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.