Activation of 5-HT(6) receptors facilitates attentional set shifting.
BACKGROUND
Prefrontal cortex (PFC)-dependent executive function is disrupted in a range of psychiatric disorders and can be modelled in non-human primates and rodents using attentional set-shifting paradigms. There are few current pharmacological strategies for enhancing attentional set shifting, although the PFC is rich in relevant neurotransmitter targets, including 5-hydroxytryptamine (5-HT). Although 5-HT depletion studies do not support a role for 5-HT in attentional set shifting, the effect of 5-HT activation using specific receptor agonists has not been tested.


OBJECTIVE
This study investigated the effect of a novel, selective 5-HT(6) receptor agonist, WAY181187, in a rat model of PFC-dependent extra-dimensional (ED) attentional set shifting. The effect of this agent on immediate early gene expression in the medial PFC and other regions was also examined.


RESULTS
Compared to vehicle-injected controls, WAY181187 facilitated ED set shifting but did not change other non-ED phases of the task (including intra-dimensional set shifting and reversal). This effect was blocked by the selective 5-HT(6) antagonist SB399885, which alone had no effect. WAY181187 enhanced ED set shifting even when administered after the attentional set had been acquired, thereby ruling out impairments in attentional set formation. In separate experiments, at a dose that increased ED set shifting, WAY181187 increased Fos-like immunoreactivity in the medial PFC in a SB399885-sensitive manner, suggesting a 5-HT(6) receptor-mediated activation of this region.


CONCLUSIONS
Through use of a novel 5-HT agonist, these experiments reveal a previously unrecognised role for 5-HT activation in PFC-dependent executive function, mediated by 5-HT(6) receptor activation.
Burnham
Katherine E
KE
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
Baxter
Mark G
MG
Bainton
John R
JR
Southam
Eric
E
Dawson
Lee A
LA
Bannerman
David M
DM
Sharp
Trevor
T
D000818:Animals; D001288:Attention / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012193:Reversal Learning / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D012718:Set, Psychology; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014363:Tryptamines / Q000008:administration & dosage / Q000494:pharmacology*
C525454:N(1)-(6-chloroimidazo(2,1-b)(1,3)thiazole-5-sulfonyl)tryptamine; D010879:Piperazines; D011985:Receptors, Serotonin; C503990:SB 399885; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D013844:Thiazoles; D014363:Tryptamines; C097216:serotonin 6 receptor