REVIEW Neuropeptides: implications for alcoholism

The role of neuromodulatory peptides in the aetiology of alcoholism has been relatively under-explored; however, the development of selective ligands for neuropeptide receptors, the characterization and cloning of receptors, and the development of transgenic mouse models have greatly facilitated this analysis. The present review considers the most recent preclinical evidence obtained from animal models for the role of two of the opioid peptides, namely b-endorphin and enkephalin; corticotropin-releasing factor (CRF), urocortin I and neuropeptide Y (NPY) in deleterious and excessive alcohol consumption, focussing on specific brain regions, in particular the central nucleus of the amygdala, that appear to be implicated in the pathophysiology of alcoholism. The review also outlines potential directions for further research to clarify neuropeptide involvement in neuromodulation within discrete brain nuclei pertinent to behavioural patterns. J. Neurochem. (2004) 89, 273–285. Alcohol causes as much, if not more death and disability as measles, malaria, tobacco or illegal drugs (World Health Organization, 2001) . In economic terms, alcohol abuse has been estimated at US$167 billion per year; however, ‘in human terms, the costs are incalculable’ (National Institute on Alcohol Abuse and Alcoholism, 2001). For these reasons there has been extensive research into the pathophysiology underlying alcoholism; however, current therapeutic approaches cannot be regarded as a comprehensive solution to this extensive problem (Graham et al. 2002). A number of brain regions have been identified as being significantly involved in the reinforcing (and ultimately addictive) properties of alcohol, including the ventral tegmental area, the nucleus accumbens and the amygdala (Fig. 1; see Koob et al. 1998). In particular, as will be emphasised in this review, the central nucleus of the amygdala (CeA) appears to have a significant role in this regard. Several neurotransmitters have now been implicated in the pathophysiology of alcoholism, including dopamine, serotonin, GABA (Koob et al. 1998) and glutamatergic-mediated neurotransmission (Tsai and Coyle 1998). Until relatively recently however, the role of neuromodulatory peptides in the aetiology of alcoholism has been somewhat under-explored (with the possible exception of opioid peptides), due in part to the lack of selective ligands for neuropeptide receptors, the late characterization and cloning of the receptors themselves, and the relatively recent development of other tools (such as transgenic/knockout mice and genetic analysis of trait loci) that can facilitate this analysis. However, drugs that interact with neuropeptide systems have great potential in the pharmacotherapy of alcoholism: witness the widespread (although somewhat less than satisfactory) use of the opioid antagonist naltrexone in the treatment of alcoholism (O’Malley et al. 1992; Volpicelli et al. 1992), identified prior to clinical use via a large body of preclinical data (see Cowen and Lawrence 1999). Based on the preclinical and other data, several other neuropeptides may have a significant role in the aetiology of alcoholism; these are discussed herein. Opioid peptides A reasonable body of evidence now indicates that ethanol, at reward-relevant doses, causes the release of b-endorphin from both neuronal (hypothalamic) and non-neuronal (i.e. the anterior pituitary) sources. As indicated in Table 1, people at high risk for the development of alcoholism (strong family history) show a significantly greater ethanol-induced pituitary release of b-endorphin (reflected in serum levels) Received May 12, 2003; revised manuscript received October 12, 2003; accepted November 7, 2003. Address correspondence and reprint requests to Dr Michael Cowen, The Howard Florey Institute, University of Melbourne, VIC 31010, Australia. E-mail: [email protected] Abbreviations used: CeA, Central nucleus of the amygdala; CRF, corticotropin-releasing factor; i.c.v., intracerebroventricular; i.p., intraperitioneal; NPY, neuropeptide Y. Journal of Neurochemistry, 2004, 89, 273–285 doi:10.1111/j.1471-4159.2004.02394.x 2004 International Society for Neurochemistry, J. Neurochem. (2004) 89, 273–285 273 compared with people at low risk for the development of alcoholism. Paralleling the human situation, alcohol-preferring strains of rats and mice show a significantly greater release of b-endorphin from the hypothalamus compared to alcohol-non-preferring strains of rat and mice. Although the parallels between the animal models with the human situation are intriguing, the role of the release of b-endorphin from the anterior pituitary in the reinforcing properties of ethanol is unclear, although there remains the possibility of retrograde transport to the median eminence and hypothalamus (Gianoulakis et al. 1989, 1996). Serum b-endorphin levels may simply be a reflection of the ethanol-induced synthesis and release of CRF (and vasopressin) from the paraventricular nucleus of the hypothalamus (Rivier et al. 1984; Ogilvie et al. 1997), which causes the release of adrenocorticotropic hormone (ACTH) and b-endorphin from the anterior pituitary (Rivier et al. 1982; Jackson et al. 1984). Given the generally recognised association of the nucleus accumbens with reward processes (Koob 1992; Koob et al. 1998), the release of b-endorphin within the nucleus accumbens in response to ethanol, as well in response to the psychostimulants cocaine and D-amphetamine (Olive et al. 2001) would appear to be significant. Since the effect of ethanol on b-endorphin release in the nucleus accumbens may occur via stimulation of the endorphinergic cell bodies within the hypothalamus (de Waele et al. 1992; de Waele et al. 1994), ethanol may induce release of b-endorphin from other terminal regions. We also posit a role for enkephalinergic neurons within the central nucleus of the amygdala (see Fig. 1) in the reinforcing properties of ethanol. Induction of c-Fos protein occurs in the central nucleus of the amygdala (CeA) following either acute injection of alcohol (Chang et al. 1995; Ryabinin et al. 1997) in rats or during the acquisition of alcohol selfadministration by C57BL/6 J mice (Ryabinin et al. 2001), but not once the self-administration is established (Weitemier et al. 2001; Ryabinin et al. 2003). However, we have recently demonstrated that chronic free-choice ethanol consumption by alcohol-preferring Fawn-Hooded rats led to an up-regulation in preproenkephalin mRNA in the CeA GP