Responsivity of serotonin transporter knockout rats to short and long access to cocaine: Modulation of the glutamate signalling in the nucleus accumbens shell.

Background and Purpose: It has been well established that glutamate in the nucleus accumbens (NAc) plays 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 investigated whether SERT deletion influences glutamate homeostasis under control conditions as well as after short access (ShA: 1 h per session) or long access (LgA: 6 h per session) to cocaine self-administration. Rats were killed at 24 h after the last self-administration session for ex vivo molecular analyses of the main determinants of the glutamate system, including transporters (vesicular and glial), receptors (main post-synaptic subunits of NMDA and AMPA receptors together with the metabotropic subunit mGLUR5), and scaffolding proteins (SAP102, SAP97, and GRIP) in the NAc shell (sNAc) KEY RESULTS: In cocaine-naive animals, SERT deletion was associated with changes indicative for a reduction in glutamate signalling. ShA and LgA exposure led to a further dysregulation of the glutamatergic synapse.
Conclusion: SERT deletion may render the glutamatergic synapses of the NAc shell more responsive to both ShA and LgA intake of cocaine.
(© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)