A preclinical assessment of d.l-govadine as a potential antipsychotic and cognitive enhancer

• Published in: The international journal of neuropsychopharmacology 2012-11, Vol.15 (10), p.1441-1455
• Main Authors: Lapish, Christopher C., Belardetti, Francesco, Ashby, Donovan M., Ahn, Soyon, Butts, Kelly A., So, Kitty, Macrae, Cassie M., Hynd, Jordan J., Miller, James J., Phillips, Anthony G.
• Format: Article
• Language: English
• Subjects: Animals; Antipsychotic Agents - chemistry; Antipsychotic Agents - pharmacology; Avoidance Learning - drug effects; Avoidance Learning - physiology; Berberine Alkaloids - chemistry; Berberine Alkaloids - pharmacology; Cognition - drug effects; Cognition - physiology; Drug Evaluation, Preclinical - methods; Male; Motor Activity - drug effects; Motor Activity - physiology; Nootropic Agents - chemistry; Nootropic Agents - pharmacology; Rats; Rats, Long-Evans
• ISSN: 1461-1457; 1469-5111
• DOI: 10.1017/S146114571100157X

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.