, 2006, Everitt and Robbins, 2005 and Everitt et al., 2008). These behavioral transitions may correspond to a transition from limbic and prefrontal cortical control over goal-directed behavior to dorsostriatal control as drug intake becomes compulsive (Haber et al., 2000, Kalivas

and Volkow, 2005, Everitt and Robbins, 2005, Everitt et al., 2008, Hyman et al., 2006 and Ikemoto, 2007). The immediate (within 1 day) modification of synapses on mesoaccumbens DA neurons by cocaine http://www.selleckchem.com/Androgen-Receptor.html administration versus the lack of such changes at synapses on nigrostriatal DA neurons can be viewed as consistent with this proposal and suggests that prolonged exposure to cocaine may be required for changes in nigrostriatal cells to occur. Our results can also be viewed as consistent with

a hierarchical organization of drug-evoked plasticity in these circuits (Kalivas and O’Brien, 2008) such that DA neurons projecting to the NAc underlie the initial reinforcing effects of drugs of abuse, whereas DA neurons projecting to the mPFC and dorsolateral striatum are more engaged later during the transition to addiction. In summary, this study provides evidence in support of the hypothesis that selleck inhibitor midbrain DA neurons are not homogeneous but instead subserve a variety of functions in support of the control over over motivated behaviors (Berridge et al., 2009, Bromberg-Martin et al., 2010 and Ungless et al., 2010). They suggest that the long-lasting modulation of individual DA neuron activity by salient stimuli is associated with the specific target brain areas they influence, a conclusion that is not surprising but nevertheless is important because its corollary is that the pathological behaviors involving mesocorticolimbic DA circuitry involve modulation of distinct DA neuron

subpopulations. Clearly, the ex vivo approach taken here cannot be used to define the behavioral roles of the DA neuron subpopulations. However, the differences we have demonstrated provide motivation to develop molecular tools that will allow precise in vivo control over the activity of these subpopulations so that their behavioral functions can be clearly elucidated. Recordings from retrogradely labeled DA neurons were performed essentially as previously described (Lammel et al., 2008). All experimental procedures are described in detail in Supplemental Experimental Procedures. This work was supported by grants from the National Institute on Drug Abuse and by a fellowship from the German Academy of Sciences Leopoldina (to S.L.). Retrograde tracing and immunohistochemistry were by S.L. and D.I.I. Electrophysiology was by S.L.