Journal of Neurochemistry, 2004, 89, 273–285 doi:10.1111/j.1471-4159.2004.02394.x
REVIEW Neuropeptides: implications for alcoholism
Michael S. Cowen*, , Feng Chen*, and Andrew J. Lawrence*,
*The Howard Florey Institute, University of Melbourne, VIC 3010, Australia Department of Pharmacology, Monash University, VIC 3800 Australia
Abstract (CRF), urocortin I and neuropeptide Y (NPY) in deleterious The role of neuromodulatory peptides in the aetiology of and excessive alcohol consumption, focussing on specific alcoholism has been relatively under-explored; however, the brain regions, in particular the central nucleus of the development of selective ligands for neuropeptide receptors, amygdala, that appear to be implicated in the pathophysi- the characterization and cloning of receptors, and the ology of alcoholism. The review also outlines potential development of transgenic mouse models have greatly directions for further research to clarify neuropeptide facilitated this analysis. The present review considers the involvement in neuromodulation within discrete brain nuclei most recent preclinical evidence obtained from animal pertinent to behavioural patterns. models for the role of two of the opioid peptides, namely J. Neurochem. (2004) 89, 273–285. b-endorphin and enkephalin; corticotropin-releasing factor
Alcohol causes as much, if not more death and disabilityas analysis. However, drugs that interact with neuropeptide measles, malaria, tobacco or illegal drugs (World Health systems have great potential in the pharmacotherapy of Organization, 2001) . In economic terms, alcohol abuse has alcoholism: witness the widespread (although somewhat less been estimated at US$167 billion per year; however, ‘in than satisfactory) use of the opioid antagonist naltrexone in human terms, the costs are incalculable’ (National Institute the treatment of alcoholism (O’Malley et al. 1992; Volpicelli on Alcohol Abuse and Alcoholism, 2001). For these reasons et al. 1992), identified prior to clinical use via a large bodyof there has been extensive research into the pathophysiology preclinical data (see Cowen and Lawrence 1999). Based on underlying alcoholism; however, current therapeutic approa- the preclinical and other data, several other neuropeptides ches cannot be regarded as a comprehensive solution to this mayhave a significant role in the aetiologyof alcoholism; extensive problem (Graham et al. 2002). A number of brain these are discussed herein. regions have been identified as being significantlyinvolved in the reinforcing (and ultimatelyaddictive) properties of Opioid peptides alcohol, including the ventral tegmental area, the nucleus A reasonable bodyof evidence now indicates that ethanol, at accumbens and the amygdala (Fig. 1; see Koob et al. 1998). reward-relevant doses, causes the release of b-endorphin In particular, as will be emphasised in this review, the central from both neuronal (hypothalamic) and non-neuronal (i.e. the nucleus of the amygdala (CeA) appears to have a significant anterior pituitary) sources. As indicated in Table 1, people at role in this regard. Several neurotransmitters have now been high risk for the development of alcoholism (strong family implicated in the pathophysiology of alcoholism, including history) show a significantly greater ethanol-induced dopamine, serotonin, GABA (Koob et al. 1998) and gluta- pituitaryrelease of b-endorphin (reflected in serum levels) matergic-mediated neurotransmission (Tsai and Coyle 1998). Until relativelyrecentlyhowever, the role of neuromodula- torypeptides in the aetiologyof alcoholism has been Received May12, 2003; revised manuscript received October 12, 2003; somewhat under-explored (with the possible exception of accepted November 7, 2003. opioid peptides), due in part to the lack of selective ligands Address correspondence and reprint requests to Dr Michael Cowen, The Howard FloreyInstitute, Universityof Melbourne, VIC 31010, for neuropeptide receptors, the late characterization and Australia. E-mail: m.cowen@hfi.unimelb.edu.au cloning of the receptors themselves, and the relativelyrecent Abbreviations used: CeA, Central nucleus of the amygdala; CRF, development of other tools (such as transgenic/knockout corticotropin-releasing factor; i.c.v., intracerebroventricular; i.p., mice and genetic analysis of trait loci) that can facilitate this intraperitioneal; NPY, neuropeptide Y.