Disulfiram stimulates dopamine release from noradrenergic terminals and potentiates cocaine-induced dopamine release in the prefrontal cortex
- 359 Downloads
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
- Deutch AY (1992) The regulation of subcortical dopamine system by the prefrontal cortex: interaction of central dopamine systems and the pathogenesis of schizophrenia. J Neural Transm 36:61–89Google Scholar
- Devoto P, Flore G, Vacca G, Pira L, Arca A, Casu MA, Pani L, Gessa GL (2003b) Co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex induced by clozapine, the prototype atypical antipsychotic. Psychopharmacol 167:79–84Google Scholar
- Park WK, Bari AA, Jey AR, Anderson SM, Spealman RD, Rowlett JK, Pierce RC (2002) Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by increasing AMPA receptor-mediated glutamate transmission in the nucleus accumbens. J Neurosci 22:2916–2925PubMedGoogle Scholar
- Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, 3rd edn. Academic, San DiegoGoogle Scholar
- Pirot S, Godbout R, Mantz J, Tassin JP, Glowinski J, Thierry AM (1992) Inhibitory effects of ventral tegmental area stimulation on the activity of prefrontal cortical neurons: evidence for the involvement of both dopaminergic and GABAergic components. Neuroscience 49:857–865PubMedCrossRefGoogle Scholar
- Schroeder JP, Cooper DA, Schank JR, Lyle MA, Gaval-Cruz M, Ogbonmwan YE, Pozdeyev N, Freeman KG, Iuvone PM, Edwards GL, Holmes PV, Weinshenker D (2010) Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine β-hydroxylase. Neuropsychopharmacology 35:2440–2449PubMedCrossRefGoogle Scholar
- Stanley WC, Li B, Bonhaus DW, Johnson LG, Lee K, Porter S, Walker K, Martinez G, Eglen RM, Whiting RL, Hegde SS (1997) Catecholamine modulatory effects of nepicastat (RS-25560-197), a novel, potent and selective inhibitor of dopamine-beta-hydroxylase. Br J Pharmacol 121:1803–1809PubMedCrossRefGoogle Scholar
- Weinshenker D, Ferrucci M, Busceti CL, Biagioni F, Lazzeri G, Liles LC, Lenzi P, Pasquali L, Murri L, Paparelli A, Fornai F (2008) Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioral, and neurotoxic effects of methamphetamine. J Neurochem 105:471–483PubMedCrossRefGoogle Scholar
- Yao L, Fan P, Arolfo M, Jiang Z, Olive MF, Zablocki J, Sun HL, Chu N, Lee J, Kim HY, Leung K, Shryock J, Blackburn B, Diamond I (2010) Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use-dependent inhibitor of dopamine synthesis. Nat Med 16:1024–1028PubMedCrossRefGoogle Scholar