Cerebellar Lingula Thickness as a Novel Risk Factor for Alcohol and Drug Abuse

Abstract

The identification of developmental risk factors for alco-holism and drug abuse is a matter of intense research.Human twin and adoption studies have shown that alcoholintake is a highly heritable trait [1, 2]. Also, large-samplestudies of alcoholism have documented moderately stronggenetic contributions to variation in alcohol dependence,typically accounting for 40% to 60% of variation in risk [3].The genetic background interacts with environmentalevents to produce risk for substance abuse [4]. A classicexample is the individual with a low level of response toalcohol. Indeed, subjects who require greater amounts ofalcohol to exhibit balance deficits or impaired psychomotorperformance are at risk for developing alcohol use disorders[5].Genetic susceptibility interacts with experience to deter-mine outcome [6]. Exposure to childhood adversity is nowconsidered as a major experiential risk factor. There is adose-dependent relationship between the number of adversechildhood experiences, such as recurrent physical abuse orrecurrent emotional abuse, and risk for alcoholism or drugabuse [7]. The understanding of this relationship is highlyrelevant.Cerebellum is a key target of alcohol toxicity in thecentral nervous system [8]. Gait disturbances and ataxia inlower limbs are common both in acute intoxication and inchronic alcoholism. As a result of the closed loops betweencerebellar circuitry and cerebral cortex, cerebellar damagemight contribute to the visuospatial difficulties and im-paired verbal learning observed in alcoholism [9].Individual differences in cerebellar morphology seem toplay a role in the development of alcohol dependence andsubstance abuse [10]. Cerebellar vermis is particularlyvulnerable to alcohol abuse [11]. The anterior vermis istypically affected both in case of fetal exposure and inadults [12, 13]. Atrophy of this region of the cerebellum isone of the first consequences visible on brain magneticresonance imaging. Other areas of the cerebellum such asthe flocculonodular lobe and the central white matter alsoshow volume loss [14]. A 42% atrophy of vermal whitematter has been found in ataxic alcoholics and appears tosignificantly contribute to ataxia [14]. However, cerebellardegeneration may be discovered in alcoholics without signsof ataxia [15]. Purkinje cell loss and impaired dendriticnetworks in the molecular layer are common [16, 17].Successive episodes of ethanol withdrawal also causes aloss of Purkinje cells [18]. Granule cells are less vulnerablethan Purkinje neurons [19].The mechanisms of ethanol-induced cerebellar degen-eration include thiamine deficiency and defects in energyproduction, deficits in growth factors, and apoptosis [20].Thiamine is a cofactor of key enzymes of the energymetabolism. Not only chronic alcoholics present a deficitin thiamine resulting from inadequate intake, but alsoethanol inhibits the conversion into its active metaboliteby blocking the pyrophosphokinase [21]. Thiamine defi-ciency contributes to the pathogenesis of Wernickeencephalopathy. Alcohol interacts with neurotrophins,whose roles in the developing and mature cerebellum arecritical [22, 23]. Excitotoxicity is another detrimental actorof the cascade of events implicated in ethanol-inducedcerebellar degeneration. Acute doses potentiate GABA-Areceptors, hence, the antianxiety effect. Intranuclearadministration of ethanol decreases the levels of GABAand raises the concentrations of nitric oxide [20]. Chronic