Clozapine-induced dopamine release in the medial prefrontal cortex is augmented by a moderate concentration of locally administered tyrosine but attenuated by high tyrosine concentrations or by tyrosine depletion

Jaskiw, George E.; Kirkbride, Bobbi; Newbould, Erica; Young, Damon; Durkalski, Valerie; Bongiovanni, Rodolfo

doi:10.1007/s00213-004-2091-4

Cited by 15 publications

(11 citation statements)

References 84 publications

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“…Other studies reported that acute treatment with SSRI-antipsychotic combination, including Hal-Flu, increased extracellular DA release in rat PFC (Ago et al 2005 ;Koch et al 2004 ;Zhang et al 2000). Clz has also been reported to increase DA release in PFC (Devoto et al 2003 ;Jaskiw et al 2005). Such apparent discrepancy with our findings can be explained by methodological differences between the studies.…”

Section: The Regulatory Effects Of Hal-flu On Cell-signaling Pathwayscontrasting

confidence: 82%

The involvement of GABAA receptor in the molecular mechanisms of combined selective serotonin reuptake inhibitor-antipsychotic treatment

Danovich

Weinreb

Youdim³

et al. 2010

Int. J. Neuropsychopharm.

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There is evidence that combining selective serotonin reuptake inhibitor (SSRI) antidepressant and antipsychotic drugs may improve negative symptoms in schizophrenia and resistant symptoms in obsessive-compulsive and affective disorders. To examine the mechanism of action of this treatment we investigated the molecular modulation of γ-aminobutyric acid-A (GABA(A)) receptor components and biochemical pathways associated with GABA(A) receptor function following administration of the SSRI fluvoxamine (Flu) combined with the first-generation antipsychotic haloperidol (Hal) and compared it to the individual drugs and the atypical antipsychotic clozapine (Clz). We analysed prefrontal cortices of Sprague-Dawley rats injected intraperitoneally (i.p.) with the combination of Flu (10 mg/kg) and Hal (1 mg/kg), each drug alone, or Clz (10 mg/kg) after 30 min and 1 h. We found that haloperidol plus fluvoxamine (Hal-Flu) co-administration, and Clz, decreased the level of GABAAβ2/3 receptor subunit in the cytosolic fraction, and increased it in the membrane compartment in rat PFC. Flu or Hal alone did not produce changes in GABAAβ2/3 receptor protein expression. Additionally, Hal-Flu and Clz regulated molecular signalling pathways that modulate GABA(A) receptor function, including protein kinase C (PKC) and extracellular signal-regulated kinase-2 (ERK2). In primary cortical culture, short-term treatment (15 min) with Hal-Flu combination and Clz increased GABAAβ subunit phosphorylation levels. Pretreatment of the cells with PKC inhibitor abolished the effect of the combined treatment, or Clz on phosphorylation of GABA(A) receptor. Inhibition of ERK2 did not alter the effect of drugs on GABA(A) receptor phosphorylation levels. Our findings provide evidence that the combined treatment regulates GABA(A) receptor function and does so via a PKC-dependent pathway.

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Section: The Regulatory Effects Of Hal-flu On Cell-signaling Pathwayscontrasting

confidence: 82%

The involvement of GABAA receptor in the molecular mechanisms of combined selective serotonin reuptake inhibitor-antipsychotic treatment

Danovich

Weinreb

Youdim³

et al. 2010

Int. J. Neuropsychopharm.

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“…Groups of animals (n=6) were treated with vehicle (saline), LiCl 2 chloride (3 mg/kg IP) or selected combinations of these treatments and HAL (0.19 mg/kg SC)+TYR (100 mg/kg SC). For comparison, some groups also were treated with NAA(−), a mixture of neutral amino acids known to lower brain TYR levels (Jaskiw et al, 2005; McTavish et al, 1999). The treatment schedule was the same as that for evaluation of catalepsy.…”

Section: Resultsmentioning

confidence: 99%

“…In order for TYR administration to augment DA synthesis and/or efflux, the availability of TYR rather than activity of tyrosine hydroxylase must become rate limiting for DA synthesis; this normally requires activation of tyrosine hydroxylase as well and/or a lowering of tyrosine availability (Bongiovanni et al, 2005; Jaskiw and Bongiovanni, 2004; Jaskiw et al, 2001, 2005, 2008; Milner and Wurtman, 1986). HAL, for instance, potently activates tyrosine hydroxylase (Salvatore et al, 2000; Zivkovic and Guidotti, 1974) and modestly lowers TYR levels in striatal tissue (Bongiovanni et al, 2006; Westerink and Wirix, 1983).…”

Section: Discussionmentioning

confidence: 99%

Acute lithium administration selectively lowers tyrosine levels in serum and brain

