Dopaminergic transmission and (+)amphetamine-induced lethality in aggregated mice

In aggregated mice the lethal dose 50% (LD50) of (+)amphetamine was found to be clearly lower than in isolated animals (dose ratio: 6:1), whereas with the pure dopamine uptake inhibitor GBR 12783, the ratio was only 2. Pretreatment of mice with GBR 12783 (20 or 40 mg/kg ip) did not reduce the lethality of (+)amphetamine (10 mg/kg) in aggregated mice. Taking into account their relative affinity for D1 and D2 dopamine receptors, various DA antagonists were opposed to (+)amphetamine (20 mg/kg) in aggregated mice. The specific D1 antagonist SCH 23390 was especially effective (ID50 10 micrograms/kg). The specific D2 antagonists (+/-) sulpiride and metoclopramide were effective for high doses (ID50 = 43 and 19 mg/kg respectively). The dopamine antagonists haloperidol and alpha-flupenthixol, less specific as regards D1 vs D2 receptors, had an ID50 of 66 and 186 micrograms/kg respectively. Association of the D1 antagonist SCH 23390 with the D2 antagonist (+/-) sulpiride resulted in an apparent additive effect for reducing the (+)amphetamine-induced lethality. A semi-chronic treatment with either the D1 agonist SKF 38393 (7 x 20 mg/kg) or (+)amphetamine (6 x 10 mg/kg) performed in isolated mice did not reduce the lethality induced by (+)amphetamine (20 mg/kg) in aggregated mice. The antagonism of the (+)amphetamine-induced lethality in aggregated mice, frequently used to screen meuroleptics, reveals their antagonistic activity towards D1 or D2 dopamine receptor types.