Alcohol works on the brain to produce its desired effects, e.g., sociability and intoxication, and hence the brain is an important organ for exploring subsequent harms. These come in many different forms such as the consequences of damage during intoxication, e.g., from falls and fights, damage from withdrawal, damage from the toxicity of alcohol and its metabolites and altered brain structure and function with implications for behavioral processes such as craving and addiction. On top of that are peripheral factors that compound brain damage such as poor diet, vitamin deficiencies leading to Wernicke-Korsakoff syndrome. Prenatal alcohol exposure can also have a profound impact on brain development and lead to irremediable changes of fetal alcohol syndrome. This chapter briefly reviews aspects of these with a particular focus on recent brain imaging results. Cardiovascular effects of alcohol that lead to brain pathology are not covered as they are dealt with elsewhere in the volume.

SUMMARY Addiction is a global health problem with a chronic relapsing nature for which there are few treatment options. In the past few decades, neuroimaging has allowed us to better understand the neurobiology of addiction. Functional neuroimaging paradigms have been developed to probe the neural circuits underlying addiction, including reward, inhibitory control, stress, emotional processing and learning/memory networks. Functional neuroimaging has also been used to provide biological support for the benefits of psychosocial and pharmacological interventions, although evidence remains limited and often inconclusive in this area, which may contribute to the variability in treatment efficacy. In this article, we discuss the changing definitions and clinical criteria that describe and classify addictive disorders. Using examples from functional neuroimaging studies we summarise the neurobiological mechanisms that underpin drug use, dependence, tolerance, withdrawal and relapse. We discuss the links between functional neuroimaging and treatment, outline clinical management in the UK and give an overview of future directions in research and addiction services.

Background Opiate addiction is a major health challenge with substantial societal cost. Though harm minimisation strategies have been effective, there is a growing need for new treatments for detoxification and relapse prevention. Preclinical research has found neurokinin 1 (NK 1 ) receptors have prominent effects on opiate reward and reinforcement, and human studies have found NK 1 antagonism led to reductions in craving and withdrawal. However, its effect on brain mechanisms in opiate addiction has not yet been examined. Methods This study aims to assess the impact of NK 1 antagonist aprepitant on heroin cue-elicited changes in blood-oxygenation level dependent (BOLD) signal in opiate dependent individuals undergoing detoxification. Participants will attend two scanning sessions and receive a single dose of aprepitant (320 mg) and a placebo in a randomised, cross-over design. During functional magnetic resonance imaging participants will undergo two runs of a cue reactivity task, which consists of passive viewing of drug cues or neutral cues in a block design fashion. We hypothesise that NK 1 antagonism will attenuate the BOLD response to drug cues in the caudate nucleus and amygdala. Regions of interest were selected based on NK 1 receptor density and their role in cue reactivity and craving.

IntroductionNegative affective states contribute to the chronic-relapsing nature of addiction. Mesolimbic dopamine D3 receptors are well placed to modulate emotion and are dysregulated in substance dependence. Selective antagonists might restore dopaminergic hypofunction, thus representing a potential treatment target. We investigated the effects of selective D3 antagonist, GSK598809, on the neural response to negative emotional processing in substance dependent individuals and healthy controls.MethodologyFunctional MRI BOLD response was assessed during an evocative image task, 2 h following acute administration of GSK598809 (60 mg) or placebo in a multi-site, double-blind, pseudo-randomised, cross-over design. Abstinent drug dependent individuals (DD, n = 36) comprising alcohol-only (AO, n = 19) and cocaine-alcohol polydrug (PD, n = 17) groups, and matched controls (n = 32) were presented with aversive and neutral images in a block design (contrast of interest: aversive > neutral). Whole-brain mixed-effects and a priori ROI analyses tested for group and drug effects, with identical models exploring subgroup effects.ResultsNo group differences in task-related BOLD signal were identified between DD and controls. However, subgroup analysis revealed greater amygdala/insular BOLD signal in PD compared with AO groups. Following drug administration, GSK598809 increased BOLD response across HC and DD groups in thalamus, caudate, putamen, and pallidum, and reduced BOLD response in insular and opercular cortices relative to placebo. Multivariate analyses in a priori ROIs revealed differential effects of D3 antagonism according to subgroup in substantia nigra; GSK598809 increased BOLD response in AO and decreased response in PD groups.ConclusionAcute GSK598809 modulates the BOLD response to aversive image processing, providing evidence that D3 antagonism may impact emotional regulation. Enhanced BOLD response within D3-rich mesolimbic regions is consistent with its pharmacology and with attenuation of substance-related hypodopaminergic function. However, the lack of group differences in task-related BOLD response and the non-specific effect of GSK598809 between groups makes it difficult to ascertain whether D3 antagonism is likely to be normalising or restorative in our abstinent populations. The suggestion of differential D3 modulation between AO and PD subgroups is intriguing, raising the possibility of divergent treatment responses. Further study is needed to determine whether D3 antagonism should be recommended as a treatment target in substance dependence.