Although withdrawn from clinical trials because of liver toxicity, the ergot derivative
lergotrile has been useful in the treatment of disorders involving dopaminergic systems (e.g.,
parkinsonism). In various biochemical and behavioral assays, this compound acts most potently as a
dopamine (DA) agonist but also has DA antagonist as well as
serotonin (5-HT) agonist properties. To elucidate further its effects in vivo, rats were trained to discriminate 0.5 mg/kg of
lergotrile from saline in a two-lever water-reinforced task. In tests for similarities to other
ergolines, dose-related substitutions were observed with
lisuride (0.003-0.04 mg/kg) and d-
lysergic acid diethylamide (0.01-0.08 mg/kg); partial substitution occurred with
ergonovine (0.063-0.5 mg/kg). The DA agonist
apomorphine (0.016-0.5 mg/kg) also substituted for
lergotrile whereas the
5-HT agonist quipazine (0.25-2.0 mg/kg) elicited primarily saline-appropriate responding. Tests involving
drug combinations indicated that the DA antagonist
haloperidol (0.016-0.5 mg/kg) attenuated responding on the
drug-appropriate lever; however, neither the DA (D2) antagonist
sulpiride (2.0-16.0 mg/kg) nor the
5-HT antagonist BC-105 (1.0-4.0 mg/kg) had an effect upon the
lergotrile cue. These results indicate that DA neuronal systems are probably more important than
5-HT neuronal systems in mediating the discriminative stimulus properties of
lergotrile; however, the contribution of other
neurotransmitter systems (e.g.,
norepinephrine) to these effects still must be evaluated.