Int. J. Environ. Res. Public Health 2009, 6 1. Introduction 2008 Chronic misuse of alcohol leads to volume reductions in brain regions critical for associative learning using the eyeblink classical conditioning (EBCC) paradigm. First, alcohol is known to cause structural alterations in the cerebellum, a structure that is both necessary and sufficient for all forms of EBCC [1]. Such alterations have been documented by traditional post-mortem inspection [2] and more recently by in vivo neuroimaging studies confirming significant volume shrinkage in the cerebellar hemispheres [3]. Second, in addition to alcohol-related neuropathological changes in the cerebellum, abundant evidence from different methodologies indicates that the structural alterations due to alcohol extend into the prefrontal cortex and frontal circuitry. These are areas of the brain known to be essential for more complex or nonoptimal forms of EBCC. For example, using structural magnetic resonance imaging (MRI) Sullivan and her colleagues [4,5] have reported that each major node of the frontocerebellar circuit show volume reductions and each can be independently affected. MRI studies have also revealed greater volume losses in the frontal lobes compared to other structures [6,7]. White matter changes in alcoholics have been documented using Diffusion Tensor Imaging (DTI) [8,9]. Post mortem evidence from Harper [10] shows a 22% reduction in the number of neurons in the superior frontal cortex of alcoholics. Research has demonstrated that the cerebellum is essential for all forms of EBCC (e.g., [1]). This fact, in conjunction with the known neuropathological changes to this region of the brain as the result of chronic alcohol use, lead to the prediction that abstinent alcoholics would show deficits in classical associative learning. Several studies have now demonstrated deficits in classical associative learning in abstinent alcoholics [11-14]. Cerebellar structures are critical but only part of a more extensive neural network that is involved in EBCC. Specifically, the hippocampal system and fronto-cerebellar systems are involved in more complex forms of associative learning. Importantly, whether or not the forebrain structures are essential for learning depends on the associative demands of the conditioning paradigm. Thus, while cerebellar shrinkage is the likely cause of impairment in simple forms of EBCC (i.e., single cue delay), it is unclear whether alcohol related neuropathological changes to forebrain regions, such as the hippocampal formation, frontal cortex and underlying white matter, may be responsible for the observed impairment in more complex EBCC tasks, such as trace conditioning [12] and discrimination reversal learning [11,15-18]. In the present study we examined the performance of abstinent alcoholics in EBCC tasks that require an essential contribution from forebrain structures [11,15,17,18]: delay and trace discrimination and discrimination reversal. Discrimination conditioning involves the presentation of two conditioned stimuli, one of which (CS+) is paired with an airpuff US, while the other (CS-) is presented alone (i.e., with no consequence). During the initial phase of learning, individuals do not discriminate between the CS+ and the CS- and produce CRs to both trial types. However, over additional trials, CRs to the CS- drop off and are produced, for the most part, only during the CS+ trials. Once acquisition of the discrimination occurs, the contingencies of the two CSs can be reversed. During this more complex reversal conditioning task, the significance of the two CSs is switched by making the previously paired CS+ the CS-, and the previous CS- the CS+. Importantly, this reversal