Disulfiram stimulates dopamine release from noradrenergic terminals and potentiates cocaine-induced dopamine release in the prefrontal cortex
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Disulfiram efficacy in treatment of cocaine addiction is attributed to the inhibition of dopamine-β-hydroxylase and reduction in brain noradrenaline (NA)/dopamine (DA) ratio.
Using microdialysis, we investigated if disulfiram causes DA release from noradrenergic terminals and modifies cocaine-induced DA release.
Disulfiram reduced extracellular NA in the medial prefrontal (mPF) cortex, occipital cortex, accumbens and caudate nuclei, while it markedly increased DA not only in mPF but also in the occipital cortex, despite its scanty dopaminergic afferences, and modestly increased DA in the accumbens and caudate nuclei, despite their dense dopaminergic innervation. Disulfiram-induced DA accumulation was reversed in both cortices by tetrodotoxin infusion and by systemic administration of the α2-adrenoceptor agonist clonidine, but was not modified by the α2-adrenoceptor antagonist RS 79948 or the D2-like agonist quinpirole. Disulfiram prevented cocaine-induced NA release in the mPF cortex and nucleus accumbens, potentiated cocaine-induced DA release in the mPF cortex but failed to modify cocaine effect in the nucleus accumbens. DA release induced by disulfiram-cocaine combination in the mPF cortex was prevented by clonidine but not by quinpirole.
We suggested that disulfiram, by removing NA-mediated inhibitory control on noradrenergic terminals, causes an unrestrained cocaine-induced DA release from those terminals in the mPF cortex. In the accumbens and caudate nuclei, “allogenic” DA concentration might be clouded by DA originated from dopaminergic terminals. The possible role of “allogenic” DA in disulfiram ability to prevent stress-induced reinstatement of cocaine seeking is discussed.
KeywordsCocaine DBH Disulfiram Dopamine Microdialysis Noradrenaline Prefrontal cortex Nucleus accumbens α2-Autoreceptors
The authors declare no competing financial interests. This study was supported by the “Guy Everett Laboratory” Foundation. The authors state that the experiments comply with the current Italian laws on laboratory animal use.
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