Hypersensitivity to amphetamine’s psychomotor and reinforcing effects in
serotonin transporter knockout rats: glutamate in the nucleus accumbens
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.