Dopamine Beta Hydroxylase (DBH) is the catecholamine biosynthetic enzyme that converts dopamine (DA) to norepinephrine (NE) and controls the NE/DA ratio in noradrenergic neurons. Inhibition and low activity of this enzyme has been found to alter behavioral responses to cocaine. Dbh knockout mice are hypersensitive to the rewarding and aversive effects of cocaine and have reduced basal and psychostimulant-induced DA release. In humans, DBH expression, and therefore activity, is affected by a polymorphism in the promoter region of the Dbh gene. Low DBH activity is associated with increased feelings of paranoia following cocaine administration and increased success in attenuating cocaine intake when administered the pharmacological agent disulfiram (Antabuse). The mechanism of action by which disulfiram is decreasing cocaine-intake is not completely understood. As a copper chelator, disulfiram affects multiple enzymes. We hypothesize that disulfiram is causing altered responses to cocaine by inhibiting DBH (which requires copper as a co-factor). We believe that chronic inhibition of the enzyme, as that seen in Dbh -/- mice, leads to a compensatory upregulation of DA receptors. Therefore, when a psychostimulant such as cocaine is administered, there is an increase in dopaminergic signaling due to the increased number of DA receptors. Specifically, I believe D2 receptor upregulation and increased signaling are responsible for this response since Dbh -/- mice are hypersensitive to the behavioral effects of a D2 agonist, but not a D1 agonist. The overall goal of this project is to assess whether this hyperdopaminergic signaling underlies the aversive reactions to cocaine. I will use pharmacological inhibition of DBH in wildtype mice (via disulfiram and the selective DBH inhibitor nepicastat) to test this by 1) measuring how this affects basal and cocaine-induced catecholamine release using in vivo microdialysis;2) examining its effect on high affinity state D2 receptors using radioligand binding and;3) whether pharmacological DBH inhibition can elicit a D2-sensitive conditioned place aversion to cocaine. I will also use Dbh -/- mice to determine whether a D2 agonist can support a Conditioned Place Preference (CPP) and whether this can be blocked by a D2 antagonist. Given the dearth of cocaine addiction therapeutics and the small amount of preclinical data regarding the mechanism by which disulfiram works to decrease cocaine intake, these studies will shed insight into the neurobiology of cocaine addiction, and possibly identify specific targets for cocaine addiction pharmacotherapies.
| Gaval-Cruz, Meriem; Goertz, Richard B; Puttick, Daniel J et al. (2016) Chronic loss of noradrenergic tone produces ?-arrestin2-mediated cocaine hypersensitivity and alters cellular D2 responses in the nucleus accumbens. Addict Biol 21:35-48 |
| Gaval-Cruz, Meriem; Liles, Larry Cameron; Iuvone, Paul Michael et al. (2012) Chronic inhibition of dopamine ýý-hydroxylase facilitates behavioral responses to cocaine in mice. PLoS One 7:e50583 |
| Keebaugh, Alaine C; Mitchell, Heather A; Gaval-Cruz, Meriem et al. (2011) PRTFDC1 is a genetic modifier of HPRT-deficiency in the mouse. PLoS One 6:e22381 |
| Schroeder, Jason P; Cooper, Debra A; Schank, Jesse R et al. (2010) Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine ?-hydroxylase. Neuropsychopharmacology 35:2440-9 |
| Gaval-Cruz, Meriem; Weinshenker, David (2009) mechanisms of disulfiram-induced cocaine abstinence: antabuse and cocaine relapse. Mol Interv 9:175-87 |
