Desipramine enhances the ability of paliperidone to decrease alcohol drinking

anon79999497 · September 8, 2015, 11:48am

ncbi.nlm.nih.gov

Desipramine enhances the ability of paliperidone to decrease alcohol drinking.

DT Chau, JY Khokhar, D Gulick, R Dawson and AI Green, Journal of psychiatric research, Oct 2015

Alcohol use disorder commonly occurs in patients with schizophrenia and dramatically worsens their course. The atypical antipsychotic clozapine has been associated with reduced drinking in these patients, but its toxicity reduces its use. We have attempted to create a clozapine-like drug by combining agents that capture components of clozapine's pharmacologic action, including its weak dopamine D2 blockade and noradrenergic modulation. The current study assessed whether paliperidone, a dopamine D2 receptor and adrenergic alpha-2 receptor antagonist like clozapine, would attenuate alcohol drinking in the alcohol-preferring P rat and the Syrian golden hamster, and whether desipramine, a norepinephrine reuptake inhibitor, would potentiate the ability of paliperidone to attenuate alcohol drinking in the P rat and the Syrian golden hamster. Daily subcutaneous injections of paliperidone (5 mg/kg for the rat; 1 mg/kg for the hamster) over 20 days slightly and transiently attenuated initiation of alcohol consumption in both animals. Desipramine (3 mg/kg) or lower doses of paliperidone alone did not affect alcohol drinking. However, the combination of desipramine (3 mg/kg) and paliperidone essentially prevented initiation of alcohol drinking and acquisition of alcohol preference in the P rat (2.5 or 5 mg/kg), and almost as dramatically suppressed chronic alcohol intake and alcohol preference in the hamster (2.5 mg/kg). Taken together, the current data suggest that (1) the desipramine and paliperidone combination attenuates alcohol drinking in a synergistic manner, and (2) desipramine and paliperidone may serve as an effective new treatment for alcohol use disorder in patients with schizophrenia.

notmoses · September 8, 2015, 10:49pm

Makes sense because Ne works against Da, but to get this effect, the Ne has to hit the targets (probably in the striatum, nucleus accumbens and ventral tegmentum) pretty much dead on without doing “collateral damage” to some other targets. Tricky, but very interesting.

(Wonder what George Koob will have to say, since he has been The Man on this sort of stuff for 25 years.)