1-(2-(diphenylmethoxy)ethyl)-4-(3-phenyl-2-propenyl)piperazine and amineptin

The acute effects of increasing doses of the antidepressant drugs amineptine (5-40 mg/kg, IP) and desipramine (5-20 mg/kg IP) were studied in mice on three parameters of the activity (the horizontal activity, the vertical activity and the number of small movements without displacement) measured in a computerized Digiscan actimeter. The horizontal and vertical activities were dose dependently and similarly increased by acute amineptine, whereas the number of movements without displacement was increased up to 10 mg/kg with no further significant modification up to 40 mg/kg; in contrast, all three parameters were reduced in an identical manner by desipramine. The changes in the responses to the selective D-1 dopamine (DA) receptor agonist SK&F 38393 (1.87-30 mg/kg, SC), to the selective D-2 DA receptor agonist LY 171555 (0.1-1.6 mg/kg, SC) and to the selective DA uptake inhibitor GBR 12783 (1.25-20 mg/kg, IP) were measured on the three parameters of activity in mice chronically treated with amineptine (20 mg/kg, IP twice daily during 15 days) or by desipramine (10 mg/kg, IP, twice daily during 15 days). The chronic treatments with amineptine or desipramine did not modify the motor stimulant effects GBR 12783 and of SK&F 38393 on the three parameters (excepted for a slight modification of the horizontal activity for 7.5 mg/kg SK&F 38393 in mice chronically treated with amineptine). In contrast, the motor inhibitory effects of the lowest doses of LY 171555 (0.1-0.4 mg/kg) were strongly reduced in mice chronically treated with amineptine or desipramine but only on the horizontal activity with no change on the vertical activity and on the number of small movements without displacement.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Central Nervous System Stimulants; Desipramine; Dibenzocycloheptenes; Dopamine; Dopamine Agents; Dose-Response Relationship, Drug; Ergolines; Male; Mice; Motor Activity; Piperazines; Psychomotor Performance; Quinpirole

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.

Topics: 4-Butyrolactone; Animals; Antidepressive Agents, Tricyclic; Dextroamphetamine; Dibenzocycloheptenes; Dopamine; Dopamine Agents; Dopamine Antagonists; Drug Interactions; Male; Mice; Motor Activity; Piperazines; Reserpine; Synaptic Transmission

The effects of amineptine on 3H-dopamine uptake and 14C-dopamine release have been studied simultaneously in double labelling test performed on rat striatal synaptosomes. 3H-dopamine uptake was completely inhibited at 10 microM amineptine, a concentration which produced only a weak 14C-DA release (13% of the 14C-radioactivity stored). The IC 50 for the inhibition of 3H-DA uptake was not modified by a previous treatment with reserpine whereas the IC 50 of (+) amphetamine and the IC 50 of clomipramine were decreased 9 fold and increased two fold, respectively. In binding studies on rat striatal membranes amineptine displaces in vitro the 3H-GBR 12783, bound specifically to a component of the neuronal DA uptake complex. The apparent affinity of amineptine for this binding site was more than 150 times higher than its affinity for the binding site of 3H-desipramine on rat cortical membranes. In mice, increasing doses of amineptine injected i.p. reduced in a dose dependent manner the specific retention of radioactivity in the striatum after an i.v. injection of a tracer dose of 3H-GBR 12783. These data indicate that amineptine inhibits DA uptake and is virtually devoid of DA releasing effects. It displays a relatively low affinity for the NE uptake system. Its neurochemical profile in the double labelling test clearly differs from that of (+) amphetamine and from that of classical tricyclic anti-depressants.

Topics: Animals; Antidepressive Agents, Tricyclic; Cerebellum; Cerebral Cortex; Clomipramine; Corpus Striatum; Desipramine; Dextroamphetamine; Dibenzocycloheptenes; Dopamine; Dopamine Antagonists; In Vitro Techniques; Male; Mice; Piperazines; Rats; Rats, Inbred Strains; Reserpine; Synaptosomes