In the course of studying N-methyl-D-aspartate (NMDA) receptors of the nucleus accumbens (NAcc), we found that 20% of freshly isolated medium spiny neurons, as well as all interneurons, responded in an unexpected way to long (5-s) coapplication of NMDA and glycine, the coagonist of NMDA receptors. Whereas the reversal potential of the peak NMDA current of this subset of neurons was still around 0 mV, the desensitizing current became outward at hyperpolarized potentials around Ϫ30 mV. A Cl Ϫ -free solution shifted the equilibrium potentials of the desensitized currents to around 0 mV. This outward current was not blocked by a Ca 2ϩ -free, Ba 2ϩ -containing solution, suggesting that the anionic conductance was not activated by Ca 2ϩ influx through NMDA receptor channels. Interestingly, glycine alone also evoked a current with a similar hyperpolarized reversal potential in this subset of neurons. The glycine current reversed around Ϫ50 mV, rectified outwardly, and inactivated strongly. Its desensitization was best fitted with a double exponential. Only the slow desensitization showed clear voltage dependence. The glycine current was not blocked by 200 M picrotoxin and 10 M zinc, was weakly antagonized by 1 M strychnine, and was not enhanced by 1 M zinc. In addition, 1 mM taurine, but not GABA, inactivated glycine currents, and 1 mM glycine occluded 10 mM taurine-mediated currents. These data indicate that a subset of nucleus accumbens neurons expresses glycine receptors and that either glycine or taurine could be an endogenous agonist for these receptors.The nucleus accumbens (NAcc), an interface region between limbic structures (hippocampus, amygdala, and prefrontal cortex) and the extrapyramidal motor system, modulates cognitive and motivational aspects of behavior that are translated into motor activity (Dunah et al., 1996). Projecting GABAergic neurons, also containing mostly either substance P or enkephalin, account for 90% of the neuronal population of NAcc (Meredith, 1999). These neurons receive massive dopaminergic input from the ventral tegmental area, glutamatergic input from cortical and subcortical regions, and GABA innervation from interneurons. The physiology of the receptors for these transmitters is relatively well known, because they have been heavily studied with regard to addiction to psychostimulants, opiates, and alcohol (Koob et al., 1998). NAcc-projecting neurons also receive inputs from acetylcholine-and somatostatin-containing interneurons (Groenewegen et al., 1991;Meredith, 1999), but relatively little is known about the physiology of receptors for these ligands in NAcc. Furthermore, some data suggest that other receptors, including glycine receptors, remain to be identified and characterized.Glycine receptors, along with GABA receptors, represent the primary fast inhibitory mechanisms in the central nervous system. Activation of glycine receptors opens anionic channels that hyperpolarize neurons. Until recently, it was generally believed that glycine receptors were almost exclusiv...