NEUROCHEMICAL MARKERS OF ALCOHOLISM VULNERABILITY IN HUMANS

Alcohol & Alcoholism Vol. 37, No. 6, pp. 522–533, 2002 REVIEW NEUROCHEMICAL MARKERS OF ALCOHOLISM VULNERABILITY IN HUMANS JOELLE E. RATSMA*, ODIN VAN DER STELT1 and W. BOUDEWIJN GUNNING Academic Center for Child and Adolescent Psychiatry, University of Amsterdam, P. O. Box 12474, 1100 AL Amsterdam, The Netherlands and 1 Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA (Received 22 March 2002; accepted 10 May 2002) INTRODUCTION obscure the relation between a marker and a clinical syndrome. Family studies are required to determine whether the trait marker co-segregates with alcoholism within families, since all members of a family are part of the same population. However, there is as yet little information on the cosegregation of neurochemical markers with alcoholism in affected families. This review evaluates whether abnormalities in certain neurochemical indices, as assessed in alcoholics and in COA, meet the three above-mentioned criteria for the identification of a trait marker of alcoholism. Thus, the issue is addressed whether a certain neurochemical abnormality is associated with alcoholism, or with a given subtype of alcoholism, in the general population. To clarify this issue, studies are reviewed in which measures of neurochemical activity are compared between alcoholics and unrelated non-alcoholic controls. In addition, to evaluate whether a certain neurochemical abnormality is heritable, this review focuses on twin and adoption studies to find out whether the abnormality is mediated largely by genetic, as opposed to environmental, factors. Finally, to evaluate whether the neurochemical abnormality is state independent, that is, not reflecting the current state of alcoholism but present throughout an individual’s lifetime, studies are reviewed in which the neurochemical measure of interest is compared between individuals at high risk for alcoholism and low-risk controls. As opposed to this high-risk research, studies of (abstinent) alcoholics cannot distinguish between state and trait markers of alcoholism. Even after many years of abstinence from alcohol, the prolonged abuse of alcohol may have had long-term neurotoxic effects, potentially affecting neurochemical trait markers in abstinent alcoholics. This review will focus on indices of neurochemical markers. These are indices of changes in neurotransmitter systems that are studied as trait markers in alcoholism, in accordance with the three above-mentioned criteria. The state effect of alcohol on changes in neurotransmission has been widely studied within neurotransmitter systems. It has, for example, been the main approach adopted in studies of the N-methyl-D-aspartate receptor of the glutamatergic system. Alcoholism is generally assumed to be a multifactorial disease, in which polygenic influences and environmental influences interact (Goldman, 1995). This conceptualization of alcoholism has been inferred from adoption studies (Goodwin et al., 1973; Bohman et al., 1981; Cadoret et al., 1985; Cloninger et al., 1985) and twin studies (Romanov et al., 1991; Kendler et al., 1994, 1997; Reed et al., 1996; Treu et al., 1996; Heath et al., 1997). The question arises as to what is inherited in alcoholism? Over the past two decades, research on so-called phenotypic trait or vulnerability markers of alcoholism has attempted to shed light on this basic issue. This research has focused on various behavioural, electrophysiological, and neurochemical characteristics that may be related to alcoholism vulnerability (Begleiter and Porjesz, 1988; Farren and Tipton, 1999; Schuckit, 1999; Van der Stelt, 1999). This review evaluates whether abnormalities in certain neurochemical indices, as assessed in alcoholics and in the children of alcoholics (COA), may serve as neurochemical markers of alcoholism vulnerability. A trait or vulnerability marker may be defined as a ‘heritable trait, associated with a causative pathophysiological factor in an inherited disease’ (Gershon and Goldin, 1986). As opposed to a diagnostic marker, a vulnerability or pathophysiological marker is not required to have high sensitivity or high specificity to a certain clinical disorder (Nurnberger, 1992). While sensitivity and specificity are not critical criteria, it has been proposed that a certain behavioural or biological trait should meet at least three basic criteria in order to be considered as a trait marker (Goldin et al., 1986): (1) heritable; (2) associated with the disease in the general population; (3) state independent. The reason for these requirements is to prevent false-positive or false-negative conclusions about the validity of a certain characteristic as a trait marker due to certain conditions, particularly population stratification, which may *Author to whom correspondence should be addressed. 522 © 2002 Medical Council on Alcohol Abstract — This review considers several neurochemical characteristics or trait markers that may be related to a genetic vulnerability to alcoholism. These potential neurochemical markers of alcoholism vulnerability include indices of activity of five neurotransmitter systems, namely γ-aminobutyric acid, serotonin, dopamine, noradrenaline and β-endorphin. This review evaluates whether potential abnormalities in these neurochemical indices, as assessed in alcoholics and in the children of alcoholics, meet three criteria for the identification of a vulnerability marker of alcoholism: (1) heritable; (2) associated with alcoholism in the general population; (3) state independent. It is concluded that, at present, indices of increased baseline activity of the serotonin transporter in platelets and of increased responsiveness of the pituitary β-endorphin system may fulfil each of these three criteria. Additional research efforts should be devoted to the evaluation of trait marker properties of neurochemical indices in individuals at high risk for alcoholism. NEUROCHEMICAL MARKERS OF ALCOHOLISM VULNERABILITY GENERAL PRINCIPLES AND OBSERVATIONS FROM ANIMAL STUDIES This review focuses on central and peripheral indices of activity of the five neurotransmitter systems, GABA, serotonin, dopamine, noradrenaline and β-endorphin. On the basis of findings mainly from animal research, each of these neurotransmitter systems has been implicated in the aetiology and pathophysiology of alcoholism. The requisite theoretical background was provided by animal studies carried out in the 1950s, which reported that changes in neurotransmission in rat brains led to addiction-related behaviour. Olds and Milner (1954) found that intracranial stimulation of the hypothalamus and associated structures can act to reinforce operant conditioning. Brain stimulation itself activated systems that were normally activated by a reinforcing stimulus, such as feeding or drinking (Deutsch and Howarth, 1963). Brain selfstimulation (using electrodes placed in the vicinity of dopaminerg (...truncated)