Tyrosine‐free amino acid mixture attenuates amphetamine‐induced displacement of [11C]raclopride in striatum in vivo: A rat PET study

Previous neurochemical and behavioural studies show that tyrosine depletion using a nutritionally balanced tyrosine‐free amino acid mixture attenuates the dopamine‐releasing and psychostimulant properties of amphetamine. Here we investigate the effect of a tyrosine‐free amino acid mixture on striatal binding of [11C]raclopride, and amphetamine‐induced [11C]raclopride displacement, using positron emission tomography in the rat. Rats were scanned for 60 min after an i.v. injection of ∼11 MBq [11C]raclopride using a quad‐HIDAC system. Amphetamine (2 mg/kg i.p., 30 min prior to scan) caused a 12% reduction in [11C]raclopride distribution volume ratio (DVR) compared to saline‐injected controls. The tyrosine‐free amino acid mixture (1 g/kg i.p.) caused a small (+7%) but statistically insignificant increase in [11C]raclopride DVR and attenuated, although it did not fully block, the amphetamine‐induced reduction. These data are in keeping with previous neurochemical, immunocytochemical, and behavioural studies showing that tyrosine‐free amino acid mixtures reduce dopamine function and offer promise for future PET studies testing the effect of tyrosine‐depleting paradigms on dopamine release in humans. Synapse 51:151–157, 2004. © 2003 Wiley‐Liss, Inc.

[1]  J S Fowler,et al.  Striatal binding of the PET ligand 11C‐raclopride is altered by drugs that modify synaptic dopamine levels , 1993, Synapse.

[2]  R R MacGregor,et al.  GABAergic inhibition of endogenous dopamine release measured in vivo with 11C-raclopride and positron emission tomography , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[3]  J D Brodie,et al.  Serotonergic modulation of striatal dopamine measured with positron emission tomography (PET) and in vivo microdialysis , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[4]  P. Cowen,et al.  Fos immunocytochemical studies on the neuroanatomical sites of action of acute tyrosine depletion in the rat brain , 2004, Psychopharmacology.

[5]  W. Pardridge,et al.  Selective expression of the large neutral amino acid transporter at the blood-brain barrier. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[6]  S. Stone-Elander,et al.  Stereoselective binding of 11C-raclopride in living human brain — a search for extrastriatal central D2-dopamine receptors by PET , 2004, Psychopharmacology.

[7]  Adriaan A. Lammertsma,et al.  The potential of high-resolution positron emission tomography to monitor striatal dopaminergic function in rat models of disease , 1996 .

[8]  Roger N. Gunn,et al.  Pharmacological constraints associated with positron emission tomographic scanning of small laboratory animals , 1998, European Journal of Nuclear Medicine.

[9]  D J Brooks,et al.  Effect of L‐dopa and 6‐hydroxydopamine lesioning on [11C]raclopride binding in rat striatum, quantified using PET , 1995, Synapse.

[10]  P. Cowen,et al.  Tyrosine depletion attenuates the behavioural stimulant effects of amphetamine and cocaine in rats. , 2001, European journal of pharmacology.

[11]  M. Laruelle.  Imaging Synaptic Neurotransmission with in Vivo Binding Competition Techniques: A Critical Review , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[12]  R Myers,et al.  Effect of 5‐HT on binding of [11C] WAY 100635 to 5‐HT1A receptors in rat brain, assessed using in vivo microdialysis and PET after fenfluramine , 2001, Synapse.

[13]  R. Myers,et al.  Quantitation of Carbon‐11‐labeled raclopride in rat striatum using positron emission tomography , 1992, Synapse.

[14]  A. P. Jeavons,et al.  A 3D HIDAC-PET camera with sub-millimetre resolution for imaging small animals , 1998 .

[15]  R Myers,et al.  Dedicated small animal scanners: a new tool for drug development? , 2002, Current pharmaceutical design.

[16]  J. Krystal,et al.  Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[17]  P. Cowen,et al.  Tyrosine depletion attenuates dopamine function in healthy volunteers , 2001, Psychopharmacology.

[18]  P. Cowen,et al.  Antidopaminergic effects of dietary tyrosine depletion in healthy subjects and patients with manic illness , 2001, British Journal of Psychiatry.

[19]  Philip J. Cowen,et al.  Effect of a tyrosine-free amino acid mixture on regional brain catecholamine synthesis and release , 1999, Psychopharmacology.

[20]  A. Malhotra,et al.  Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[21]  A. Malhotra,et al.  Effects of NMDA antagonism on striatal dopamine release in healthy subjects: Application of a novel PET approach , 1998, Synapse.

[22]  Richard A. Robb,et al.  The biomedical imaging resource at Mayo Clinic , 2001, IEEE Transactions on Medical Imaging.