Clozapine Modulates Aromatic l-Amino Acid Decarboxylase Activity in Mouse Striatum

Abstract

Clozapine is efficacious for treating dopaminergic psychosis in Parkinson's disease and ameliorates L-DOPA-induced motor complications. Based on its pharmacology and reported enhancing effects on dopamine metabolism and tyrosine hydroxylase activity, we investigated whether it could modulate the activity of aromatic L-amino acid decarboxylase (AAAD), the second enzyme for the biosynthesis of catecholamines and indoleamines. A single dose of clozapine increased AAAD activity of striatum in a dose-and time-dependent manner. At 1 h, enhanced enzyme activity was characterized by an increased V max for substrate and cofactor and was accompanied by elevated levels of protein in striatum and mRNA in substantia nigra, ventral tegmental area, locus coeruleus, and raphe nuclei. Acute clozapine increased tyrosine hydroxylase activity in striatum but with differing temporal patterns from AAAD and heightened dopamine metabolism. Interestingly, the response of the dopaminergic markers to clozapine was greater following a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion. Chronically administered clozapine increased AAAD activity and protein and dopamine metabolism in striatum without affecting tyrosine hydroxylase. Exogenous L-DOPA decarboxylation was accelerated in the striatum of intact and MPTPlesioned mice following acute clozapine, and the effect was exaggerated in the MPTP mice. To identify receptors involved, antagonists of receptors occupied by clozapine were employed. D4, 5-HT1 A , and 5-HT2 A , in addition to D1, D2, and D3, antagonists, augmented AAAD activity in striatum, whereas 5-HT2 C , 5-HT3, muscarinic, and ␣-1 and ␣-2 adrenergic antagonists were ineffective. For the first time, these studies provide evidence that clozapine modulates AAAD activity in the brain and suggests that dopamine and serotonin receptors are involved.Aromatic L-amino acid decarboxylase (AAAD) is a ubiquitous enzyme essential for the formation of catecholamines, indoleamines, and trace amines (Berry et al., 1996). AAAD is not considered to be the rate-limiting enzyme for catecholamine or indoleamine synthesis; however, it is the rate-limiting step for the synthesis of trace amines and becomes rate-limiting for dopamine formation in Parkinson's disease patients treated with L-DOPA. AAAD is a regulated enzyme, and accumulated evidence suggests that its activity in the rodent brain is tuned by short-and long-term mechanisms that apparently involve enzyme activation and induction.Physiological stimuli (Hadjiconstantinou et al., 1988), neurotransmitter receptors (Rossetti et al., 1989(Rossetti et al., , 1990Zhu et al., 1992;Hadjiconstantinou et al., 1993Hadjiconstantinou et al., , 1995Cho et al., 1997;Fisher et al., 1998) and second messenger systems (Young et al., 1998) participate in the regulation of enzyme activity. In nigrostriatal neurons, dopamine appears to regulate AAAD via D1-and D2-like receptors. Indeed, acute blockade of dopamine D1-like receptors with SCH23390 and of dopamine D2-like receptors with haloperidol, ...

Trace Amines and Their Receptors

“…Similar responses to dopamine receptor ligands have also been observed in various rodent brain regions (Zhu et al, 1992(Zhu et al, , 1993Hadjiconstantinou et al, 1993;Cho et al, 1997Cho et al, , 1999Neff et al, 2006). Regulation of AADC by serotonergic receptors (Neff et al, 2006) and Nmethyl-D-aspartate (NMDA) glutamatergic receptors (Hadjiconstantinou et al, 1995;Fisher et al, 1998) has also been reported. There is also some evidence for AADC regulation associated with systemic lupus erythematosus (Bengtsson et al, 2016), Parkinson' disease (Gjedde et al, 1993), and schizophrenia (Reith et al, 1994).…”

“…In contrast, D1R agonists decrease both basal and lightinduced AADC activity (Rossetti et al, 1990). Similar responses to dopamine receptor ligands have also been observed in various rodent brain regions (Zhu et al, 1992(Zhu et al, , 1993Hadjiconstantinou et al, 1993;Cho et al, 1997Cho et al, , 1999Neff et al, 2006). Regulation of AADC by serotonergic receptors (Neff et al, 2006) and Nmethyl-D-aspartate (NMDA) glutamatergic receptors (Hadjiconstantinou et al, 1995;Fisher et al, 1998) has also been reported.…”

L-Tyrosine availability affects basal and stimulated catecholamine indices in prefrontal cortex and striatum of the rat

“…Even though the P2/P1 ratio did not differ between VEH, L-TYR 62.5–125 μM and D-TYR 250 μM, this still raises the possibility of some carryover effects from P1 to P2. Pharmacologically induced acute activation of striatal TH typically ceases within 60 min of drug administration and does not affect the amount of TH protein for at least 6 h (Neff et al., 2006). In most studies of DA efflux, DA terminals appear to be fully recovered 60 min after cessation of an initial stimulus (Michael et al, 1987;Ripley et al, 1997).…”

“…We applied this approach to the medial prefrontal cortex (MPFC) and striatum (Brodnik et al, 2012) and postulated that as the concentration of L-TYR increased, DOPA levels would initially increase and then plateau due to inhibition of TH by L-TYR (Lloyd and Kaufman, 1974;Quinsey et al, 1998;Ribeiro et al, 1992), or by the end-product DA, given that inhibition of AADC by NSD-1015 remains incomplete (Neff et al, 2006). We were surprised, however, that in striatum increasing concentrations of L-TYR (62.5 – 1000 μM) incrementally elevated DOPA levels without evidence of inhibition (Brodnik et al, 2012).…”

A genetic locus in 7p12.2 associated with treatment resistant schizophrenia

“…A TAAR1 agonist has been shown to have antipsychotic activity in animal models and is currently in clinical testing (Revel et al, 2013). DDC expression and activity are altered by APD administration, including clozapine, in rodents, suggesting that it could be relevant to response to APD treatment (Neff et al, 2006). DDC has been reported to be regulated by immediate and delayed mechanisms involving enzyme activation and gene expression induction (Neff et al, 2000).…”