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Pharmacological manipulation of aromatic L-amino acid decarboxylase in the rat

Fisher, Andrew; (1999) Pharmacological manipulation of aromatic L-amino acid decarboxylase in the rat. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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1. This study has investigated the pharmacological manipulation of the enzyme aromatic L-amino acid decarboxylase (AADC) by glutamate antagonists in drug-naive and reserpinised rats. AADC was thought to be responsible for the decarboxylation of L- dopa and 5HTP to form dopamine and 5HT respectively. However, recent evidence suggests that splice variants of AADC exist which may be substrate specific with regard to their decarboxylation profile. Therefore, in this study synthesis of dopamine and 5HT have been regarded as being processed by separate enzymes termed Dopa Decarboxylase (DDC) and 5-Hydroxytryptophan Decarboxylase (5HTPDC) respectively. High affinity NMDA ion channel antagonists such as MK801 and PCP significantly elevated DDC activity in drug-naive rats. The low affinity NMDA ion channel blockers, amantadine, memantine, dextromethorphan and budipine more markedly enhanced DDC activity in drug-naive rats compared with high affinity antagonists. Furthermore, elevations in DDC activity following administration of these ion channel blockers was more pronounced in the substantia nigra (SN) than in the corpus striatum (CS). Administration of glutamate antagonists which bind to other sites within the NMDA receptor, or act at the AMPA subtype, failed to modulate DDC activity in drug-naive rats with the exception of the glycine site antagonist (+)- HA 966 which elevated dopamine synthesis in the CS. 2. Dopamine loss in the nigrostriatal pathway is reported to induce hyperactivity of glutamatergic neurons within the basal ganglia. With this in mind, glutamate antagonists were administered alone, and in conjunction with L-dopa, following administration of reserpine in an attempt to assay DDC and 5HTPDC activity in the dopamine-depleted brain. Monoadministration of glutamate antagonists largely failed to potentiate DDC activity in the CS. Conversely, increased enzyme activity occurred in the SN following administration of MK801, budipine, amantadine and memantine; the glutamate recognition site antagonist CGP 40116 and the polyamine site antagonist eliprodil. Coadministration of memantine or amantadine with L-dopa potentiated DDC activity in both the CS and the SN whereas polypharmacy involving other glutamate antagonists had either no effect, or inhibited DDC activity. Glutamate antagonism, either alone or in combination with L-dopa, largely failed to modulate 5HTPDC activity in the nigrostriatal system. 3. In reserpinised rats, mesolimbic DDC activity was increased in the prefrontal cortex (PFc) following monoadministration of low affinity NMDA ion channel antagonists with onl> memantine additionally exhibiting potentiation of enzyme activity in the nucleus accumbens (NAcc). Budipine and amantadine stimulated 5H1PDC activity in the NAcc without eliciting any effect on enzyme activity in the PFc. Coadministration of budipine or memantine with L-dopa induced an increase in DDC activity in the PFc without a parallel effect in the NAcc. 5HTPDC activity was elevated in the PFC and NAcc following coadministration of budipine with L-dopa whereas polypharmacy involving other ion channel antagonists failed to induce any effect. 4. Antagonism of gabaergic or cholinergic receptors in drug-naive rats failed to induce any changes in DDC activity in the nigrostriatal system. In dopamine depleted rats, atropine elevated DDC activity in the SN without any effect in the CS whereas bicucumine only increased activity of this enzyme in the NAcc. Cholinergic modulation of monoamine synthesis in the reserpinised brain may partially explain the marked effects of the low-affinity NMDA ion channel antagonists as these drugs not only block the proposed increase of glutamatergic activity, but will also reduce excitability of NMDA-induced cholinergic neurotransmission. Our results indicate that DDC activity in the brain can be regulated by various glutamate antagonists with the most prominent effects following NMDA-ion channel blockade. In addition the present data support the idea that DDC and 5HTPDC activity can be differentially modified in various dopaminergic pathways in the brain. Reduction of glutamate hyperactivity following dopamine depletion can in some instances increase monoamine synthesis and may contribute to the antiparkinsonian effects of these drugs.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Pharmacological manipulation of aromatic L-amino acid decarboxylase in the rat
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10110851
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