Disulfiram stimulates dopamine release from noradrenergic terminals and potentiates cocaine-induced dopamine release in the prefrontal cortex

Abstract

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.

Dopamine β-Hydroxylase Inhibitors Enhance the Discriminative Stimulus Effects of Cocaine in Rats

“…Recent in vivo microdialysis studies in rats found that disulfiram or nepicastat alone produced robust increases in extracellular DA levels (approximately 300% above baseline) within the prefrontal cortex (PFC) (Devoto et al, 2012(Devoto et al, , 2013, a terminal region of DAergic mesocorticolimbic projections known to play a prominent role in the abuse-related effects of cocaine (Wise, 2009). In contrast, neither DBH inhibitor altered basal DA levels within the nucleus accumbens (NAc).…”

“…Because cocaine-induced increases in DA within the NAc rather than the PFC predominantly mediate the discriminative stimulus effects of cocaine (Callahan et al, 1997), it is not surprising that in the present studies, cocaine failed to generalize to either disulfiram or nepicastat. Importantly, our dose range (up to 100 mg/kg disulfiram and 56 mg/kg nepicastat) and pretreatment time (2 hours) were chosen based on our own previous work and the aforementioned microdialysis studies, which reported maximal increases in DA levels within the PFC and reductions of NE levels across multiple brain regions using these parameters (Schroeder et al, 2010;Devoto et al, 2012Devoto et al, , 2013. Thus, the experiments were optimized to detect the presence of a cocaine-like interoceptive stimulus.…”

“…Discrimination studies have consistently shown a predominant role for DA systems in mediating the interoceptive stimulus effects of cocaine and related psychostimulants (Woolverton, 1991;Callahan et al, 1997). Recent microdialysis experiments in rats indicate that short-term pretreatment with disulfiram blunts basal and cocaine-induced increases in NE overflow but enhances basal and cocaine-induced increases in DA overflow (Devoto et al, 2012). Those studies also determined that the excess DA detected after disulfiram treatment originated from noradrenergic neurons, which were unable to convert DA to NE due to DBH inhibition.…”

Disulfiram Implantation in Alcohol Dependency: Influence of Sociodemographic and Clinical Variables on Treatment Response

“…In recent years, it has been discovered that disulfiram has a significant effect on noradrenaline and dopamine pathways (20). Possibly because of these effects of disulfiram, there are growing research findings indicating that disulfiram might be used safely for alcohol dependent individuals, who have comorbidities with cocaine dependence or pathological gambling (20)(21)(22)(23).…”

“…Possibly because of these effects of disulfiram, there are growing research findings indicating that disulfiram might be used safely for alcohol dependent individuals, who have comorbidities with cocaine dependence or pathological gambling (20)(21)(22)(23). Disulfiram also can be used safely in combination with other medications treating alcohol dependence such as acamprosate, naltrexone and topiramate and it may be effective alone for adolescents with alcohol abuse and dependence.…”