A key difference between antibodies and the ligand interacting with the transferrin receptor is the bivalent nature of the TfR:antibody interaction. High-affinity, bivalent TfR antibodies are invariably sorted to lysosomes, possibly by interfering with TfR sorting via irreversible receptor crosslinking. Although the exact mechanism of this sorting event is unknown, it seems plausible that antibodies with reduced affinity at endosomal pH might relieve receptor cross-linking due to lower complex stability, allowing the receptor to pursue its physiological sorting pathway. It needs to be stressed that transcytosis supported by pH-dependent receptor binding has so far only been demonstrated in vitro using the hCMEC/D3 model system. For a more general applicability, other sytems like primary brain endothelial cells and, more importantly, in vivo experiments, need to be performed.In summary, we have developed a human BBB transcytosis assay enabling us to quickly screen antibodies for putative brain shuttle receptors for their transcytosis potential. Furthermore, our data suggest a mechanism in addition to reduction of binding affinity, which might facilitate antibody transcytosis over the BBB, namely pH-dependent binding to a transcytosis receptor. The nucleus accumbens, which forms the ventral part of the striatum, has been proposed to serve as an interface between limbic and motor systems. The nAcb receives glutamatergic innervation from the medial prefrontal cortex and other limbic structures, including the hippocampus and amygdala and it also receives a dense dopaminergic input from midbrain ventral tegmental area. Glutamatergic and dopaminergic afferents have been found to converge on the same dendritic spines of medium spiny GABAergic projecting neurons in the nAcb,,. This closed spatial relationship suggests a possible interaction between the glutamatergic and dopaminergic systems at the pre- and/or postsynaptic levels. Behavioral studies have shown that interactions between DA and glutamatergic synaptic transmission, particularly those mediated by NMDA receptors, play a key role in animal behaviors associated with the nAcb. Recent finding of D1/NMDA receptor complexes in striatal and hippocampal tissue indicates possible direct protein-protein interactions between D1 and NMDA receptors. In the nAcb, expression of NMDA receptor-dependent longterm potentiation has been demonstrated and plasticity within nAcb is thought to mediate instrumental learning processes and many aspects of drug addiction in which coincident activation of NMDA and dopamine D1 receptors is required. The nAcb may thus constitute a locus where NMDA receptors promote drug reinforcement. In addition, the nAcb appears to be involved in a number of functions such as motivation, attention and reward which are modulated by the mesolimbic dopaminergic system. Despite the well-known role of nAcb dopaminergic innervation in the modulation of motivated behaviors.