title: The effects of PRX-07034, a novel 5-HT6 antagonist, on cognitive flexibility and working memory in rats.
abstract: BACKGROUND
  Accumulating evidence indicates that schizophrenia and autism spectrum disorder patients are marked by cognitive deficits in working memory and strategy switching. There is accumulating evidence that 5-hydroxytryptamine (5-HT)(6) receptors may serve as a useful target to improve cognitive functioning.
  
  
  OBJECTIVE
  In the present experiments, the novel 5-HT(6) antagonist, PRX-07034, was examined for its selectivity of the 5-HT(6) receptor, as well as its effect on delayed spontaneous alternation and strategy switching.
  
  
  METHODS
  The binding affinity of PRX-07034 to the 5-HT(6) receptor, other 5-HT receptors, as well as other G-protein coupled receptors, ion channels, and transporters was evaluated. Cyclic AMP production was measured from transfected HEK-293 cells. In separate behavioral experiments, rats received different doses of PRX-07034 (0.1, 1, or 3 mg/kg, i.p.) 30 min prior to delayed spontaneous alternation testing or prior to the acquisition and switch phases in a place-response switch test.
  
  
  RESULTS
  The results indicated that PRX-07034 is both a potent (Ki = 4-8 nM) and highly selective 5-HT(6) receptor antagonist (≥100-fold selectivity for the 5-HT(6) receptor compared to 68 other GPCRs, ion channels, and transporters, except D(3) (Ki = 71 nM) and 5-HT(1B) (Ki = 260 nM) receptors. For cyclic AMP quantification, PRX-07034 demonstrated antagonist activity (IC(50) = 19 nM) without an effect on basal levels and did not show any agonist activity up to 10 μM. PRX-07034 at 1 and 3 mg/kg (but not 0.1 mg/kg) significantly enhanced delayed spontaneous alternation. The drug at 1 and 3 mg/kg also enhanced switching between a place and response strategy, but did not affect initial learning of either a place or response discrimination.
  
  
  CONCLUSIONS
  These findings demonstrate that PRX-07034 is a selective 5-HT(6) receptor antagonist that may represent a novel treatment for enhancing working memory and cognitive flexibility.
authors: Department of Psychology, University of Illinois at Chicago, 1007 West Harrison Street, Chicago, IL 60607, USA.
authors: Eric G
authors: EG
authors: Mohler
authors: Phillip M
authors: PM
authors: Baker
authors: Kimberly S
authors: KS
authors: Gannon
authors: Simon S
authors: SS
authors: Jones
authors: Sharon
authors: S
authors: Shacham
authors: John A
authors: JA
authors: Sweeney
authors: Michael E
authors: ME
authors: Ragozzino
mesh_terms: D000818:Animals; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects* / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D020318:Rats, Long-Evans; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor