The comparative effects of L-3,4-dihydroxphenylalanine (L-DOPA) on dopamine 
synthesis, release and behaviour were studied in the reserpine-treated rat. 
Acute administration of L-DOPA (25-200 mg/kg) dose-dependently inhibited the 
activity of aromatic L-amino acid decarboxylase (AADC) in the substantia nigra 
and corpus striatum. The antiparkinsonian drugs budipine (10 mg/kg) and 
amantadine (40 mg/kg) enhanced AADC activity in these regions, and prevented or 
reversed AADC inhibition by L-DOPA. Dual probe dialysis revealed that low doses 
of L-DOPA (25-50 mg/kg) dose-dependently stimulated the release of dopamine and 
3,4-dihydroxyphenylacetic acid (DOPAC) in nigra and striatum, whilst high doses 
of L-DOPA (100-200 mg/kg) completely suppressed the release of dopamine, but not 
DOPAC. Sulpiride (50 microM) administered via the probes antagonized dopamine 
release in response to 25 mg/kg L-DOPA, but greatly facilitated release by 200 
mg/kg L-DOPA. Dopamine release was blocked by the centrally acting AADC 
inhibitor NSD 1015, but facilitated by the central AADC activator budipine. In 
behavioural tests L-DOPA (plus benserazide, 50 mg/kg) only reversed akinesia at 
200 mg/kg, and not at 25-100 mg/kg. Pretreatment with either NSD 1015 (100 
mg/kg) or budipine (10 mg/kg) markedly potentiated the motor stimulant action of 
a threshold dose of L-DOPA (100 mg/kg). A combination of NSD 1015 (100 mg/kg) 
and benserazide (50 mg/kg) potentiated L-DOPA behaviour more effectively than 
either inhibitor alone. NSD 1015-facilitated L-DOPA behaviour was antagonized by 
sulpiride (100 mg/kg) and not by SCH 23390 (1 mg/kg), whereas 
budipine-facilitated L-DOPA behaviour was fully antagonized by SCH 23390 and 
only partially by sulpiride. These results show that behaviourally active doses 
of L-DOPA in the reserpinized rat are not accompanied by significant increases 
in extracellular dopamine and are therefore probably not dopamine mediated. We 
propose that L-DOPA is capable of directly stimulating dopamine D2 and possibly 
non-dopamine receptors, thereby inhibiting dopamine efflux presynaptically and 
promoting motor activation postsynaptically. A stimulant action of L-DOPA on 
motor behaviour, preferentially mediated by D1 > D2 receptors, suggests that 
L-DOPA may also be capable of yielding a dopamine-like response in the absence 
of detectable dopamine release. These findings are incorporated into a new model 
of L-DOPA's actions in the reserpinized rat, and their possible implications for 
our understanding of L-DOPA in Parkinson's disease are discussed.