Background and Purpose: (S)-ketamine induced rapid-acting antidepressant effects have revolutionized pharmacotherapy of major depression, however this medication produces also psychotomimetic effects including timing distortion. In contrast, (R)-ketamine appears to produce less of dissociative effects, but its antidepressant actions were less studied. It has been suggested that opioid receptors are involved in the antidepressant effect of ketamine. In addition, recent report suggests that while (S)-ketamine induced time underestimation, the (R)-isomer did not affect timing. Experimental approach: (R)- and (S)-ketamine, and fluoxetine as a positive control were tested in the differential-reinforcement-of-low-rate (DRL) 72-s schedule of reinforcement in male rats following naloxone pretreatment. Several DRL classic metrics as well as peak deviation analyses served to determine antidepressant-like actions and those associated with timing. Key Results: Antidepressant-like effect of (S)-ketamine (30-60 mg/kg) resembled fluoxetine (2.5-10 mg/kg) actions. Fluoxetine and (S)-ketamine increased reinforcement rate and peak location, suggesting increased performance, reduced premature responses, suggesting time underestimation and decreased Weber’s fraction, suggesting increased timing precision. In contrast, (R)-ketamine (60 mg/kg) increased reinforcement rate and peak location without affecting premature responses. Only fluoxetine decreased burst responses, suggesting decreased impulsivity. Naloxone pretreatment did not block ketamine enantiomers’ actions, but unexpectedly, increased fluoxetine’ performance. Conclusions & Implications: Fluoxetine’ and (S)- but not (R)- ketamine induced time underestimation could be associated with their antidepressant effects. The potentiation of DRL performance of fluoxetine by naloxone was unexpected and warrants further clinical studies.

Lucia Caffino

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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.