Allows for the maintenance of relatively normal secondary structure while diminishing enzymatic activity to levels similar to that observed with luxS deletion mutants suggest that this amino acid is critical for normal enzyme function. Use of this isolate may be helpful in further defining the roles of AI-2 in quorum sensing in a wide variety of bacterial species since it does provide a potential enzymatic intermediate between fully functional and enzymatically incompetent. The VTA, which is the origin of the mesolimbic DA system, has been implicated in both the signaling of natural rewards and in the formation of drug addiction. Much previous data has shown that animals will readily self-administer electrical currents or addictive drugs into the VTA. However due to the non-specificity of these interventions, it has been difficult to isolate the component that initiates the reinforcing behavior, which may eventually lead to addiction. Nevertheless, neurons of the VTA that release DA in target regions including the nucleus accumbens and the prefrontal cortex as well as locally appear to be centrally involved. Despite their diverse molecular targets, addictive drugs have in common that they U0126 increase mesolimbic DA levels. One of the leading hypotheses posits that this surge in mesolimbic DA levels triggers synaptic adaptations, first in the VTA, which may be permissive for subsequent more general changes in other parts of the brain. Such circuit reorganization may eventually cause behavioral changes that underlie addiction. According to the cellular mechanism engaged to increase DA levels, addictive drugs have been classified into three groups. Opioids, cannabinoids, benzodiazepines and the club drug gamma-hydroxybutyrate reduce transmitter release from inhibitory afferents onto DA neurons, indirectly increasing the firing rate of DA neurons, a mechanism defined as disinhibition. Nicotine, as a member of the second group, directly depolarizes DA neurons by activating alpha4beta 2-containing acetylcholine receptors, whereas the third group, comprised of cocaine, ecstasy and amphetamines, targets the DAT. Despite the observation that the representatives of this third group decrease the firing frequency of the VTA neurons through D2 receptor mediated autoinhibition, extracellular DA levels actually surge. This is due the block of the reuptake of the somato-dendritically released DA. Drug-evoked synaptic plasticity in the VTA appears at excitatory afferents onto DA neurons of the VTA already 24 h after a single injection of addictive drugs. In the case of cocaine it is induced by D1/D5 receptor and NMDAR activation and expressed in part by an insertion of GluA2lacking AMPARs. When rendered persistent through repetitive drug application, such adaptations in the VTA trigger synaptic plasticity downstream in the NAc. Several studies have identified the effects of cocaine on the DA system as a key contributor to its addictive properties.