Interaction of amineptine with agents modifying dopaminergic transmission

Amineptine, administered at increasing doses (5-40 mg/kg, i.p.) in mice, induces a dose-dependent hyperactivity (measured either in classical activity cages or in a DIGISCAN actimeter) which persists for about 8 h at 20 mg/kg. The increase of locomotor activity induced by 20 mg/kg amineptine is dose-dependently antagonized by metoclopramide (1.25-120 mg/kg i.p.), by SCH 23390 (7.5-8,000 micrograms/kg s.c.) and by amisulpride (1.56-50 mg/kg i.p.). Nevertheless, whereas the increase of locomotor activity induced by amineptine is completely antagonized at a relatively low dose of the discriminant benzamide derivative amisulpride (50 mg/kg i.p.), it is completely antagonized only at high doses of the selective D-2 antagonist metoclopramide (80 mg/kg i.p.) and of the selective D-1 antagonist SCH 23390 (4,000 micrograms/kg s.c.). The increase in locomotor activity induced by amineptine is significantly reduced (a) by low doses of apomorphine (25-300 micrograms/kg s.c.) stimulating dopamine autoreceptors; (b) by a pretreatment with reserpine (4 mg/kg s.c. 24 h prior to testing), which depletes the vesicular stores of monoamines; and (c) by gammabutyrolactone (100 mg/kg i.p. 30 min after amineptine), which inhibits the firing rate of dopaminergic neurons. Similar results are also obtained with the selective dopamine uptake inhibitor GBR 12783 (10 mg/kg i.p.) but not with dexamphetamine (5 mg/kg i.p.), the effects of which persist in reserpine-pretreated mice in gamma-butyrolactone-treated mice. Finally, the study of the interaction of increasing doses of amineptine with dexamphetamine (5 mg/kg i.p.) indicates that a low dose of amineptine (5 mg/kg) potentiates dexamphetamine-induced hyperactivity, whereas a high dose of amineptine (40 mg/kg) reduces dexamphetamine-induced hyperactivity. These data indicate that the stimulation of dopamine receptors induced by amineptine depends to a large degree on the dopamine released from the vesicular stores by the firing rate of dopaminergic neurons. The similarity of the results obtained with amineptine and with the selective dopamine uptake inhibitor GBR 12783 suggests a common mechanism of action that differs from that of dexamphetamine.