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Improved cognitive flexibility in serotonin transporter knockout rats is unchanged following chronic cocaine self-administration

Authors

  • Lourens J. P. Nonkes,

    1. Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Centre, The Netherlands
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  • Joseph H. R. Maes,

    1. Donders Institute for Brain, Cognition, and Behaviour, Centre for Cognition, Department of Biological Psychology, Radboud University Nijmegen, The Netherlands
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  • Judith R. Homberg

    Corresponding author
    1. Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Centre, The Netherlands
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Judith R. Homberg, Radboud University Nijmegen Medical Centre, Geert Grooteplein 21 (route 126), 6525 EZ Nijmegen, The Netherlands. E-mail: j.homberg@cns.umcn.nl

ABSTRACT

Cocaine dependence is associated with orbitofrontal cortex (OFC)-dependent cognitive inflexibility in both humans and laboratory animals. A critical question is whether cocaine self-administration affects pre-existing individual differences in cognitive flexibility. Serotonin transporter knockout (5-HTT−/−) mice show improved cognitive flexibility in a visual reversal learning task, whereas 5-HTT−/− rats self-administer increased amounts of cocaine. Here we assessed: (1) whether 5-HTT−/− rats also show improved cognitive flexibility (next to mice); and (2) whether this is affected by cocaine self-administration, which is increased in these animals. Results confirmed that naïve 5-HTT−/− rats (n = 8) exhibit improved cognitive flexibility, as measured in a sucrose reinforced reversal learning task. A separate group of rats was subsequently trained to intravenously self-administer cocaine (0.5 mg/kg/infusion), and we observed that the 5-HTT−/− rats (n = 10) self-administered twice as much cocaine [632.7 mg/kg (±26.3)] compared with 5-HTT+/+ rats (n = 6) [352.3 mg/kg (±62.0)] over 50 1-hour sessions. Five weeks into withdrawal the cocaine-exposed animals were tested in the sucrose-reinforced reversal learning paradigm. Interestingly, like the naïve 5-HTT−/− rats, the cocaine exposed 5-HTT−/− rats displayed improved cognitive flexibility. In conclusion, we show that improved reversal learning in 5-HTT−/− rats reflects a pre-existing trait that is preserved during cocaine-withdrawal. As 5-HTT−/− rodents model the low activity s-allele of the human serotonin transporter-linked polymorphic region, these findings may have heuristic value in the treatment of s-allele cocaine addicts.

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