Background and Purpose: Hyperdopaminergia is a key feature of neuropsychiatric disorders including schizophrenia, attention deficit hyperactivity disorder, and bipolar disorder and can be modeled using dopamine transporter knockout (DAT KO) rats. Previous studies have shown that acute amphetamine has a paradoxical calming effect in DAT KO rats, but the effects of repeated amphetamine treatment are unknown. Experimental Approach: We studied the effect of subchronic amphetamine on hyperdopaminergia-related disease symptoms and underlying mechanisms using male and female DAT KO rats. We measured locomotor activity, anxiety-like behaviour, social behaviour, anhedonia and problem-solving behaviour at baseline and after 10 days of amphetamine treatment and assessed protein expression changes in the glutamate system in the prefrontal cortex. Key Results: Both female and male DAT KO rats exhibited hyperlocomotion compared to control rats. Subchronic amphetamine treatment significantly dampened this effect in female, but not in male DAT KO rats. Additionally, amphetamine increased sociability and reduced anhedonia in female, but not in male DAT KO rats. From a molecular point of view, we observed differences in the modulation of glutamatergic transmission between males and females mainly at the level of the infralimbic, but not prelimbic, prefrontal cortex, suggesting that the glutamatergic synapse may contribute to the behavioral response to amphetamine between the two sexes. Conclusion and Implications: Subchronic amphetamine treatment decreased the hyperactivity, anxiety-like, anti-social and anhedonic phenotypes of female DAT KO rats, potentially by modulating glutamate transmission in the prefrontal cortex. These findings foster further research into the treatment of hyperdopaminergia-related disorders.

Environmental enrichment (EE) has been shown to produce beneficial effects in addiction disorders; however, due to its configurational complexity, the underlying mechanisms are not yet fully elucidated. Recent evidence suggests that EE, acting as a metaplastic agent, may affect glutamatergic mechanisms underlying appetitive memory and, in turn, modulate reward-seeking behaviors: here, we have investigated such possibility following a brief EE exposure. Adult male Sprague-Dawley rats were exposed to EE for 22h and the expression of critical elements of the glutamate synapse was measured 2h after the end of EE in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and hippocampus (Hipp) brain areas, which are critical for reward and memory. We focused our investigation on the expression of NMDA and AMPA receptor subunits, their scaffolding proteins SAP102 and SAP97, vesicular and membrane glutamate transporters vGluT1 and GLT-1, and critical structural components such as proteins involved in morphology and function of glutamatergic synapses, PSD95 and Arc/Arg3.1. Our findings demonstrate that a brief EE exposure induces metaplastic changes in glutamatergic mPFC, NAc, and Hipp. Such changes are area-specific and involve postsynaptic NMDA/AMPA receptor subunit composition, as well as changes in the expression of their main scaffolding proteins, thus influencing the retention of such receptors at synaptic sites. Our data indicate that brief EE exposure is sufficient to dynamically modulate the glutamatergic synapses in mPFC-NAc-Hipp circuits, which may modulate rewarding and memory processes.

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.