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

Abstract

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.

Esketamine Inhibits Cocaine-Seeking Behaviour Subsequent to Various Abstinence Conditions in Rats

“…The complexity of the pharmacological mechanism of the action of esketamine was not investigated here, and remains unanswered. However, several possibilities should be taken into account: (1) the primary mode of the action of cocaine is the indirect increase in the extracellular level of DA [ 56 ] and thought activation; however, the psychostimulant also modulates glutamate release from corticostriatal terminal DA D 2 receptors [ 57 ]; (2) cocaine seeking and relapse are mediated through experience-built synaptic plasticity and the rise in the incentive motivational value of cocaine through which the neurochemical background is stored within glutamate signalling [ 16 , 26 , 58 , 59 , 60 ]; (3) cocaine withdrawal reduces basal glutamate levels [ 61 ]; and (4) changes in glutamate ionotropic NMDA receptor subunit composition transit from the occasional use of cocaine to CUD [ 62 ].…”

Glioma‑neuronal interactions in tumor progression: Mechanism, therapeutic strategies and perspectives (Review)

“…Dopamine receptor D4 is a receptor that is involved in autophagy and apoptosis, which interferes with glioma-cell proliferation ( 29 ). Serotonin exerts an impact on the glutamatergic system through influencing AMPARs and NMDARs ( 30 ). Selective serotonin reuptake inhibitor (SSRI) has been indicated to impair glioma cell growth via inducing autophagy and apoptosis ( 31 ), although such effects were also observed in patients with a history of long-term drug therapy using tricyclic antidepressants ( 32 ).…”