Effects of clozapine, thioridazine, perlapine and haloperidol on the metabolism of the biogenic amines in the brain of the rat

Bürki, Hans R.; Ruch, W.; Asper, Helmuth

doi:10.1007/bf00421302

Cited by 105 publications

(17 citation statements)

References 24 publications

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“…The latter is based upon the assumption that, like its role in catecholamine synthesis, L-AAAD is not rate limiting for the conversion of tryptophan to 5-HT. Our results and those of Christenson et al (1970) suggest that, under the same assay conditions, 5-HTP is only decarboxylated at one-tenth the rate of DOPA. However, there is in uiuo evidence to suggest that L-AAAD is not the rate-limiting enzyme in 5-HT synthesis (Grahame-Smith, 1974).…”

Section: -Hydroxytryptamine In Chick Retina But Significant Amounts supporting

confidence: 77%

Evidence for a neurotransmitter role for 5-hydroxytryptamine in chick retina

Parkinson¹,

Rando²

1981

J. Neurosci.

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Retinal 5-hydroxytryptamine levels were reduced by local injection of a-fluoromethyldopa, an inhibitor of aromatic L-amino acid decarboxylase, or reserpine, indicating that this amine is both synthesized and stored in this tissue. The retinae of light-adapted chicks have higher levels of 5-hydroxytryptamine and its major metabolite, 5-hydroxyindoleacetic acid, than dark-adapted animals. The turnover of 5-hydroxytryptamine appears to be greater in the light after inhibition of synthesis. Conversely, the rate of synthesis of 5-hydroxytryptamine appears to be greater in the dark. The possible interaction of dopaminergic neurons and the 5-hydroxytryptamine-containing cells and the effect of a-fluoromethyldopa on this relationship are discussed. The data lend support to the notion that 5-hydroxytryptamine in chick retina may have a neurotransmitter function.Much evidence has been accumulated to indicate that the biogenic amines, norepinephrine, dopamine, and 5-hydroxytryptamine (5-HT),3 may be the neurotransmitters for some neurons in the central nervous system. In the vertebrate retina, dopamine has been identified as the possible transmitter for a class of amacrine cells with cell bodies in the inner nuclear layer (Ehinger, 1976). Sufficient 5-HT to justify a possible neuronal role for this amine has been measured only in chick (Suzuki et al., 1975) and bovine retina (Thomas and Redburn, 1979).

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Section: -Hydroxytryptamine In Chick Retina But Significant Amounts supporting

confidence: 77%

Evidence for a neurotransmitter role for 5-hydroxytryptamine in chick retina

Parkinson¹,

Rando²

1981

J. Neurosci.

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“…Following a single administration of clozapine, tyrosine hydroxylase activity and dopamine synthesis, release, and metabolism are enhanced in striatum (Burki et al, 1975;Zivkovic et al, 1975;Invernizzi et al, 1990;Karoum and Egan, 1992;Broderick and Piercey, 1998). The novelty of our studies lies in the finding that clozapine also increases the activity of the second enzyme in the biosynthetic pathway for dopamine, AAAD.…”

Section: Discussionmentioning

confidence: 67%

“…Dopamine metabolism is the reflection of multiple control mechanisms, e.g., presynaptic and postsynaptic receptors, feedback loops, neuronal firing rate, synthesis, release, and reuptake, which might be affected by clozapine. Notwithstanding, clozapine alters the metabolism of serotonin and norepinephrine as well (Burki et al, 1975;McMillen and Shore, 1978), and AAAD is involved with the synthesis of trace amines (Berry et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…The lack of extrapyramidal signs has been attributed to their propensity to partially block striatal dopamine D2 receptors, their fast dissociation and lower occupancy of D2 receptors, and their inherent antimuscarinic action and 5-HT2 A antagonism (Kapur and Remington, 2001;Meltzer et al, 2003). Based on its dopamine receptor antagonistic profile and reports that it increases the activity of tyrosine hydroxylase (Zivkovic et al, 1975;Hetey et al, 1985) and enhances dopamine metabolism (Burki et al, 1975;Zivkovic et al, 1975;Invernizzi et al, 1990;Karoum and Egan, 1992;Broderick and Piercey, 1998), we hypothesized that clozapine enhances AAAD activity as well. Toward this goal, we investigated the effect of clozapine on AAAD activity, protein, and kinetics in the striatum of mice, characterized the pharmacology of the response, examined the effect of a dopaminergic lesion on the clozapineinduced modulation of AAAD, and determined whether clozapine affects exogenous L-DOPA decarboxylation.…”

mentioning

confidence: 98%

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

Neff¹,

Wemlinger²,

Duchemin³

et al. 2006

J Pharmacol Exp Ther

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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, ...

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“…This stimulatory action of neuroleptic drugs appears to be due to an increased activity of tyrosine hydroxylase resulting from a decrease in the Km for its pteridine cofactor (Zivkovic & Guidotti, 1974). However, these changes are maximal within a few hours of administration of the drugs and return to normal 8 to 48 h later (Nyback & Sedvall, 1968;Hyttel, 1974b;Burki, Ruch & Asper, 1975) and are reduced during chronic drug treatment. For this reason their relevance as part of a description of the mode of action of these neuroleptics in man must be questioned since their therapeutic action at the low daily doses normally given (e.g.…”

Section: Introductionmentioning

confidence: 99%