, 2000 and Lammel et al., 2008). These target areas, which include the mPFC, different subregions of the NAc, Adriamycin and the dorsal striatum, are key components of anatomically and functionally related circuits that are involved in a wide range of adaptive and pathologically motivated behaviors (Wise, 2004, Everitt and Robbins, 2005, Ikemoto, 2007, Everitt et al., 2008, Berridge et al., 2009, Schultz, 2010, Bromberg-Martin et al., 2010, Ungless et al., 2010 and Wolf, 2010). In particular, because DA cell activity and the consequent release of DA in target structures are associated not only with rewards and reinforcement-dependent learning (Schultz, 2010),

but also appear to play an important role in the motivational responses to aversive as well as other salient stimuli (Berridge et al., 2009, Bromberg-Martin et al., 2010 and Ungless et al., 2010), we wanted to compare the effects of a simple rewarding versus aversive experience on these different DA subpopulations. The major finding of this study was that excitatory synapses on subpopulations of DA neurons with different axonal projection targets were modified distinctly

after a rewarding cocaine experience versus an aversive experience (Figure 4E). Synapses on DA neurons projecting to NAc medial shell were selectively modified by the rewarding stimulus while synapses on DA neurons projecting to mPFC were Tariquidar price modified only by the aversive stimulus. In contrast, synapses on DA cells projecting to NAc lateral shell were modified by both rewarding and aversive stimuli, suggesting that this modulation may encode the occurrence of a salient stimulus independent of its valence. These findings are consistent with the idea that mesocorticolimbic DA circuitry may comprise multiple parallel circuits that encode distinct aspects of a motivational stimulus, its valence in terms of its rewarding or aversive properties as well as its salience (Bromberg-Martin

et al., 2010). Parallel processing and representation of the distinct features of a motivational stimulus in different circuits can be viewed as analogous to the neural circuit mechanisms by which many sensory systems encode complex sensory stimuli. In the context of this hypothesis, an important topic for future research will be to elucidate the mechanisms by which stress and drugs of abuse interact and cross-sensitize, both in terms of their behavioral consequences and the changes they elicit in extracellular dopamine. The larger and longer lasting increase in the AMPAR/NMDAR ratio in DA neurons projecting to NAc medial shell compared to those projecting to NAc lateral shell is consistent with studies reporting that cocaine administration elicits the largest increase in extracellular DA concentration within the NAc medial shell (Stuber et al., 2005, Di Chiara and Bassareo, 2007 and Aragona et al., 2008).