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Contains fulltext : 175064.pdf (Publisher’s version ) (Closed access) Alcohol use disorder (AUD) is characterized by excessive alcohol use and persistent alcohol seeking despite knowledge of its negative consequences. Importantly, AUD typically develops after chronic excessive alcohol use in a subgroup of individuals who drink alcohol, suggesting that AUD results from an interaction between individual vulnerability and prolonged alcohol exposure. The present study assessed the contribution of prolonged exposure to alcohol and individual levels of alcohol intake to the development of loss of control over alcohol seeking in a conditioned suppression model. To investigate the impact of prolonged alcohol exposure, conditioned suppression of alcohol seeking was assessed after 2 and 4 months of intermittent alcohol access (IAA) in a subgroup of rats drinking moderate amounts of alcohol. We observed that suppression of alcohol seeking was reduced after 4 months compared with 2 months of IAA. The influence of individual levels of alcohol intake on loss of control over alcohol seeking was subsequently determined by assessing conditioned suppression in subgroups of low and high alcohol drinking rats. Unlike the low alcohol drinking rats, the high alcohol drinking rats showed aversion-resistant alcohol seeking after 2 months of IAA, although both groups showed comparable levels of conditioned freezing. These findings show that the development of loss of control over alcohol seeking, a key characteristic of AUD in humans, is dependent on both the extent of alcohol exposure and the individual's propensity to consume alcohol.

There is a considerable degree of individual vulnerability for alcohol use disorder (AUD) as only a subpopulation of individuals who regularly consume alcohol develop AUD. It is therefore very important to understand the factors and mechanisms that contribute towards the individual risk for AUD. In this respect, social influences, in particular during development, may be relevant for AUD as disruptions in early social experiences are associated with an increased risk for AUD. Social play, the most prominent form of social behaviour shown by young mammals, is rewarding and considered to be important for social, emotional and cognitive development. Recent studies suggest that early social isolation, effectively depriving animals from social play, increases the risk for addictive behaviour. The aim of this study was therefore to explore the long-term consequences of early social isolation on alcohol consumption and motivation for alcohol. To this end, rats were socially isolated from postnatal days 21-42, followed by 4 weeks of social housing, and voluntary alcohol consumption and operant responding for alcohol were determined in adulthood. We observed enhanced levels of alcohol consumption in adulthood in previously isolated rats, whereas operant responding for alcohol was not altered. The impact of early social isolation was independent of the individual variation in alcohol consumption. These data indicate that social isolation, during a developmental period when social play is highly abundant, enhances the propensity to consume alcohol in adulthood. This implies that early social experience may be a protective factor against excessive alcohol use.

Attention-deficit/hyperactivity disorder (ADHD) is accompanied by impairments in cognitive control, such as task-switching deficits. We investigated whether such problems, and their remediation by medication, reflect abnormal reward motivation and associated striatal dopamine transmission in ADHD. We used functional genetic neuroimaging to assess the effects of dopaminergic medication and reward motivation on task-switching and striatal BOLD signal in 23 adults with ADHD, ON and OFF methylphenidate, and 26 healthy controls. Critically, we took into account interindividual variability in striatal dopamine by exploiting a common genetic polymorphism (3'-UTR VNTR) in the DAT1 gene coding for the dopamine transporter. The results showed a highly significant group by genotype interaction in the striatum. This was because a subgroup of patients with ADHD showed markedly exaggerated effects of reward on the striatal BOLD signal during task-switching when they were OFF their dopaminergic medication. Specifically, patients carrying the 9R allele showed a greater striatal signal than healthy controls carrying this allele, whereas no effect of diagnosis was observed in 10R homozygotes. Aberrant striatal responses were normalized when 9R-carrying patients with ADHD were ON medication. These pilot data indicate an important role for aberrant reward motivation, striatal dopamine and interindividual genetic differences in cognitive processes in adult ADHD. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.

The reinforcing and addictive properties of cocaine are thought to rely on the dopaminergic innervation of the striatum. The ventromedial [i.e. nucleus accumbens shell (NAcc) shell] and dorsolateral [dorsolateral striatum (DLS)] regions of the striatum are serially connected, and it is thought that slowly developing neuroadaptations are responsible for the recruitment of the DLS in mediating habitual drug use after extended drug experience. Remarkably, we have recently shown that the DLS is also involved in cocaine self-administration after limited use, to modulate the reinforcing properties of the drug, a function usually ascribed to the NAcc shell. Here, we investigated whether the involvement of the DLS in cocaine reinforcement requires dopaminergic activity within the NAcc shell, by performing a pharmacological disconnection study. We infused the dopamine receptor antagonist α-flupenthixol unilaterally into the NAcc shell and infused this same antagonist into the contralateral DLS, thereby disrupting dopaminergic interconnectivity within the striatum. We show that this disconnection results in increased responding for cocaine under a fixed ratio-1 schedule of reinforcement in rats with limited cocaine experience. These data suggest that a functional dopaminergic interaction between the NAcc shell and the DLS mediates cocaine reinforcement during the early stages of drug use.