Disulfiram (DSF), used for the treatment of
alcohol use disorders (AUDs) for over six decades, most recently has shown promise for treating
cocaine dependence. Although DSF's mechanism of action in
alcohol abuse is due to the inhibition of liver
mitochondrial aldehyde dehydrogenase (ALDH2), its mechanism of action in the treatment of
cocaine dependence is unknown. DSF is a
pro-drug, forming a number of metabolites each with discrete pharmacological actions. One metabolite formed during DSF bioactivation is S-(N, N-diethylcarbamoyl)
glutathione (
carbamathione) (carb). We previously showed that carb affects
glutamate binding. In the present studies, we employed microdialysis techniques to investigate the effect of carb administration on
dopamine (DA),
GABA, and
glutamate (Glu) in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), two brain regions implicated in
substance abuse dependence. The effect of DSF on DA,
GABA, and Glu in the NAc also was determined. Both studies were carried out in male rats. Carb (20, 50, 200 mg/kg i v) in a dose-dependent manner increased DA, decreased
GABA, and had a biphasic effect on Glu, first increasing and then decreasing Glu in both the NAc and mPFC. These changes all occurred concurrently. After carb administration, NAc and mPFC carb, as well as carb in plasma, were rapidly eliminated with a half-life for each approximately 4 min, while the changes in DA,
GABA, and GLu in the NAc and mPFC persisted for approximately two hours. The maximal increase in carb (Cmax) in the NAc and mPFC after carb administration was dose-dependent, as was the area under the curve (AUC). DSF (200 mg/kg i p) also increased DA, decreased
GABA, and had a biphasic effect on Glu in the NAc similar to that observed in the NAc after carb administration. When the
cytochrome P450 inhibitor
N-benzylimidazole (NBI) (20 mg/kg i p) was administered before DSF dosing, no carb could be detected in the NAc and plasma and also no changes in NAc DA,
GABA, and GLu occurred. Changes in these
neurotransmitters occurred only if carb was formed from DSF. When NBI was administered prior to dosing with carb, the increase in DA, decrease in
GABA, and biphasic effect on GLu was similar to that seen after dosing with carb only. The i p or i v administration of carb showed similar changes in DA,
GABA, and GLu, except the time to reach Cmax for DA as well as the changes in
GABA, and GLu after i p administration occurred later. The elimination half-life of carb and the area under the curve (AUC) were similar after both routes of administration. It is concluded that carb must be formed from DSF before any changes in DA,
GABA, and GLu in the NAc and mPFC are observed. DSF and carb, when administered to rats, co-release DA,
GABA, and GLu. Carb, once formed can cross the blood brain barrier and enter the brain. Although inhibition of liver ALDH2 is the accepted mechanism for DSF's action in treating AUDs, the concurrent changes in DA,
GABA, and GLu in the NAc and mPFC after DSF administration suggest that changes in these
neurotransmitters as a potential mechanism of action not only for AUDs, but also for
cocaine dependence cannot be excluded.