title: Selective inhibition of dopamine-beta-hydroxylase enhances dopamine release from noradrenergic terminals in the medial prefrontal cortex.
abstract: BACKGROUND
  Disulfiram has been claimed to be useful in cocaine addiction therapy, its efficacy being attributed to dopamine-beta-hydroxylase (DBH) inhibition. Our previous results indicate that disulfiram and the selective DBH inhibitor nepicastat increase extracellular dopamine (DA) in the rat medial prefrontal cortex (mPFC), and markedly potentiated cocaine-induced increase. Concomitantly, in rats with cocaine self-administration history, cocaine-seeking behavior induced by drug priming was prevented, probably through overstimulation of D1 receptors due to the DA increase. The present research was aimed at studying the neurochemical mechanisms originating the enhanced DA release.
  
  
  METHODS
  Noradrenergic system ablation was attained by intracerebroventricular (i.c.v.) administration of the neurotoxin anti-DBH-saporin (aDBH-sap). DA, noradrenaline (NA), and DOPAC were assessed by HPLC after ex vivo tissue extraction or in vivo microdialysis. Control and denervated rats were subjected to microdialysis in the mPFC and caudate nucleus to evaluate the effect of nepicastat-cocaine combination on extracellular DA levels and their regulation by α2-adrenoceptors.
  
  
  RESULTS
  Fifteen days after neurotoxin or its vehicle administration, tissue and extracellular NA were reduced to less than 2% the control value, while extracellular DA was increased by approximately 100%. In control rats, nepicastat given alone and in combination with cocaine increased extracellular DA by about 250% and 1100%, respectively. In denervated rats, nepicastat slightly affected extracellular DA, while in combination with cocaine increased extracellular DA by 250%. No differences were found in the caudate nucleus. Clonidine almost totally reversed the extracellular DA elevation produced by nepicastat-cocaine combination, while it was ineffective in denervated rats.
  
  
  CONCLUSIONS
  This research shows that the increase of extracellular DA produced by nepicastat alone or in combination with cocaine was prevented by noradrenergic denervation. The results indicate that nepicastat enhances DA release from noradrenergic terminals supposedly by removing NA from α2-autoreceptors. In addition to the inhibition of DA uptake, the latter mechanism may explain the synergistic effect of cocaine on nepicastat-induced DA release.
authors.affiliation: Department of Biomedical Sciences Section of Neuroscience and Clinical Pharmacology University of Cagliari Cagliari Italy ; "Guy Everett Laboratory" University of Cagliari Cagliari Italy ; Center of Excellence "Neurobiology of Addiction" University of Cagliari Cagliari Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Devoto
authors.affiliation: Department of Medical Sciences University of Cagliari Cagliari Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Flore
authors.affiliation: Department of Biomedical Sciences Section of Neuroscience and Clinical Pharmacology University of Cagliari Cagliari Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Saba
authors.affiliation: Department of Biomedical Sciences Section of Neuroscience and Clinical Pharmacology University of Cagliari Cagliari Italy ; "Guy Everett Laboratory" University of Cagliari Cagliari Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Frau
authors.affiliation: Department of Biomedical Sciences Section of Neuroscience and Clinical Pharmacology University of Cagliari Cagliari Italy ; "Guy Everett Laboratory" University of Cagliari Cagliari Italy ; National Research Council CNR, Institute of Neuroscience Cagliari Italy.
authors.forename: Gian L
authors.initials: GL
authors.lastname: Gessa
mesh_terms: D059331:Adrenergic Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage; D004298:Dopamine / Q000378:metabolism*; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D007276:Injections, Intraventricular; D008297:Male; D017551:Microdialysis; D009638:Norepinephrine / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D013871:Thiones / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D013871:Thiones; D004299:Dopamine beta-Hydroxylase; D003042:Cocaine; C109487:nepicastat; D004298:Dopamine; D009638:Norepinephrine
keywords: cocaine; corelease; microdialysis; nepicastat; α2‐adrenoceptor