Dopamine release and metabolism in the rat frontal cortex, nucleus accumbens, and striatum: a comparison of acute clozapine and haloperidol

Karoum, Farouk; Egan, Michael

doi:10.1111/j.1476-5381.1992.tb09042.x

Cited by 42 publications

(32 citation statements)

References 59 publications

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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: 64%

“…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.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 64%

mentioning

confidence: 99%

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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“…However, there is strong evidence that clozapine preferentially elevates dopamine (DA) neurotransmission in the prefrontal cortex, and that this might be an important ingredient of its therapeutic effects (Moghaddam and Bunney, 1990;Karoum and Egan, 1992;Youngren et al, 1994;Broderick and Piercey, 1998;Kuroki et al, 1999;Melis et al, 1999;Youngren et al, 1999;Westerink et al, 2001). This hypothesis is compelling because reduced dopaminergic innervation to the prefrontal cortex occurs in schizophrenia (Akil et al, 1999;Egan et al, 2001;Guo et al, 2003), and dysfunction of the prefrontal DA system is thought to contribute to the cognitive deficits of the disorder (Davis et al, 1991;Knable and Weinberger, 1997;Goldman-Rakic et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Clozapine Normalizes Prefrontal Cortex Dopamine Transmission in Monkeys Subchronically Exposed to Phencyclidine

Elsworth

Jentsch

Morrow

et al. 2007

Neuropsychopharmacol

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The mechanism responsible for the therapeutic effects of the prototypical atypical antipsychotic drug, clozapine, is still not understood; however, there is persuasive evidence from in vivo studies in normal rodents and primates that the ability to elevate dopamine neurotransmission preferentially in the prefrontal cortex is a key component to the beneficial effects of clozapine in schizophrenia. Theoretically, such an effect of clozapine would counteract the deficient dopaminergic innervation of the prefrontal cortex that appears to be part of the pathophysiology of schizophrenia. We have previously shown that following repeated, intermittent administrations of phencyclidine to monkeys there is lowered prefrontal cortical dopamine transmission and impairment of cognitive performance that is dependent on the prefrontal cortex; these biochemical and behavioral changes therefore model certain aspects of schizophrenia. We now investigate the effects of clozapine on the dopamine projections to prefrontal cortex, nucleus accumbens, and striatum in control monkeys and in those withdrawn from repeated phencyclidine treatment, using a dose regimen of clozapine that ameliorates the cognitive deficits described in the primate phencyclidine (PCP) model. In normal monkeys, clozapine elevated dopamine turnover in all prefrontal cortical, but not subcortical, regions analyzed. In the primate PCP model, clozapine normalized dopamine (DA) turnover in the dorsolateral prefrontal cortex, prelimbic cortex, and cingulate cortex. Thus, the present data support the hypothesis that the therapeutic effects of clozapine in this primate model and perhaps in schizophrenia may be related at least in part to the restoration of DA tone in the prefrontal cortex.

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“…The frontal cortex, hypothalamus, nucleus accumbens and striatum were dissected and analysed by mass fragmentography essentially as previously described (Karoum, 1985;Karoum et al, 1990;Karoum & Egan, 1992).…”

Section: Introductionmentioning

confidence: 99%

Regional effects of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine release and metabolism in the rat brain

Karoum

Chrapusta

Brinjak

et al. 1994

British J Pharmacology

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1 The effects of single-dose regimens of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine (DA) release and metabolism were evaluated in the frontal cortex, hypothalamus, nucleus accumbens and striatum. The regimens selected are known to produce substantial behavioural effects. 2 3-Methoxytyramine (3MT) and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were used to assess DA metabolism by catechol-O-methyltransferase and monoamine oxidase respectively. The rate of formation of 3MT was used as an index of synaptic DA. The ratio and sum, respectively, of 3MT and DOPAC rates of formation were used to assess DA reuptake inhibition and turnover. 3 The effects of amphetamine on 3MT production and DOPAC steady-state levels were similar in all regions, suggesting similar pharmacodynamic actions. Amphetamine increased 3MT formation and steady-state levels, and reduced DOPAC steady-state levels. DOPAC formation was significantly reduced only in the nucleus accumbens and striatum. Total DA turnover remained unchanged except in the nucleus accumbens. Apparently, the amphetamine-induced increase in DA release occurred at the expense of intraneuronal DA metabolism and did not require stimulation of synthesis. 4 Nomifensine elevated 3MT formation in all regions. A similar effect was produced by cocaine except in the nucleus accumbens. GBR 12909 elevated 3MT production only in the hypothalamus, the striatum and the nucleus accumbens. 5 Cocaine selectively reduced DOPAC formation in the frontal cortex. Nomifensine increased and reduced, respectively, DOPAC formation in striatum and hypothalamus. GBR 12909 elevated DOPAC formation in all regions except the cortex, where pargyline did not reduce DOPAC levels in GBR 12909-treated rats. 6 Ratios and sum of 3MT and DOPAC rates of formation also exhibited wide regional variations for each drug. In contrast to the other drugs, the ratio was not increased after GBR 12909. Apparently, the DA uptake properties of this drug are poorly related to its in vivo effects on the ratio of 3MT production to that of DOPAC, which should increase when DA reuptake is inhibited. 7 Total DA turnover was increased by GBR 12909 in the hypothalamus, nucleus accumbens and striatum, while cocaine and nomifensine increased it only in the nucleus accumbens and striatum respectively. 8 It is concluded that: (a) 3MT and DOPAC rates of formation provide better indices of DA release and metabolism than do their steady-state concentrations. (b) Some effects of DA uptake blockers on DA transmission, especially those of nomifensine and cocaine, may be attributed to increased DA release. (c) Patterns of regional effects of psychostimulants on the dynamics of DA release and metabolism may be better biochemical correlates of stimulant-induced behaviours than would changes in any single region.

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Dopamine release and metabolism in the rat frontal cortex, nucleus accumbens, and striatum: a comparison of acute clozapine and haloperidol

Cited by 42 publications

References 59 publications

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

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

Clozapine Normalizes Prefrontal Cortex Dopamine Transmission in Monkeys Subchronically Exposed to Phencyclidine

Regional effects of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine release and metabolism in the rat brain

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