ABSTRACT
The effect of N-caproyl-L-prolyl-L-tyrosine methyl ester (GZR-123, Dilept), a new antipsychotic drug with a dipeptide structure, on cognitive functions was studied using the passive avoidance conditioned reflex (PACR) test. It was found that the drug improved both the acquisition and retrieval of PACR under the conditions of undertraining and prevented the amnesic effect of transcorneal electroshock. The neurotransmitter analysis of these effects using the corresponding blockers showed the ability of dilept to facilitate the central glutamatergic (NMDA type) and cholinergic (of both muscarine and nicotine types) neurotransmission. No evidence of the involvement of the GABAergic system was observed. The experimental data on the combination of antipsychotic effect with memory improving activity suggests that dilept may be effective in cases of negative symptoms of schizophrenia and psychotic manifestations in Alzheimer disease.
Subject(s)
Antipsychotic Agents/administration & dosage , Behavior, Animal/drug effects , Neurotensin/analogs & derivatives , Proline/analogs & derivatives , Proline/administration & dosage , Signal Transduction/drug effects , Tyrosine/analogs & derivatives , Tyrosine/administration & dosage , Alzheimer Disease/drug therapy , Animals , Avoidance Learning/drug effects , Male , Neurotensin/administration & dosage , Rats , Schizophrenia/drug therapyABSTRACT
The effects of dilept (N-caproyl-L-prolyl-L-tyrosine methyl ester) - a new peptidomimetic of neurotensine - on the level of monoamines and their main metabolites in four functionally important brain structures has been studied upon single and subchronic administration in intact rats and in those pretreated with the NMDA receptor blocker ketamine. Repeated administration of dilept favors the accumulation of DOPAC and accelerates the dopamine (DA) turnover in nucleus accumbens, as manifested by an increase in the DOPAC/DA ratio. The opposite effect (decrease in the DOPAC/DA ratio) was observed in the hypothalamus, where the subchronic treatment with dilept completely inhibited the activating action of ketamine on the DA turnover. The selective influence of dilept on the dopaminergic system activity in nucleus accumbens (but not in striatum), together with the previously obtained behavioral data, suggest that dilept is a new atypical neuroleptic producing no extrapyramidal side effects.
