The central aromatic amino acid DOPA decarboxylase inhibitor, NSD‐1015, does not inhibit l‐DOPA‐induced circling in unilateral 6‐OHDA‐lesioned‐rats

Abstract

The centrally acting aromatic amino acid dopa decarboxylase (AADC) inhibitor, 3-hydroxybenzyl hydrazine (NSD-1015), is widely used to study the neurotransmitter-like actions of L-DOPA. However, the effects of NSD-1015 on L-DOPA-induced motor activity are unclear as both increases and decreases have been reported. We now investigate the effects of NSD-1015 on L-DOPA-induced contralateral circling behaviour in 6-OHDA-lesioned rats and on striatal levels of L-DOPA, 3-O-methyl-DOPA (3-OMD), dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) using microdialysis techniques. NSD-1015 (50-200 mg/kg i.p.) inhibited AADC activity both in the liver and striatum of normal rats. Administration of NSD-1015 (50-200 mg/kg i.p.), delayed the onset of circling produced by administration of L-DOPA (25 mg/kg i.p.) and carbidopa (12.5 mg/kg i. p.), suggesting blockade of central AADC activity. However, the duration of the L-DOPA-induced circling was prolonged and overall no inhibition of circling behaviour occurred. L-DOPA (25 mg/kg i.p.) plus carbidopa (12.5 mg/kg i.p.) increased extracellular levels of L-DOPA, 3-OMD, dopamine, DOPAC and HVA in the 6-OHDA-lesioned striatum. Pretreatment of rats with the central AADC inhibitor, NSD-1015 (100 mg/kg i.p.), potentiated the increase in dialysate levels of L-DOPA and 3-OMD. However, it did not reduce striatal dopamine levels in the 6-OHDA-lesioned hemisphere, which were elevated following L-DOPA administration. The increases in DOPAC and HVA levels were abolished by NSD-1015 pretreatment. These results suggest that, while NSD-1015 blocks central AADC activity, it also acts as a monoamine oxidase inhibitor so maintaining striatal dopamine concentration by reducing dopamine metabolism. NSD-1015, therefore, may not be an appropriate tool for the study of brain AADC activity and for assessing the neuromodulatory role of L-DOPA.

The effects of central aromatic amino acid DOPA decarboxylase inhibition on the motor actions of L‐DOPA and dopamine agonists in MPTP‐treated primates

“…The administration of L‐DOPA following pretreatment with NSD‐1015 resulted in an accumulation of L‐DOPA in plasma and a concomitant fall in the levels of dopamine and DOPAC, indicating that AADC was effectively inhibited. Furthermore, studies in rats have shown that AADC activity is comparably inhibited both centrally and peripherally following the administration of NSD‐1015 (Treseder et al ., 1999). Central AADC inhibition abolished the reversal of motor deficits induced by administration of L‐DOPA also indicating effective enzyme inhibition.…”

Cystathionine-β-synthase: Molecular Regulation and Pharmacological Inhibition

“…This compound is traditionally viewed as a PLP-enzyme inhibitor (that reacts with PLP to form 3-hydroxybenzylhydrazone). It is known as an inhibitor of GABA aminotransferase and L-aromatic amino acid decarboxylase; it is also known to have a good ability for crossing the blood-brain barrier [502]. However (as opposed to benserazide or 2,3,4-trihydroxybenzylhydrazine) it is not a clinically used compound, nor is it a metabolite thereof.…”

Activación de receptores dopaminérgicos por L-DOPA. De la acción terapéutica a las discinesias.

“…En una segunda propuesta, los efectos de la administración de L-DOPA son atribuidos a la activación directa de los receptores D1 y D2. Estudios farmacológicos en presencia de inhibidores de la AADC, han mostrado efectos de la L-DOPA mediados por la activación de los receptores D1 (16), así como D2 en ratas normales (26), tratadas con reserpina (27) y con Parkinson experimental (31). A este respecto, tampoco existe evidencia directa de estudios de unión receptor-ligando específica.…”