Differential effects of d- and l-enantiomers of govadine on distinct forms of cognitive flexibility and a comparison with dopaminergic drugs

Rationale There is an urgent need for novel drugs for treating cognitive deficits that are defining features of schizophrenia. The individual d- and l -enantiomers of the tetrahydroprotoberberine (THPB) d,l- govadine have been proposed for the treatment of cognitive deficiencies and positive symptoms of schizophrenia, respectively. Objectives We examined the effects of d- , l-, or d,l -govadine on two distinct forms of cognitive flexibility perturbed in schizophrenia and compared them to those induced by a selective D1 receptor agonist and D2 receptor antagonist. Methods Male rats received d- , l- , or d,l- govadine (0.3, 0.5, and 1.0 mg/kg), D1 agonist SKF81297(0.1, 0.3, and 1.0 mg/kg), or D2 antagonist haloperidol (0.1–0.2 mg/kg). Experiment 1 used a strategy set-shifting task (between-subjects). In experiment 2, well - trained rats were tested on a probabilistic reversal task (within-subjects). Results d- Govadine improved set-shifting across all doses, whereas higher doses of l- govadine impaired set-shifting. SKF81297 reduced perseverative errors at the lowest dose. Low/high doses of haloperidol increased/decreased set-shifting errors, the latter “improvement” attributable to impaired retrieval of a previous acquired rule. Probabilistic reversal performance was less affected by these drugs, but d- govadine reduced errors during the first reversal, whereas l- govadine impaired initial discrimination learning. d,l- Govadine had no reliable cognitive effects but caused psychomotor slowing like l- govadine and haloperidol. Conclusions These findings further highlight differences between two enantiomers of d,l -govadine that may reflect differential modulation of D1 and D2 receptors. These preclinical findings give further impetus to formal clinical evaluation of d -govadine as a treatment for cognitive deficiencies related to schizophrenia.