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



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



Male Long-Evans rats were treated systemically withd- orl-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.



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 withl-, but notd-, govadine (1.0 mg/kg) blocked the effect of apomorphine and MK-801 on PPI. Treatment of rats withl-govadine alone (0.3, 1.0, 3.0 mg/kg) also dose-dependently increased PPI.



Given the high affinity ofl-govadine for dopamine D2 receptors, these results suggest that further testing ofl-govadine as an antipsychotic is warranted.
Department of Physiology, University of Saskatchewan, GD30.7, Health Sciences Building, 107 Wiggins Rd, Saskatoon, SK, S7N 5E5, Canada.
Brittney R
BR
Lins
Department of Physiology, University of Saskatchewan, GD30.7, Health Sciences Building, 107 Wiggins Rd, Saskatoon, SK, S7N 5E5, Canada.
Wendie N
WN
Marks
Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
Anthony G
AG
Phillips
Department of Physiology, University of Saskatchewan, GD30.7, Health Sciences Building, 107 Wiggins Rd, Saskatoon, SK, S7N 5E5, Canada. john.howland@usask.ca.
John G
JG
Howland
D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology*; D001058:Apomorphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001600:Berberine Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D065808:Prepulse Inhibition / Q000187:drug effects*; D051381:Rats; D020318:Rats, Long-Evans; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy; D013237:Stereoisomerism
D014150:Antipsychotic Agents; D001600:Berberine Alkaloids; D018491:Dopamine Agonists; D018691:Excitatory Amino Acid Antagonists; D017448:Receptors, Dopamine D2; C103305:govadine; D016291:Dizocilpine Maleate; D001058:Apomorphine
Antipsychotic; Dopamine; Schizophrenia