The racemate dl-tetrahydropalmatine (dl-THP) is known for its analgesic and sedative effects, and has been shown by us to be a potential agent for the treatment of anxiety.Herein, to delineate the therapeutic potentials of its different isomeric forms, the behavioral effects of l-THP, dl-THP and d-THP were compared regarding their anxiolytic and antidepressant properties in mouse behavioral models using the elevated plus-maze test and tail suspension test respectively. The anxiolytic and antidepressant effects of both l-THP and dl-THP were evident in forty-five minutes following oral administration. Moreover, l-THP exhibited much greater anxiolytic potency in the elevated plus-maze (0.1-2.5 mg/kg) and antidepressant potency in the tail suspension test (0.5-5.0 mg/kg) than dl-THP, whereas d-THP was inactive in either of these tests. As well, l-THP enhanced sociability and preference for social novelty at 0.1-0.5 mg/kg in Crawley’s three-chamber behavioral tests, and inhibited the amphetamine-induced manic-like hyperactivity of amphetamine-sensitized mice at 0.05-0.2 mg/kg. These pharmacological actions of l-THP were unaccompanied by any significant locomotor or myorelaxant side-effects. Co-administration of flumazenil, a GABAA receptor antagonist, inhibited the anxiolytic and antidepressant effects of l-THP, even though the binding affinity of l-THP was higher for dopamine D2-like receptors than for GABAA receptors. On this basis, l-THP displayed potential as a fast-acting drug for the treatment of anxiety, depression and bipolar disorder.
Keywords: l-THP; dl-THP; Anxiolysis; Antidepressant; GABAA receptor; Fast-acting
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