Brittney R Lins1, Wendie N Marks1, Anthony G Phillips2, John G Howland3. 1. Department of Physiology, University of Saskatchewan, GD30.7, Health Sciences Building, 107 Wiggins Rd, Saskatoon, SK, S7N 5E5, Canada. 2. Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada. 3. Department of Physiology, University of Saskatchewan, GD30.7, Health Sciences Building, 107 Wiggins Rd, Saskatoon, SK, S7N 5E5, Canada. john.howland@usask.ca.
Abstract
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 d,l-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 (d- and l-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 d- or l-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, d-govadine alone significantly disrupted PPI in the apomorphine experiment. Pretreatment with l-, but not d-, govadine (1.0 mg/kg) blocked the effect of apomorphine and MK-801 on PPI. Treatment of rats with l-govadine alone (0.3, 1.0, 3.0 mg/kg) also dose-dependently increased PPI. CONCLUSIONS: Given the high affinity of l-govadine for dopamine D2 receptors, these results suggest that further testing of l-govadine as an antipsychotic is warranted.
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 d,l-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 (d- and l-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 d- or l-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, d-govadine alone significantly disrupted PPI in the apomorphine experiment. Pretreatment with l-, but not d-, govadine (1.0 mg/kg) blocked the effect of apomorphine and MK-801 on PPI. Treatment of rats with l-govadine alone (0.3, 1.0, 3.0 mg/kg) also dose-dependently increased PPI. CONCLUSIONS: Given the high affinity of l-govadine for dopamine D2 receptors, these results suggest that further testing of l-govadine as an antipsychotic is warranted.
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