Although the exact cause of schizophrenia remains a mystery, accumulated evidence suggests that it is due, at least in part, to abnormal levels of the neurotransmitter dopamine in the brain. As a result, the vast majority of drugs used to treat schizophrenia block some aspect of the dopamine signaling pathway. These drugs all have serious side effects, however, leading many investigators to search for new therapeutic approaches that work by alternative mechanisms. Among these are Vanderbilt Basic Sciences researchers Jeff Conn, Carrie Jones, Craig Lindsley, and Larry Marnett. They now report that specific blockade of a receptor for the neurotransmitter acetylcholine, the M4 muscarinic receptor, produces antipsychotic effects through a novel mechanism. Earlier studies had shown that stimulation of muscarinic receptors could inhibit dopamine release in the brain, but the mechanisms for this effect were complex and not completely understood. Using a specific modulator that acts only on M4, the investigators showed that activation of this receptor results in a prolonged reduction in dopamine release. They identified the neurons in the brain responsible for this effect, and showed that they propagate the M4 signal by releasing an endocannabinoid (an endogenous compound that acts like the active ingredient of marijuana). These results define a previously unknown pathway by which dopamine neurotransmission is modulated and lay the foundation for a new approach to the treatment of schizophrenia. The availability of a drug that targets only the M4 receptor, leaving other muscarinic receptors fully functional, offers hope that this approach would be associated with fewer unwanted side effects than are observed with current antipsychotic drugs. The work is published in the journal Neuron [D. J. Foster, et al. (2016) Neuron, 91, 1244].