An Orexin Hotspot in Ventral Pallidum Amplifies Hedonic ‘liking’ for Sweetness.

An orexin hotspot in ventral pallidum amplifies hedonic ‘liking’ for sweetness.

Neuropsychopharmacology. 2013 Mar 5;
Ho CY, Berridge KC

Orexin (hypocretin) is implicated in stimulating appetite as well as arousal, and in both food reward and drug reward. The ventral pallidum (VP) receives orexin projections from lateral hypothalamus neurons (LH), and orexin terminals are especially dense in the posterior half of ventral pallidum, which is also the location of an opioid hedonic hotspot. The VP hotspot is a roughly cubic-millimeter site where mu opioid stimulation can amplify the hedonic impact of sweetness, expressed as an increase in ‘liking’ reactions to sucrose taste. The anatomical overlap in posterior VP between opioid hotspot and orexin inputs raises the possibility that the hedonic hotspot might allow orexin to amplify ‘liking’ too. We examined whether microinjections of orexin-A into the VP hotspot enhance the hedonic impact of sucrose, as assessed via affective taste reactivity measures of ‘liking’ reactions, and additionally compared effects at nearby sites in adjacent lateral hypothalamus and extended amygdala. Taste reactivity results indicated that orexin stimulation specifically in the VP hotspot nearly doubled the magnitude of positive ‘liking’ reactions elicited by the taste of sucrose. Mapping results for localization of function, aided by Fos plume measures of the local spread of orexin impact, suggested that hedonic enhancement was generated by essentially the same cubic-millimeter of posterior VP previously identified as the opioid hotspot. By contrast, microinjection sites in the anterior half of VP, or in LH or extended amygdala, generally failed to produce any hedonic enhancement. We conclude that an orexin hedonic hotspot exists in posterior VP, with similar boundaries to the opioid hotspot. An orexin hedonic hotspot may permit regulatory hypothalamic circuitry to make foods more ‘liked’ during hunger by acting through VP. Dysfunction in a VP orexin hotspot in addiction or mood disorders might also contribute to some types of affective psychopathology.Neuropsychopharmacology accepted article preview online, 5 March 2013; doi:10.1038/npp.2013.62. HubMed – addiction


CYP2A6 slow nicotine metabolism is associated with increased quitting by adolescent smokers.

Pharmacogenet Genomics. 2013 Apr; 23(4): 232-5
Chenoweth MJ, O’Loughlin J, Sylvestre MP, Tyndale RF

Variation in the CYP2A6 gene, which decreases the rate of nicotine metabolic inactivation, is associated with higher adult smoking cessation rates during clinical trials. We hypothesized that slow metabolism is associated with increased quitting during adolescence. White adolescent smokers (N=308, aged 12-17, 36.3% male) from a cohort study were genotyped for CYP2A6, resulting in 7.8% slow, 14.0% intermediate and 78.2% normal metabolizers. Overall, 144 smokers quit smoking, as indicated by being abstinent for at least 12 months. In logistic regression analyses, the odds ratio for quitting was 2.25 (95% confidence interval 1.05, 4.80; P=0.037) for slow metabolizers relative to normal metabolizers. A linear trend toward increased quitting with decreasing CYP2A6 activity was also observed (odds ratio=1.44, 95% confidence interval 1.02, 2.01; P=0.034). Thus, CYP2A6 slow metabolism is associated with increased adolescent smoking cessation, indicating that even early in the smoking history, genetic variation is influencing smoking cessation. HubMed – addiction


The role of impulsivity in relapse vulnerability.

Curr Opin Neurobiol. 2013 Feb 22;
Pattij T, De Vries TJ

Drug dependence in humans is often accompanied by behavioral disturbances such as maladaptive levels of impulsivity. In turn, there is accumulating evidence from preclinical laboratory animal and clinical studies indicating that impulsive behavior might be causally linked to several distinct processes in drug addiction, including the onset, maintenance and relapsing nature of drug use. This leads to the question as to whether pharmacological or behavioral approaches aimed at ameliorating impulsivity might prove effective therapeutic interventions in human drug dependence. This paper reviews evidence for an important role of impulsivity as a determinant of drug dependence with a particular focus on relapse vulnerability and addresses the implications of these findings for the clinical management of relapse prevention. HubMed – addiction


Is alcoholism learned? Insights from the fruit fly.

Curr Opin Neurobiol. 2013 Feb 22;
Robinson BG, Atkinson NS

Alcohol addiction is a complex, unique human disease. Breaking addiction down into contributing endophenotypes enables its study in a variety of model systems. The Drosophila model system has been most often used to study alcohol sensitivity, tolerance, and physiological dependence. However, none of these endophenotypes can account for the near-permanent quality of the addicted state. It has been recently discussed that addictive drugs may hijack the learning-and-memory machinery to produce persistent behavioral changes. Learning and memory is amenable to experimental study, and provides us with a window into how alcohol affects higher-order mental functions that are likely to contribute compulsive drug use. Here, we review the Drosophila literature that links alcohol-related behaviors to learning and memory. HubMed – addiction


Genes, Environments, and Developmental Research: Methods for a Multi-Site Study of Early Substance Abuse.

Twin Res Hum Genet. 2013 Mar 6; 1-11
Costello EJ, Eaves L, Sullivan P, Kennedy M, Conway K, Adkins DE, Angold A, Clark SL, Erkanli A, McClay JL, Copeland W, Maes HH, Liu Y, Patkar AA, Silberg J, van den Oord E

The importance of including developmental and environmental measures in genetic studies of human pathology is widely acknowledged, but few empirical studies have been published. Barriers include the need for longitudinal studies that cover relevant developmental stages and for samples large enough to deal with the challenge of testing gene-environment-development interaction. A solution to some of these problems is to bring together existing data sets that have the necessary characteristics. As part of the National Institute on Drug Abuse-funded Gene-Environment-Development Initiative, our goal is to identify exactly which genes, which environments, and which developmental transitions together predict the development of drug use and misuse. Four data sets were used of which common characteristics include (1) general population samples, including males and females; (2) repeated measures across adolescence and young adulthood; (3) assessment of nicotine, alcohol, and cannabis use and addiction; (4) measures of family and environmental risk; and (5) consent for genotyping DNA from blood or saliva. After quality controls, 2,962 individuals provided over 15,000 total observations. In the first gene-environment analyses, of alcohol misuse and stressful life events, some significant gene-environment and gene-development effects were identified. We conclude that in some circumstances, already collected data sets can be combined for gene-environment and gene-development analyses. This greatly reduces the cost and time needed for this type of research. However, care must be taken to ensure careful matching across studies and variables. HubMed – addiction