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Psychopharmacology (Berl). 2017 Apr;234(7):1079-1091. doi: 10.1007/s00213-017-4540-x. Epub 2017 Feb 8.

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

Author information

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.

KEYWORDS:

Antipsychotic; Dopamine; Schizophrenia

PMID:
28180960
DOI:
10.1007/s00213-017-4540-x
[Indexed for MEDLINE]

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