Dissociable effects of the - and - enantiomers of govadine on the disruption of prepulse inhibition by MK-801 and apomorphine in male Long-Evans rats.

Rationale: The search for novel antipsychotic drugs to treat schizophrenia is driven by the poor treatment efficacy, serious side effects, and poor patient compliance of current medications. Recently, a class of compounds known as tetrahydroprotoberberines, which includes the compound -govadine, have shown promise in preclinical rodent tests relevant to schizophrenia. To date, the effect of govadine on prepulse inhibition (PPI), a test for sensorimotor gating commonly used to assess the effects of putative treatments for schizophrenia, has not been determined.

Objectives: The objective of the present study was to determine the effects of each enantiomer of govadine (- and -govadine) on PPI alone and its disruption by the distinct pharmacological compounds apomorphine and MK-801.

Methods: Male Long-Evans rats were treated systemically with - or -govadine and apomorphine or MK-801 prior to PPI. The PPI paradigm employed here included parametric manipulations of the prepulse intensity and the interval between the prepulse and pulse.

Results: Acute MK-801 (0.15 mg/kg) significantly increased the startle response to startle pulses alone, while both MK-801 and apomorphine (0.2 mg/kg) significantly increased reactivity to prepulse-alone trials. Both MK-801 and apomorphine disrupted PPI. In addition, -govadine alone significantly disrupted PPI in the apomorphine experiment. Pretreatment with -, but not -, govadine (1.0 mg/kg) blocked the effect of apomorphine and MK-801 on PPI. Treatment of rats with -govadine alone (0.3, 1.0, 3.0 mg/kg) also dose-dependently increased PPI.

Conclusions: Given the high affinity of -govadine for dopamine D2 receptors, these results suggest that further testing of -govadine as an antipsychotic is warranted.