title: A preclinical assessment of d.l-govadine as a potential antipsychotic and cognitive enhancer.
abstract: Tetrahydroprotoberberines (THPBs) are compounds derived from traditional Chinese medicine and increasing preclinical evidence suggests efficacy in treatment of a wide range of symptoms observed in schizophrenia. A receptor-binding profile of the THPB, d.l-govadine (d.l-Gov), reveals high affinity for dopamine and noradrenaline receptors, efficacy as a D2 receptor antagonist, brain penetrance in the 10-300 ng/g range, and thus motivated an assessment of the antipsychotic and pro-cognitive properties of this compound in the rat. Increased dopamine efflux in the prefrontal cortex and nucleus accumbens, measured by microdialysis, is observed following subcutaneous injection of the drug. d.l-Gov inhibits both conditioned avoidance responding (CAR) and amphetamine-induced locomotion (AIL) at lower doses than clozapine (CAR ED50: d.l-Gov 0.72 vs. clozapine 7.70 mg/kg; AIL ED50: d.l-Gov 1.70 vs. clozapine 4.27 mg/kg). Catalepsy is not detectable at low biologically relevant doses, but is observed at higher doses. Consistent with previous reports, acute d-amphetamine disrupts latent inhibition (LI) while a novel finding of enhanced LI is observed in sensitized animals. Treatment with d.l-Gov prior to conditioned stimulus (CS) pre-exposure restores LI to levels observed in controls in both sensitized animals and those treated acutely with d-amphetamine. Finally, possible pro-cognitive properties of d.l-Gov are assessed with the spatial delayed win-shift task. Subcutaneous injection of 1.0 mg/kg d.l-Gov failed to affect errors at a 30-min delay, but decreased errors observed at a 12-h delay. Collectively, these data provide the first evidence that d.l-Gov may have antipsychotic properties in conjunction with pro-cognitive effects, lending further support to the hypothesis that THPBs are a class of compounds which merit serious consideration as novel treatments for schizophrenia.
authors.affiliation: Department of Psychiatry, University of British Columbia, Canada. lapishc@gmail.com
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Lapish
authors.forename: Francesco
authors.initials: F
authors.lastname: Belardetti
authors.forename: Donovan M
authors.initials: DM
authors.lastname: Ashby
authors.forename: Soyon
authors.initials: S
authors.lastname: Ahn
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Butts
authors.forename: Kitty
authors.initials: K
authors.lastname: So
authors.forename: Cassie M
authors.initials: CM
authors.lastname: Macrae
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Hynd
authors.forename: James J
authors.initials: JJ
authors.lastname: Miller
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Phillips
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects* / Q000502:physiology; D001600:Berberine Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D018697:Nootropic Agents / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans
chemical_list: D014150:Antipsychotic Agents; D001600:Berberine Alkaloids; D018697:Nootropic Agents; C103305:govadine