Abstract
Background and purpose: Amphetamine use disorder is a serious health concern, but surprisingly little is known about the vulnerability to the moderate and compulsive use of this psychostimulant and its underlying mechanisms. Previous research showed that inherited serotonin transporter (SERT) down-regulation increases the motor response to cocaine, as well as moderate and compulsive intake of this psychostimulant. Here we sought to investigate whether these findings generalize to amphetamine and the underlying mechanisms in the nucleus accumbens. Experimental Approach: In serotonin transporter knockout (SERT−/−) and wild-type control (SERT+/+) rats we assessed the locomotor response to acute amphetamine (AMPH) and intravenous AMPH self-administration under short access (ShA: 1 hr daily sessions) and long access (LgA: 6 hr daily sessions) conditions. 24 hrs after AMPH self-administration we analysed the expression of glutamate system components in the nucleus accumbens shell and core. Key results: We found that SERT−/− animals displayed an increased AMPH-induced locomotor response and increased AMPH self-administration under LgA, but not ShA conditions. Further, we observed changes in the vesicular and glial glutamate transporters, NMDA and AMPA receptor subunits and their respective postsynaptic scaffolding proteins as function of serotonin transporter genotype, AMPH exposure (baseline, ShA and LgA) and nucleus accumbens sub region. Conclusion and implications: We demonstrate that SERT gene deletion increases the psychomotor and reinforcing effects of AMPH, and that the latter is potentially mediated, at least in part, by homeostatic changes in the glutamatergic synapse of the nucleus accumbens shell and/or core.
Highlights
Amphetamine (AMPH) is a psychostimulant substance widely used across the world because of its euphoric effects, making it a remaining public health issue (United Nations Office on Drugs and Crime, 2018)
Examining the individual treatment effects, we found that serotonin transporter (SERT) deletion in both nucleus accumbens core (cNAc) and nucleus accumbens shell (sNAc) led to a significant increase of glutamate transporter 1 (GLT-1) expression in response to the long access (LgA) but not to the short access (ShA) procedure, whereas no significant effect was observed in SERT−/− versus their wild-type counterparts (SERT+/+)rats
Twenty-four hours into withdrawal from AMPH self-administration, we found that vesicular glutamate transporter 1 (vGlut1) expression was reduced at baseline in the sNAc of SERT−/− rats compared to SERT+/+ rats, suggesting reduced vesicular release of glutamate in SERT−/− rats with lower extracellular levels in the synapse
Summary
Amphetamine (AMPH) is a psychostimulant substance widely used across the world because of its euphoric effects, making it a remaining public health issue (United Nations Office on Drugs and Crime, 2018). Up to date, it is not clear which factors shape vulnerability to AMPH dependency, and the underlying mechanisms are still elusive. This would be critical as such insight would help to inform early interventions or treatments. Experimental Approach: In serotonin transporter knockout (SERT−/−) and wild-type control (SERT+/+) rats, we assessed the locomotor response to acute AMPH and i.v. AMPH self-administration under short access (ShA: 1-h daily sessions) and long access (LgA: 6-h daily sessions) conditions. We observed changes in the vesicular and glial glutamate transporters, NMDA and AMPA receptor subunits, and their respective postsynaptic scaffolding proteins as function of SERT genotype and AMPH exposure (baseline, ShA, and LgA), in the nucleus accumbens shell
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