title: 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.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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 mug/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 mug/ml did not affect basal DA levels either in MPFC or striatum. Within the MPFC, tyrosine 50.0 mug/ml significantly increased CLZ-induced DA levels. Within the striatum, tyrosine 25.0 mug/ml significantly increased while 150.0 mug/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.
authors.affiliation: Psychiatry Service, Louis Stokes Cleveland Veterans Administration Medical Center, Cleveland, Ohio, USA. gxj5@po.cwru.edu
authors.forename: George E
authors.initials: GE
authors.lastname: Jaskiw
authors.forename: Bobbi
authors.initials: B
authors.lastname: Kirkbride
authors.forename: Erica
authors.initials: E
authors.lastname: Newbould
authors.forename: Damon
authors.initials: D
authors.lastname: Young
authors.forename: Valerie
authors.initials: V
authors.lastname: Durkalski
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Bongiovanni
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000494:pharmacology* / Q000502:physiology
chemical_list: D000596:Amino Acids; D014150:Antipsychotic Agents; D014443:Tyrosine; D003024:Clozapine; D006220:Haloperidol; D004298:Dopamine