Acute phenylalanine/tyrosine depletion of phasic dopamine in the rat brain
- 303 Downloads
Dopamine plays a critical role in striatal and cortical function, and depletion of the dopamine precursors phenylalanine and tyrosine is used in humans to temporarily reduce dopamine and probe the role of dopamine in behavior. This method has been shown to alter addiction-related behaviors and cognitive functioning presumably by reducing dopamine transmission, but it is unclear what specific aspects of dopamine transmission are altered.
We performed this study to confirm that administration of an amino acid mixture omitting phenylalanine and tyrosine (Phe/Tyr[−]) reduces tyrosine tissue content in the prefrontal cortex (PFC) and nucleus accumbens (NAc), and to test the hypothesis that Phe/Tyr[−] administration reduces phasic dopamine release in the NAc.
Rats were injected with a Phe/Tyr[−] amino acid mixture, a control amino acid mixture, or saline. High-performance liquid chromatography was used to determine the concentration of tyrosine, dopamine, or norepinephrine in tissue punches from the PFC and ventral striatum. In a separate group of rats, phasic dopamine release was measured with fast-scan cyclic voltammetry in the NAc core after injection with either the Phe/Tyr[−] mixture or the control amino acid solution.
Phe/Tyr[−] reduced tyrosine content in the PFC and NAc, but dopamine and norepinephrine tissue content were not reduced. Moreover, Phe/Tyr[−] decreased the frequency of dopamine transients, but not their amplitude, in freely moving rats.
These results indicate that depletion of tyrosine via Phe/Tyr[−] decreases phasic dopamine transmission, providing insight into the mechanism by which this method modifies dopamine-dependent behaviors in human imaging studies.
Keywords(Up to 10) Dopamine Norepinephrine Tyrosine Fast-scan cyclic voltammetry Nucleus accumbens Prefrontal cortex Depletion
Authors thank Dr. Paul Kropp for consultation on protocols for the amino acid mixtures, Dr. Chris Wiesen (UNC Odum Institute for Research in Social Science) for statistical consultation, and Drs. Margaret Broadwater and Aric Madayag for technical assistance and critical comments on the manuscript.
DLR and CAB conceptualized the experiments. TAS, SCT, DLR, and WL collected and analyzed the voltammetric data. SJS, SZ, RUC, JMD, and RAG set up HPLC procedures and collected and analyzed the tissue content data. DLR, TAS, SJS, SZ, CAB, and RAG interpreted the data and prepared the manuscript.
Compliance with ethical standards
This research was funded by the NIH (P60 AA011605, Project no. 3), the UNC Bowles Center for Alcohol Studies, R37 AA011852 and R01 AA014874. SCT was supported on a Summer Undergraduate Research Fellowship from UNC Chapel Hill. SJS was supported on 5P60AA011605-17S1 and JMD was supported on T32 AA007471.
Conflict of interest
The authors declare that they have no competing conflict of interest.
- Jaskiw GE, Kirkbride B, Newbould E, Young D, Durkalski V, Bongiovanni R (2005) 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 179:713–724CrossRefPubMedGoogle Scholar
- Robinson DL, Heien ML, Wightman RM (2002) Frequency of dopamine concentration transients increases in dorsal and ventral striatum of male rats during introduction of conspecifics. J Neurosci 22:10477–10486Google Scholar
- Schultz W (2016) Dopamine reward prediction-error signalling: a two-component response. Nat Rev NeurosciGoogle Scholar
- Sombers LA, Beyene M, Carelli RM, Wightman RM (2009) Synaptic overflow of dopamine in the nucleus accumbens arises from neuronal activity in the ventral tegmental area. J Neurosci 29:1735–1742Google Scholar
- Volkow ND, Chang L, Wang GJ, Fowler JS, Leonido-Yee M, Franceschi D, Sedler MJ, Gatley SJ, Hitzemann R, Ding YS, Logan J, Wong C, Miller EN (2001) Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiatry 158:377–382CrossRefPubMedGoogle Scholar