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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

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Abstract

Rationale

Tyrosine availability can affect indices of dopamine (DA) release in activated central DA systems. There are, however, inconsistencies between studies. One possibility is that the relationship between tyrosine availability and DA release is non-linear.

Objectives

This study aimed to determine how tyrosine depletion as well as a range of administered tyrosine concentrations affect antipsychotic drug-induced extracellular DA levels in the MPFC or striatum.

Methods

A guide cannula was implanted over the medial prefrontal cortex or striatum of adult male rats. After a 24-h recovery period, a microdialysis probe was inserted. Microdialysate collection began on the following day. Some rats received vehicle or a tyrosine- and phenylalanine-free neutral amino acid solution NAA(−) (IP) prior to clozapine (CLZ 10 mg/kg IP). Others received vehicle, CLZ (10 mg/kg IP) or haloperidol (HAL) (1 mg/kg IP) while the probe was perfused with artificial cerebrospinal fluid containing tyrosine 0–200 μg/ml.

Results

NAA(−) reduced tyrosine levels in MPFC dialysate by 35%. This reduction did not affect basal MPFC DA levels but attenuated the peak of CLZ-induced MPFC DA levels. The NAA(−) effect could be reversed by administration of tyrosine. Infused tyrosine 12.5–200 μg/ml did not affect basal DA levels either in MPFC or striatum. Within the MPFC, tyrosine 50.0 μg/ml significantly increased CLZ-induced DA levels. Within the striatum, tyrosine 25.0 μg/ml significantly increased while 150.0 μg/ml significantly decreased HAL-induced DA levels.

Conclusions

Basal extracellular levels of DA in the MPFC and striatum are not affected by wide changes in tyrosine availability. However, modestly increased brain tyrosine levels can augment CLZ-induced MPFC and HAL-induced DA levels. Very high tyrosine concentrations attenuate HAL-induced striatal DA levels. These data may explain inconsistencies in the literature and suggest that tyrosine availability could be exploited to modulate psychotropic drug-induced DA levels in the brain.

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Abbreviations

DA:

Dopamine

CLZ:

Clozapine

MPFC:

Medial prefrontal cortex

HPLC:

High pressure liquid chromatography

NAA(−):

Tyrosine- and phenylalanine-free neutral amino acid mixture

TH:

Tyrosine hydroxylase

SAL:

Saline

VEH:

Vehicle

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Acknowledgements

The authors thank Dr. Bryan Yamamoto for his technical consultation.

This research was supported by the Office of Research and Development, Medical Research Service of the Department of Veterans Affairs. Dr. Jaskiw has conducted clinical trials for and/or received lecture sponsorship from the following: Bristol-Myers, Janssen, Lilly, Novartis, Pfizer, Zeneca Inc.

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  1. Rodolfo Bongiovanni

    Present address: Louis Stokes Cleveland VAMC, 116A(B), 10000 Brecksville Road, 44141, Brecksville, OH, USA

Authors and Affiliations

  1. Psychiatry Service, Louis Stokes Cleveland Veterans Administration Medical Center, Cleveland, Ohio, USA

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

  2. Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio, USA

    George E. Jaskiw

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Jaskiw, G.E., Kirkbride, B., Newbould, E. et al. 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. Psychopharmacology 179, 713–724 (2005). https://doi.org/10.1007/s00213-004-2091-4

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