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Hypersensitivity to amphetamine’s psychomotor and reinforcing effects in serotonin transporter knockout rats: glutamate in the nucleus accumbens
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  • Lucia Caffino,
  • Michel Verheij,
  • Karine Roversi,
  • Giorgia Targa,
  • Francesca Mottarlini,
  • Piotr Popik,
  • Agnieszka Nikiforuk,
  • Joanna Golebiowska,
  • Fabio Fumagalli,
  • Judith Homberg
Lucia Caffino
University of Milan
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Michel Verheij
Radboud Universiteit Nijmegen Donders Institute for Brain Cognition and Behaviour
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Karine Roversi
Radboud Universiteit Nijmegen Donders Institute for Brain Cognition and Behaviour
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Giorgia Targa
University of Milan
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Francesca Mottarlini
University of Milan
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Piotr Popik
Institute of Pharmacology of the Polish Academy of Sciences
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Agnieszka Nikiforuk
Institute of Pharmacology of the Polish Academy of Sciences
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Joanna Golebiowska
Institute of Pharmacology of the Polish Academy of Sciences
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Fabio Fumagalli
University of Milan
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Judith Homberg
Radboud Universiteit Nijmegen Donders Institute for Brain Cognition and Behaviour
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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.

Peer review status:ACCEPTED

27 Mar 2020Submitted to British Journal of Pharmacology
30 Mar 2020Submission Checks Completed
30 Mar 2020Assigned to Editor
06 Apr 2020Reviewer(s) Assigned
22 May 2020Editorial Decision: Revise Minor
06 Jun 20201st Revision Received
09 Jun 2020Submission Checks Completed
09 Jun 2020Assigned to Editor
11 Jun 2020Reviewer(s) Assigned
01 Jul 2020Review(s) Completed, Editorial Evaluation Pending
07 Jul 2020Editorial Decision: Revise Minor
09 Jul 20202nd Revision Received
10 Jul 2020Submission Checks Completed
10 Jul 2020Assigned to Editor
10 Jul 2020Review(s) Completed, Editorial Evaluation Pending
10 Jul 2020Editorial Decision: Revise Minor
14 Jul 20203rd Revision Received
15 Jul 2020Submission Checks Completed
15 Jul 2020Assigned to Editor
15 Jul 2020Review(s) Completed, Editorial Evaluation Pending
15 Jul 2020Editorial Decision: Accept