Co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex induced by clozapine, the prototype atypical antipsychotic

Rationale: 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 α2-adrenoceptors. Objectives: Since clozapine binds to α2-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 α2-agonist clonidine (0.15 mg/kg) reversed the effect of clozapine in both cortices, while the D2-agonist quinpirole (0.1 mg/kg IP) was ineffective. Conclusions: The results suggest that clozapine, by inhibiting α2-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.