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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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Abstract

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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Acknowledgements

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, and Zeneca Inc.

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  1. Louis Stokes Department of Veterans Affairs Medical Center, Cleveland, OH, USA

    George E. Jaskiw, Bobbi Kirkbride & Rodolfo Bongiovanni

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

    George E. Jaskiw

  3. Psychiatry Service 116A(B), Louis Stokes Cleveland VAMC, 10000 Brecksville Road, Brecksville, OH, 44141, USA

    George E. Jaskiw

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  1. George E. Jaskiw
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Correspondence to George E. Jaskiw.

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Jaskiw, G.E., Kirkbride, B. & Bongiovanni, R. In rats chronically treated with clozapine, tyrosine depletion attenuates the clozapine-induced in vivo increase in prefrontal cortex dopamine and norepinephrine levels. Psychopharmacology 185, 416–422 (2006). https://doi.org/10.1007/s00213-005-0283-1

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