Conclusion
In conclusion, our data show that SERT removal and AMPH self-administration converge on a common set of glutamate abnormalities that may contribute to shape both the behavioral and molecular effects herein observed. The finding that, after ShA to AMPH, genotype differences at the level of the glutamate system are not accompanied by genotype differences in drug intake, suggest that the observed SERT-induced changes in the glutamate system functioning result from AMPH self-administration. On the other hand, the finding that, after LgA to AMPH, genotype differences at the level of the glutamate system are accompanied by genotype differences in drug intake, suggests that SERT-induced changes in the glutamate system may also drive AMPH self-administration. It appears that the combination of SERT deletion and AMPH exposure leads to effects that are unique and distinguishable from those of the individual experimental conditions. Accordingly, we can make several considerations: 1) the glutamate system is differently regulated by AMPH in SERT-/- rats when compared to SERT+/+ rats; this is observed not only in terms of expression of the different glutamate receptors, but also in terms of their retention (i.e. stability) at synaptic sites, 2) the molecular determinants of the glutamate synapse are differently regulated in cNAc and sNAc confirming that these two subregions have their own function in regulating drug dependence and, 3) the LgA paradigm shapes the glutamatergic synapse differently from the ShA condition. Taken together, the perturbation of serotonin activity may, via dysregulation of glutamate homeostasis in these NAc regions, contribute to drive the transition from goal-directed drug intake toward addictive states. Hence, we propose that manipulation of serotonergic and/or glutamatergic systems may affect not only cocaine, but also AMPH, dependence.