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.

Synthesis and evaluation of C9 alkoxy analogues of (-)-stepholidine as dopamine receptor ligands

“…13-20 Govadine ( 4 ) has cognitive enhancement properties which have been attributed to antagonist activity at D1 and D2 receptors. 21-24 The synthetic THPB 12-chloroscoulerine ( 5 ) displays D1 agonist/D2 antagonist activity and potent antipsychotic properties. 25-27 Overall, it appears that the dopamine receptor polypharmacology of THPBs is relevant to their central nervous system (CNS) therapeutic potential.…”

Effects of D- and L-govadine on the disruption of touchscreen object-location paired associates learning in rats by acute MK-801 treatment

“…Tetrahydroprotoberberines, including the synthetic compound govadine, have recently shown an interesting profile in preclinical assays relevant to the positive, negative, and cognitive symptoms of schizophrenia (Lapish et al 2012(Lapish et al , 2014Ashby et al 2015). The effects of govadine have been assessed following administration as both a racemic mixture and separate enantiomers (D-and L-govadine; Zhai et al 2012).…”

“…Both enantiomers reverse amphetaminedisrupted latent inhibition and mitigate social interaction deficits in the neonatal ventral hippocampal lesion (NVHL) model. Taken together, these data suggest that govadine may have a unique ability to improve all three categories of schizophrenia symptoms, which makes it an attractive option for further investigation (Lapish et al 2012(Lapish et al , 2014. Given the different profiles of D-and L-govadine, the goal of the present study was to test the effects of each enantiomer separately in the rodent PAL task both alone and in combination with acute administration of the NMDA receptor antagonist MK-801.…”

Repeated injections of D-Amphetamine evoke rapid and dynamic changes in phase synchrony between the prefrontal cortex and hippocampus

“…The fact that synchrony between the PFC and HC develops more quickly and is more robust after repeated AMPH exposure may reflect a physiological adaptation whereby synchrony can also develop with modest changes in monoamine efflux, such as those observed during spatial working memory (Phillips et al, 2004). Interestingly, accumulating evidence suggests that spatial working memory is improved in sensitized rodents (Ito and Canseliet, 2010; Lapish et al, 2012b), while other forms of cognition function, such as flexible decision-making and visual attention, are impaired (Fletcher et al, 2005, 2007). These parallel changes in physiology and behavior may reflect changes in information processing between the PFC and HC after repeated AMPH.…”