Neurochemical effects of minaprine, a novel psychotropic drug, on the central cholinergic system of the rat.

Abstract

Minaprine, a novel psychotropic drug with antidepressant, anticataleptic and antiaggressive properties, produced an increase in rat brain regional acetylcholine content at a subconvulsant dose of 30 mg/kg IP. The greatest increase (60%) was produced in the striatum, whereas an increase of about 35% was obtained in the hippocampus and the rest of the cortex. A small but significant increase of 14% was also found in the midbrain-hindbrain region. Minaprine decreased choline content only in the striatum. No tolerance to acute challenge was observed after 10-day chronic treatment. In vitro, the drug had no effect on striatal choline acetyltransferase activity up to a concentration of 160 microM and only weakly displaced (3H) dexetimide from its specific muscarinic receptor binding sites in striatum (IC50, 2 X 10(-4) M). After in vivo administration the drug did not affect sodium-dependent high affinity choline uptake by a hippocampal homogenate. On the other hand, the drug inhibited both striatal and hippocampal acetylcholinesterase activity at high (40-160 microM) concentrations in vitro. In vivo the drug produced a brief (5 min), small (18%) decrease in the enzymic activity which corresponded in time to the peak drug level attained in the brain, but was not concomitant with a change in striatal acetylcholine content. By contrast, the increase in striatal acetylcholine appeared after 30 min when there was no longer inhibition of acetylcholinesterase activity and when the level of minaprine in brain was reduced by 78%. Blockade of dopamine receptors by pimozide pretreatment partially prevented the increase in striatal acetylcholine produced by minaprine, whereas interference with cholinergic or serontonergic neurotransmission was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)