Different adaptations in AMPA receptor transmission in the nucleus accumbens after short vs long access cocaine self-administration regimens.

Ca(2+)-permeable AMPA receptors (CP-AMPARs) accumulate in the nucleus accumbens (NAc) after ∼1 month of withdrawal from a long-access cocaine self-administration regimen (6 h/d, 10d). This is functionally significant because CP-AMPARs mediate the 'incubated' cue-induced cocaine craving produced by this regimen. Our present goal was to determine if other commonly employed cocaine self-administration regimens also elicit CP-AMPAR accumulation. We compared four regimens, named according to whether sessions were short-access (ShA, 2 h) or long-access (LgA, 6 h) and the total number of sessions: LgA/10d (already shown to elicit CP-AMPAR accumulation), ShA/11d, ShA/20-24d, and LgA/20-24d. In the latter regimens, rats began with 10 days of ShA and then entered a differential phase (10-14 days) in which ShA sessions either continued or switched to LgA. Controls self-administered saline. After >40 days of withdrawal, whole-cell patch-clamp recordings were performed in NAc core medium spiny neurons to assess the contribution of CP-AMPAR transmission, based on the magnitude of synaptic suppression elicited by bath application of the selective CP-AMPAR antagonist naspm (100 μM). Naspm produced a non-significant (∼10%) attenuation of electrically evoked local excitatory postsynaptic current in the saline and ShA groups. By contrast, a significant naspm-induced synaptic attenuation (25-30%) was observed in both the LgA groups. Further analyses indicate that this emergence of CP-AMPAR transmission in the LgA groups is associated with increased baseline responsiveness of MSN to excitatory drive. Together with data on cocaine infusions in each group, our results show that CP-AMPAR accumulation and enhanced glutamate transmission is associated with longer sessions (6 h), rather than the number of sessions or cocaine infusions.