Translating the neuroscience of alcoholism into clinical treatments: from blocking the buzz to curing the blues.
Understanding the pathophysiology of addictive disorders is critical for development of new treatments. A major focus of addiction research has for a long time been on systems that mediate acute positively reinforcing effects of addictive drugs, most prominently the mesolimbic dopaminergic (DA) system and its connections. This research line has been successful in shedding light on the physiology of both natural and drug reward, but has not led to therapeutic breakthroughs. The role of classical reward systems is perhaps least clear in alcohol addiction. Here, recent work is summarized that points to some clinically important conclusions. First, important pharmacogenetic differences exist with regard to positively reinforcing effects of alcohol and the ability of this drug to activate classical reward pathways. This offers an opportunity for personalized treatment approaches in alcoholism. Second, brain stress and fear systems become pathologically activated in later stages of alcoholism and their activation is a major influence in escalation of alcohol intake, sensitization of stress responses, and susceptibility to relapse. These findings offer a new category of treatment mechanisms. Corticotropin-releasing hormone (CRH) signaling through CRH1 receptors is a major candidate target in this category, but recent data indicate that antagonists for substance P (SP) neurokinin 1 (NK1) receptors may have a similar potential.
Heilig
Markus
M
Laboratory of Clinical and Translational Studies, National Inst. on Alcohol Abuse and Alcoholism, National Inst of Health, Bethesda, MD, United States. markus.heilig@mail.nih.gov
Thorsell
Annika
A
Sommer
Wolfgang H
WH
Hansson
Anita C
AC
Ramchandani
Vijay A
VA
George
David T
DT
Hommer
Daniel
D
Barr
Christina S
CS
D000437:Alcoholism / Q000188:drug therapy / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D003346:Corticotropin-Releasing Hormone / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods; D000431:Ethanol / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D064729:Neurokinin-1 Receptor Antagonists; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D013373:Substance P / Q000502:physiology; D057170:Translational Research, Biomedical / Q000379:methods*; D000099052:CRF Receptor, Type 1
D064729:Neurokinin-1 Receptor Antagonists; D018019:Receptors, Corticotropin-Releasing Hormone; D013373:Substance P; D000431:Ethanol; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone