J Neurosci. 2012 Feb 1; 32(5): 1884-97
Ponomarev I, Wang S, Zhang L, Harris RA, Mayfield RD

Alcohol abuse causes widespread changes in gene expression in human brain, some of which contribute to alcohol dependence. Previous microarray studies identified individual genes as candidates for alcohol phenotypes, but efforts to generate an integrated view of molecular and cellular changes underlying alcohol addiction are lacking. Here, we applied a novel systems approach to transcriptome profiling in postmortem human brains and generated a systemic view of brain alterations associated with alcohol abuse. We identified critical cellular components and previously unrecognized epigenetic determinants of gene coexpression relationships and discovered novel markers of chromatin modifications in alcoholic brain. Higher expression levels of endogenous retroviruses and genes with high GC content in alcoholics were associated with DNA hypomethylation and increased histone H3K4 trimethylation, suggesting a critical role of epigenetic mechanisms in alcohol addiction. Analysis of cell-type-specific transcriptomes revealed remarkable consistency between molecular profiles and cellular abnormalities in alcoholic brain. Based on evidence from this study and others, we generated a systems hypothesis for the central role of chromatin modifications in alcohol dependence that integrates epigenetic regulation of gene expression with pathophysiological and neuroadaptive changes in alcoholic brain. Our results offer implications for epigenetic therapeutics in alcohol and drug addiction.

Brain Struct Funct. 2012 Feb 3;
Franklin TR, Wang Z, Shin J, Jagannathan K, Suh JJ, Detre JA, O'Brien CP, Childress AR

Voxel-based morphometry (VBM) studies have interpreted longitudinal medication- or behaviorally induced changes observed on T1-weighted magnetic resonance images (MRIs) as changes in neuronal structure. Although neurogenesis or atrophy certainly occurs, the use of T1-weighted scans to identify change in brain structure in vivo in humans has vulnerability: the T1 relaxation time for arterial blood and gray matter are not clearly distinguishable and therefore, apparent reported structural findings might be at least partially related to changes in blood flow or other physiological signals. To examine the hypothesis that apparent structural modifications may reflect changes introduced by additional mechanisms irrespective of potential neuronal growth/atrophy, we acquired a high-resolution T1-weighted structural scan and a 5-min perfusion fMRI scan (a measurement of blood flow), before and after administration of an acute pharmacological manipulation. In a within-subject design, 15 subjects were either un-medicated or were administered a 20 mg dose of baclofen (an FDA-approved anti-spastic) approximately 110 min before acquiring a T1-weighted scan and a pseudo continuous arterial spin labeled perfusion fMRI scan. Using diffeomorphic anatomical registration through exponentiated lie algebra within SPM7, we observed macroscopic, and therefore implausible, baclofen-induced decreases in VBM 'gray matter' signal in the dorsal rostral anterior cingulate (family wise error corrected at p < 0.04, T = 6.54, extent: 1,460 voxels) that overlapped with changes in blood flow. Given that gray matter reductions are unlikely following a single dose of medication these findings suggest that changes in blood flow are masquerading as reductions in gray matter on the T1-weighted scan irrespective of the temporal interval between baseline measures and longitudinal manipulations. These results underscore the crucial and immediate need to develop in vivo neuroimaging biomarkers for humans that can uniquely capture changes in neuronal structure dissociable from those related to blood flow or other physiological signals.

Behav Brain Res. 2012 Jan 24;
Philpot RM, Engberg ME, Wecker L

Behavioral reactivity to novel stimuli, which is greater in the adolescent than young adult population, is associated with drug abuse liability, suggesting that the increased addiction vulnerability of adolescents may be related to heightened novel stimulus reactivity and underlying cellular processes. We examined the hypothesis that adolescent animals who exhibit higher novel stimulus reactivity, exhibit greater locomotor activity in response to nicotine than adolescents who exhibit lower novel stimulus reactivity, and that this difference is associated with alterations in CREB expression and activity in the ventral striatum (vStr) and prefrontal cortex (PFC). Adolescents exhibiting high locomotor activity (HLA) in the novel open field developed tolerance to the locomotor depressant effects of nicotine with fewer exposures and at lower doses than adolescents with low locomotor activity (LLA). Further, HLA adolescents exhibited lower CREB activity in the vStr than LLA adolescents and this difference was attenuated by repeated exposure to high, but not low doses of nicotine. Thus, inherent differences in the reactivity to novel stimulation during the adolescent period appear to predict sensitivity to the behavioral and cellular effects of nicotine and may underlie differences in progression to addiction.

