rat frontal cortex is induced by SS IgG. This article supports the participation of humoral immune alterations in SS, resulting in central parasympathetic functional deregulation. These antibodies alter mAChR activation, NOS activity, and eNOS and nNOS gene expression.