DA-Phen as a new potential DA-mimetic agent for treatment of alcohol addiction: preclinical in vivo studies

Abstract

Rewarding and reinforcing properties of alcohol are mediated by activation of the mesolimbic dopaminergic system1. This neurosystem is hypofunctional in the addicted brain, even beyond somatic and psychological signs of withdrawal. Boosting strategy on the dopaminergic tone could represent a valid approach to alcohol addiction treatment2. The effects of a new dopamine conjugate3 (2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide, DA-Phen) on operant behaviour and on withdrawal behaviour, following alcohol deprivation, were evaluated. The concentration of acetaldehyde (ACD), ethanol's first metabolite, as an indirect measure of the possible DA-Phen modulation in alcohol consumption, was also assessed. Male Wistar rats were tested in an operant paradigm, made by different phases: Habituation (Ethanol 5%), Training (Ethanol 20%), Extinction and Deprivation/Relapse (3 cycles). Rats were treated with DA-Phen (0.03 mmol/kg i.p) during abstinence, or during relapse. Behavioural reactivity and anxiety-like behaviour during withdrawal were also evaluated. At the end of described paradigm, animals were sacrificed, and DA-Phen distribution in organ homogenates was detected and quantified. Da-Phen promoted a reduction in alcohol intake by 50% from the second day of relapse (p<0.001). DA-Phen administration was also able to induce significant reductions in chronically alcohol-treated rats on main OF (total distance travelled, p<0.001; percentage of time on centre, p<0.05) and EPM parameters (percentage of open time, p<0.001; open arm entries, p<0.05; and head dippings, p<0.001). Quantitative Da-Phen analysis indicated a distribution in kidneys (0.806±0.088g/g), spleen (0.432±0.035 g/g), plasma (0.223±0.065 g/g), liver (0.138±0.006 g/g) and cerebral region (0.101±0.008 g/g). The quantification of ACD in brain and liver homogenates of ethanol drinking rats showed a reduction in ACD levels when DA-Phen was administered (25.24±1.30 g/g in the brain and 3.20±0.60 g/g in the liver), with respect to untreated subjects (30.28±2.80 g/g in the brain and 2.25±0.40 g/g in the liver).In conclusion, DA-Phen reduces ethanol intake, likely enhancing dopaminergic tone, and reduced withdrawal behaviour. Our data also suggest that DA-Phen is able to produce the decrease of ACD concentration in both brain and liver, probably due to a condensation between ACD and DA-Phen. Further studies are ongoing in order to verify this hypothesis.