Long-access to cocaine self-administration dysregulates the glutamate synapse in the nucleus accumbens core of serotonin transporter knockout rats.

Background and purpose It is well established that the nucleus accumbens (NAc) and glutamate play a critical role in the motivation to take drugs of abuse. We have previously demonstrated that rats with ablation of the serotonin transporter (SERT-/- rats) show increased cocaine intake reminiscent of compulsivity. Experimental approach By comparing SERT-/- to SERT+/+ rats, we set out to explore whether SERT deletion influences glutamate neurotransmission under control conditions as well as after short access (ShA: 1 hr. / session) or long access (LgA: 6 hrs. /session) to cocaine self-administration. Key results Rats were sacrificed at 24 hrs. after the final self-administration session for ex vivo molecular analyses of the glutamate system (vesicular and glial transporters, post-synaptic subunits of NMDA and AMPA receptors and their related scaffolding proteins). Such analyses were undertaken in the NAc core (cNAc). In cocaine-naive animals, SERT deletion evoked widespread abnormalities in markers of glutamatergic neurotransmission that, overall, indicate a reduction of glutamate signaling. These results suggest that serotonin is pivotal for the maintenance of accumbal glutamate homeostasis. We also found that SERT deletion altered glutamate homeostasis mainly after LgA, but not ShA, to cocaine. Conclusion and implications Our findings reveal that SERT deletion may sensitize the glutamatergic synapses of the NAc core to the LgA, but not ShA, intake of cocaine.