McFarlane¹,

Steele²,

Vinion³

et al. 2011

Brain Research

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Lithium exerts anti-dopaminergic behavioral effects. We examined whether some of these might be mediated by changes in brain levels of tyrosine (TYR), the precursor to dopamine. Lithium chloride (LiCl2) 3.0 mEq/kg IP acutely lowered serum TYR and the ratio of serum TYR to other large neutral amino acids (LNAAs); it also selectively lowered striatum TYR levels as measured in tissue or in vivo. While LiCl2 3.0 mEq/kg IP also augmented haloperidol (0.19 mg/kg SC)-induced catalepsy, this lithium effect was not attenuated by administration of TYR 100 mg/kg IP. We conclude that lithium acutely and selectively lowers brain TYR by lowering serum levels of tyrosine relative to the LNAAs that compete with it for transport across the blood–brain barrier. However, the lowering of TYR does not appear to significantly contribute to the ability of lithium to potentiate haloperidol-mediated catalepsy.

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“…When TH is activated, however, tyrosine availability can affect DA synthesis (Carlsson and Lindqvist 1978;Sved and Fernstrom 1981;Westerink and Wirix 1983) as well as levels of DA and metabolites (Scally et al 1977;Sved and Fernstrom 1981;Fernstrom et al 1984Fernstrom et al , 1989Milner and Wurtman 1986;During et al 1989;DePietro and Fernstrom 1999;Jaskiw et al 2001Jaskiw et al , 2005. This phenomenon is particularly evident when TH activation is superimposed on limited tyrosine availability (McTavish et al 1999b;Jaskiw et al 2005).…”

Section: Introductionmentioning

confidence: 91%

“…Tyrosine crosses the BBB by facilitated diffusion, via a carrier that it shares competitively with other large neutral amino acids (NAAs) (Pardridge and Oldendorf 1975;Pardridge 1977;Smith et al 1987;Verrey 2003). Systemic administration of a tyrosine-and phenylalanine-free mixture of large NAAs [NAA(−)] can reduce brain tyrosine levels both by increasing competition for BBB transport and by lowering plasma tyrosine levels through stimulation of peripheral protein synthesis (Biggio et al 1976;Fernstrom and Fernstrom 1995;McTavish et al 1999b;Jaskiw et al 2005). NAA(−) reduces basal striatal DA synthesis as well as amphetamine-or haloperidol-induced extracellular striatal DA levels (McTavish et al 1999b;.…”

Section: Introductionmentioning

confidence: 99%

In rats chronically treated with clozapine, tyrosine depletion attenuates the clozapine-induced in vivo increase in prefrontal cortex dopamine and norepinephrine levels

2006

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We previously reported that depletion of brain tyrosine attenuated the acute clozapine (CLZ)-induced increase in medial prefrontal cortex (MPFC) dopamine (DA) levels. This effect was now examined after chronic CLZ treatment. Male rats received CLZ (10 mg kg(-1) day(-1)) in drinking water for 21 days. On day 18, a cannula was stereotaxically implanted over the MPFC. A microdialysis probe was inserted on day 20. On day 21 after a stable baseline was reached, rats received an acute injection of vehicle (VEH) or a tyrosine- and phenylalanine-free mixture of neutral amino acid [NAA(-)] (total 1 g kg(-1), i.p., two injections, 1 h apart) followed by CLZ (10 mg kg(-1), i.p.) or VEH. Basal tyrosine or norepinephrine (NE) levels were not different between the groups, but basal DA was higher in the group treated chronically with CLZ (p<0.05). Acute CLZ (10 mg kg(-1), i.p.) increased MPFC DA and NE levels to 370% and 510% of baseline, respectively, and similarly in rats chronically pretreated with CLZ or VEH. NAA(-) did not affect basal MPFC DA or NE levels but significantly attenuated acute CLZ-induced DA (220% of baseline) and NE (330% of baseline) levels (p<0.01) in rats pretreated chronically with CLZ or with VEH. These data demonstrate that even after chronic CLZ administration, the acute CLZ-induced increases in MPFC DA and NE levels depend on the availability of brain tyrosine. Judicious manipulation of brain tyrosine levels may provide a useful probe as well as a mechanism for enhancing psychotropic drug actions.

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Clozapine-induced dopamine release in the medial prefrontal cortex is augmented by a moderate concentration of locally administered tyrosine but attenuated by high tyrosine concentrations or by tyrosine depletion

Cited by 15 publications

References 84 publications

The involvement of GABAA receptor in the molecular mechanisms of combined selective serotonin reuptake inhibitor-antipsychotic treatment

The involvement of GABAA receptor in the molecular mechanisms of combined selective serotonin reuptake inhibitor-antipsychotic treatment

Acute lithium administration selectively lowers tyrosine levels in serum and brain

In rats chronically treated with clozapine, tyrosine depletion attenuates the clozapine-induced in vivo increase in prefrontal cortex dopamine and norepinephrine levels

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