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NEUROBIOLOGY OF ENHANCER REGULATION

Enhancer regulation, compound with enhancer effect

Drugs with enhancer effect in remarkable low concentrations (10-12 and 10-11 mol/L) are capable of increasing the impulse propagation release of biogenic amines (noradrenaline, dopamine, and serotonin) from brain tissues (prefrontal cortex, striatum). The enhancer drugs (published by Knoll and coworkers, 1999) were initiated from the chemical structure of (-)-deprenyl (selegiline). These later developed compounds, like (-)-1-(benzofuran-2-yl)-2-propylamino-pentane (BPAP) and its congeners, PPAP and IPAP, however, in contrast to (-)-deprenyl do not possess monoamine oxidase-B (MAO-B) inhibitory and dopamine-releasing properties.

 These results show that the enhancer effect is independent from the amphetamine-like catecholamine release and also independent from the MAO-B inhibitory effect which is further proved by the fact that the other selective MAO-B inhibitor, rasagiline does not show enhancer effect.

The molecular background of the enhancer effect has not yet been finely clarified. Our studies aim to determine and thoroughly analyze the mechanism of enhancer effect.

In vitro studies

Our studies revealed that BPAP, and probably also its derivatives exert enhancer effect by their agonist action on the trace-amine-associated receptor (TAAR-1). The signal transduction cascade attached to TAAR also regulates vesicular release of biogenic amines and modulation of the exocytosis process at various steps. Since catecholamine enhancer activity can also be linked to VMAT2 activity, we intend to investigate interactions between TAAR cascade and uptake of biogenic amines into vesicles.

In vivo studies

The aim of these studies is the detailed analysis of the mechanism of action of enhancer compounds with the aid of behavioral-pharmacological methods (learning performance, memory function, general activity, etc.). As the enhancer compounds amplify characteristically the stimulus-induced biogenic amine release, the following of enhancer effect in in vivo studies might be demonstrable under aggravated experimental conditions. More difficult learning conditions can be induced, for example by pretreating the animals with drugs which impair the cognitive functions, or by studying the cognitive functions of aged animals.

Another aim of our work is to determine the potential clinical uses of enhancer compounds in neurological and psychiatric disorders.