Novel Medication Targets for the Treatment of Alcoholism: Preclinical Studies
Amir H. Rezvani, Andrew J. Lawrence, Maria P. Arolfo, Edward D. Levin and David H. Overstreet
Affiliation: Dept. of Psychiatry and Behavioral Sciences, Box 104790, Duke University Medical Center, Durham, NC 27710.
Keywords: Alcohol intake, ALDH2 inhibitor, carisbamate, inbred alcohol-preferring rats, inbred fawn-hooded rats, JNJ-
5234801, JNJ-39220675, RWJ-333369, sazetidine-A, CVT-10216, GS-455534, Novel Medication Targets, Treatment of Alcoholism
Alcoholism is a complex heterogeneous disease and a number of neurotransmitter and neuromodulator systems
have been implicated in its manifestation. Consequently, it is unlikely that existing medications such as disulfiram
(Antabuse®), naltrexone (ReVia®), acamprosate (Campral®)) can be efficacious in every individual. Thus, the development
of novel therapeutic agents with greater selectivity and less unwanted effects for the treatment of this disease is one
of the major objectives of alcohol research. This review summarizes the findings of five novel compounds with different
neuronal targets for treating alcoholism. These compounds include sazetidine-A, which selectively desensitizes α4β2
nicotinic receptors; carisbamate, a novel anti-epileptic agent; JNJ5234801, a novel anxiolytic agent; GS-455534, a highly
selective inhibitor of mitochondrial aldehyde dehydrogenase; and JNJ-39220675, a selective histamine H3 antagonist. Inbred
alcohol-preferring rats (iP), Fawn-Hooded (FH) rats, and P rats were used to evaluate the compounds. Naltrexone
was used as a positive control in some experiments. All five compounds reduced alcohol consumption and preference.
The mechanisms thought to underlie these effects suggest that, in addition to dopaminergic and opioidergic systems, other
neuronal systems such as sodium channels (carisbamate), mitochondrial aldehyde dehydrogenase (GS-455534), 5-HT2
receptors (JNJ-5234801), histamine H3 receptors (JNJ-39220675), and α4β2 nicotinic receptors (sazetidine-A) can be involved
in alcohol drinking. Further work is necessary to confirm the exact mechanisms of action of each drug and to determine
any viable targets for putative treatment of alcohol-use disorders. The article presents some promising patents on
novel medication targets for the treatment of alcoholism.
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