Abstract
Background and PurposeAmphetamine (AMPH) 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 (as measured during daily 1‐h self‐administration sessions) and compulsive (as measured during daily 6‐h self‐administration sessions) intake of this psychostimulant. Here, we sought to investigate whether these findings generalize to AMPH and the underlying mechanisms in the nucleus accumbens.Experimental ApproachIn 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. Twenty‐four hours after AMPH self‐administration, we analysed the expression of glutamate system components in the nucleus accumbens shell and core.Key ResultsWe 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 SERT genotype and AMPH exposure (baseline, ShA, and LgA), specifically in the nucleus accumbens shell.Conclusion and ImplicationsWe 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 (World Drug Report, 2018)
serotonin transporter (SERT)-/- rats were found to increase the daily intake of AMPH under long access (LgA) (Fig 3B: genotype x self-administration session effect (GG corrected): p
Examining the individual treatment effects, we found that SERT deletion in both C. Nucleus accumbens core (cNAc) and sNAc led to a significant increase of GLT-1 expression in response to the LgA, but not to the ShA procedure, whereas no significant effect was observed in SERT+/+rats
Summary
Amphetamine (AMPH) is a psychostimulant substance widely used across the world because of its euphoric effects, making it a remaining public health issue (World Drug Report, 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 amphetamine (AMPH) and intravenous AMPH self-administration under short access (ShA: 1-hr daily sessions) and long access (LgA: 6-hr 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 serotonin transporter genotype and AMPH exposure (baseline, ShA and LgA), in the nucleus accumbens shell. 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
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