Science. 2012 Feb 3; 335(6068): 601-4
Ersche KD, Jones PS, Williams GB, Turton AJ, Robbins TW, Bullmore ET

Addiction to drugs is a major contemporary public health issue, characterized by maladaptive behavior to obtain and consume an increasing amount of drugs at the expense of the individual's health and social and personal life. We discovered abnormalities in fronto-striatal brain systems implicated in self-control in both stimulant-dependent individuals and their biological siblings who have no history of chronic drug abuse; these findings support the idea of an underlying neurocognitive endophenotype for stimulant drug addiction.

J Subst Abuse Treat. 2012 Jan 31;
Richardson L, Wood E, Montaner J, Kerr T

Employment is commonly upheld as an important outcome of addiction treatment. To explore this attribution, we assessed whether treatment enrollment predicts employment initiation among participants enrolled in a community-recruited Canadian cohort of people who inject drugs (IDU; N = 1,579). Survival analysis initially found no association between addiction treatment enrollment and employment initiation. However, when methadone maintenance therapy (MMT) was separated from other treatment modalities, non-MMT treatment positively predicted employment transitions, whereas MMT was negatively associated with employment initiation. Subanalyses examining transitions into temporary, informal, and under-the-table income generation echo these results. Findings suggest that individual factors impacting employment transitions may systematically apply to MMT clients and that, in this setting, the impact of treatment on employment outcomes is contingent on treatment type and design. Treatment-specific differences underscore the need to expand low-threshold MMT, explore MMT alternatives, and evaluate the impact of treatment design on the social and economic activity of IDU.

J Subst Abuse Treat. 2012 Jan 31;
Brooks AC, Diguiseppi G, Laudet A, Rosenwasser B, Knoblach D, Carpenedo CM, Carise D, Kirby KC

Training community-based addiction counselors in empirically supported treatments (ESTs) far exceeds the ever-decreasing resources of publicly funded treatment agencies. This feasibility study describes the development and pilot testing of a group counseling toolkit (an approach adapted from the education field) focused on relapse prevention (RP). When counselors (N = 17) used the RP toolkit after 3 hours of training, their content adherence scores on "coping with craving" and "drug refusal skills" showed significant improvement, as indicated by moderate to large effect sizes (Cohen's d = 0.75 and 0.60, respectively). Counselor skillfulness, in the "adequate-to-average" range at baseline, did not change. Although this feasibility study indicates some benefit to counselor EST acquisition, it is important to note that the impact of the curriculum on client outcomes is unknown. Because a majority of addiction treatment is delivered in group format, a multimedia curriculum approach may assist counselors in applying ESTs in the context of actual service delivery.

Prog Neuropsychopharmacol Biol Psychiatry. 2012 Jan 20;
El Khoury MA, Gorgievski V, Moutsimilli L, Giros B, Tzavara ET

There is a prominent role of the cannabinoid system to control basal ganglia function, in respect to reward, psychomotor function and motor control. Cannabinoid dysregulations might have a pathogenetic role in dopamine- and basal ganglia related neuropsychiatric disorders, such as drug addiction, psychosis, Parkinson's disease and Huntington's disease. This review highlights interactions between cannabinoids, and dopamine, to modulate neurotransmitter release and synaptic plasticity in the context of drug addiction, psychosis and cognition. Modulating endocannabinoid function, as a plasticity based therapeutic strategy, in the above pathologies with particular focus on cannabinoid receptor type 1 (CB1 receptor) antagonists/inverse agonists, is discussed. On the basis of the existing literature and of new experimental evidence presented here, CB1 receptor antagonists might be beneficial in disease states associated with hedonic dysregulation, and with cognitive dysfunction in particular in the context of psychosis. It is suggested that this effects might be mediated via a hyperglutamatergic state through metabotropic glutamate activation. Indications for endocannabinoid catabolism inhibitors in psychiatric disorders, that might be CB1 receptor independent and might involve TRPV1 receptors, are also discussed.

