Desipramine enhances the ability of paliperidone to decrease alcohol drinking.
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.
Department of Psychiatry, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
David T
DT
Chau
Department of Psychiatry, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
Jibran Y
JY
Khokhar
Department of Psychiatry, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
Danielle
D
Gulick
Frontier Science and Technology Research Foundation, Inc., Boston, MA 02215, USA.
Ree
R
Dawson
Department of Psychiatry, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA; Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA; Dartmouth Clinical and Translational Science Institute, Dartmouth College, Hanover, NH, USA. Electronic address: alan.i.green@dartmouth.edu.
Alan I
AI
Green
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000427:Alcohol Deterrents / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000188:drug therapy*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D002755:Choice Behavior / Q000187:drug effects; D003891:Desipramine / Q000494:pharmacology*; D004195:Disease Models, Animal; D065127:Dopamine D2 Receptor Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D060766:Drinking Water / Q000008:administration & dosage; D004357:Drug Synergism; D004435:Eating / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage; D008297:Male; D008647:Mesocricetus; D000068882:Paliperidone Palmitate / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D013045:Species Specificity
D018759:Adrenergic Uptake Inhibitors; D058669:Adrenergic alpha-2 Receptor Antagonists; D000427:Alcohol Deterrents; D002492:Central Nervous System Depressants; D065127:Dopamine D2 Receptor Antagonists; D060766:Drinking Water; D000431:Ethanol; D000068882:Paliperidone Palmitate; D003891:Desipramine
Alcoholism; Dual disorder; Hamster; Rat; Schizophrenia; Treatment