title: Improved cognitive flexibility in serotonin transporter knockout rats is unchanged following chronic cocaine self-administration.
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.
authors.affiliation: Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Centre, The Netherlands. .
authors.forename: Lourens J P
authors.initials: LJ
authors.lastname: Nonkes
authors.forename: Joseph H R
authors.initials: JH
authors.lastname: Maes
authors.forename: Judith R
authors.initials: JR
authors.lastname: Homberg
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000523:psychology; D003071:Cognition / Q000187:drug effects*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D012193:Reversal Learning / Q000187:drug effects; D012646:Self Administration; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency*
chemical_list: D018765:Dopamine Uptake Inhibitors; D050486:Serotonin Plasma Membrane Transport Proteins; D003042:Cocaine