title: Co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex induced by clozapine, the prototype atypical antipsychotic.
abstract: BACKGROUND
  Clozapine has been shown to increase extracellular dopamine (DA) and noradrenaline (NA) in the medial prefrontal cortex (mPFC). A recent study of ours suggested that extracellular DA in the PFC originates not only from dopaminergic but also from noradrenergic terminals, its release being controlled by alpha(2)-adrenoceptors.
  
  
  OBJECTIVE
  Since clozapine binds to alpha(2)-adrenoceptors, the possibility that it might co-release DA and NA was studied.
  
  
  METHODS
  By means of microdialysis coupled to HPLC with electrochemical detection, the effect of clozapine on extracellular DA and NA in the mPFC, densely innervated by DA and NA, was compared to that in the occipital cortex, equally innervated by NA but receiving few DA projections.
  
  
  RESULTS
  Extracellular NA was found to be the same in the two cortices, consistent with homogeneous NA innervation. On the other hand, extracellular DA in the occipital cortex was only 29% lower than in the mPFC, in spite of the scarce dopaminergic innervation in the occipital cortex. Clozapine (10 mg/kg IP) increased extracellular DA and NA not only in the mPFC (by about 320% and 290%, respectively) but also in the occipital cortex (by 560% and 230%, respectively). Administration of the alpha(2)-agonist clonidine (0.15 mg/kg) reversed the effect of clozapine in both cortices, while the D(2)-agonist quinpirole (0.1 mg/kg IP) was ineffective.
  
  
  CONCLUSIONS
  The results suggest that clozapine, by inhibiting alpha(2)-adrenoceptors, co-releases DA and NA from noradrenergic terminals in the occipital cortex and that the same mechanism might be responsible for the concomitant increase of the two monoamines in the mPFC.
authors.affiliation: B.B. Brodie Department of Neuroscience, University of Cagliari, Cittadella Universitaria, SS 554 km 4.500, 09042, Monserrato, Italy. pdevoto@unica.it
authors.forename: Paola
authors.initials: P
authors.lastname: Devoto
authors.forename: Giovanna
authors.initials: G
authors.lastname: Flore
authors.forename: Giada
authors.initials: G
authors.lastname: Vacca
authors.forename: Luigi
authors.initials: L
authors.lastname: Pira
authors.forename: Alessandra
authors.initials: A
authors.lastname: Arca
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Casu
authors.forename: Luca
authors.initials: L
authors.lastname: Pani
authors.forename: Gian Luigi
authors.initials: GL
authors.lastname: Gessa
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003000:Clonidine / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D017551:Microdialysis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D009778:Occipital Lobe / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000316:Adrenergic alpha-Agonists; D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D019257:Quinpirole; D003024:Clozapine; D003000:Clonidine; D004298:Dopamine; D009638:Norepinephrine