title: Clozapine reconstructed: Haloperidol's ability to reduce alcohol intake in the Syrian golden hamster can be enhanced through noradrenergic modulation by desipramine and idazoxan.
abstract: BACKGROUND
  Alcohol use disorder commonly occurs in patients with schizophrenia. Most antipsychotic drugs do not lessen alcohol use; although the atypical antipsychotic clozapine has been shown to reduce alcohol use in patients with schizophrenia, its toxicity severely limits its use in patients. With an eye toward creation of a safer clozapine-like drug, we have investigated the pharmacological basis of the clozapine's effects on alcohol drinking in the Syrian golden hamster. In this animal, as in patients with schizophrenia, clozapine reduces alcohol drinking while the typical antipsychotic haloperidol does not. We have suggested that clozapine decreases alcohol drinking due to its weak dopamine D2 receptor blockade, its potent norepinephrine α-2 receptor antagonism, as well as its ability to elevate plasma norepinephrine.
  
  
  METHODS
  We recreated a clozapine-like drug to reduce alcohol drinking in the Syrian golden hamster by combining low dose haloperidol with a norepinephrine α-2 receptor antagonist, idazoxan, and a norepinephrine reuptake inhibitor, desipramine. Hamsters were given free access to water and alcohol (15% v/v) and were treated daily with each drug or with the three-drug combination for 23 days.
  
  
  RESULTS
  The drug combination reduced alcohol drinking and preference significantly as compared to vehicle or to haloperidol, idazoxan or desipramine, while not altering food-intake or body-weight.
  
  
  CONCLUSIONS
  These findings suggest that that haloperidol, which does not reduce alcohol drinking in patients with schizophrenia or the hamster, if combined with idazoxan and desipramine (producing a drug combination that mimics aspects of clozapine's pharmacology) is able to reduce alcohol drinking in the hamster.
authors.affiliation: Department of Psychiatry, Geisel School of Medicine at Dartmouth, Dartmouth College, Lebanon, NH, United States.
authors.forename: Jibran Y
authors.initials: JY
authors.lastname: Khokhar
authors.affiliation: Department of Psychiatry, Geisel School of Medicine at Dartmouth, Dartmouth College, Lebanon, NH, United States.
authors.forename: David T
authors.initials: DT
authors.lastname: Chau
authors.affiliation: Frontier Science Research and Technology Foundation, Boston, MA, United States.
authors.forename: Ree
authors.initials: R
authors.lastname: Dawson
authors.affiliation: Department of Psychiatry, Geisel School of Medicine at Dartmouth, Dartmouth College, Lebanon, NH, United States; The Dartmouth Clinical and Translational Science Institute, Dartmouth College, Hanover, NH, United States. Electronic address: alan.i.green@dartmouth.edu.
authors.forename: Alan I
authors.initials: AI
authors.lastname: Green
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology*; D000328:Adult; D000428:Alcohol Drinking / Q000517:prevention & control*; D000818:Animals; D003024:Clozapine / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004435:Eating / Q000187:drug effects; D005260:Female; D006220:Haloperidol / Q000494:pharmacology*; D006801:Humans; D019329:Idazoxan / Q000494:pharmacology*; D008297:Male; D008647:Mesocricetus; D017448:Receptors, Dopamine D2 / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D058669:Adrenergic alpha-2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D003024:Clozapine; D006220:Haloperidol; D003891:Desipramine; D019329:Idazoxan
keywords: Addiction; Alcoholism; Antipsychotic; Norepinephrine; Schizophrenia