Addiction. 2012 Feb 2;
Agrawal A, Budney AJ, Lynskey MT

Aims:  Cannabis and tobacco use and misuse frequently co-occur. This review examines the epidemiological evidence supporting the lifetime co-occurrence of cannabis and tobacco use and outlines the mechanisms that link these drugs to each other. Mechanisms include (a) shared genetic factors; (b) shared environmental influences, including (c) route of administration (via smoking), (d) co-administration and (e) models of co-use. We also discuss respiratory harms associated with co-use of cannabis and tobacco, overlapping withdrawal syndromes and outline treatment implications for co-occurring use. Methods:  Selective review of published studies. Results:  Both cannabis and tobacco use and misuse are influenced by genetic factors and a proportion of these genetic factors influence both cannabis and tobacco use and misuse. Environmental factors such as availability play an important role, with economic models suggesting a complementary relationship where increases in price of one drug decrease the use of the other. Route of administration and smoking cues may contribute to their sustained use. Similar withdrawal syndromes, with many symptoms in common, may have important treatment implications. Emerging evidence suggests that dual abstinence may predict better cessation outcomes, yet empirically researched treatments tailored for co-occurring use are lacking. Conclusion:  There is accumulating evidence that some mechanisms linking cannabis and tobacco use are distinct from those contributing to co-occurring use of drugs in general. There is an urgent need for research to identify the underlying mechanisms and harness their potential etiological implications to tailor treatment options for this serious public health challenge.

Future Med Chem. 2012 Feb; 4(2): 227-43
Gorelick DA

The pharmacokinetic treatment strategy targets the drug molecule itself, aiming to reduce drug concentration at the site of action, thereby minimizing any pharmacodynamic effect. This approach might be useful in the treatment of acute drug toxicity/overdose and in the long-term treatment of addiction. Phase IIa controlled clinical trials with anticocaine and antinicotine vaccines have shown good tolerability and some efficacy, but Phase IIb and III trials have been disappointing because of the failure to generate adequate antibody titers in most participants. Monoclonal antibodies against cocaine, methamphetamine and phencyclidine have shown promise in animal studies, as has enhancing cocaine metabolism with genetic variants of human butyrylcholinesterase, with a bacterial esterase, and with catalytic monoclonal antibodies. Pharmacokinetic treatments offer potential advantages in terms of patient adherence, absence of medication interactions and benefit for patients who cannot take standard medications.

Future Med Chem. 2012 Feb; 4(2): 177-86
Wang JB, Mantsch JR

Levo-tetrahydropalmatine (l-THP) is an active constituent of herbal preparations containing plant species of the genera Stephania and Corydalis and has been approved and used in China for a number of clinical indications under the drug name Rotundine. The pharmacological profile of l-THP, which includes antagonism of dopamine D1 and D2 receptors and actions at dopamine D3, α adrenergic and serotonin receptors, suggests that it may have utility for treating cocaine addiction. In this review, we provide an overview of the pharmacological properties of l-THP and the evidence supporting its development as an anti-addiction medication. The results of preclinical work demonstrating that l-THP attenuates cocaine's reinforcing/rewarding effects and reinstatement in rat models of cocaine relapse are summarized, and the outcomes of studies demonstrating efficacy in human addicts are described. Finally, an overview of the safety profile of l-THP is provided and challenges associated with US FDA approval of l-THP are discussed.

Future Med Chem. 2012 Feb; 4(2): 151-62
Brimijoin S, Gao Y

Rapid progress in the past decade with re-engineering of human plasma butyrylcholinesterase has led to enzymes that destroy cocaine so efficiently that they prevent or interrupt drug actions in the CNS even though confined to the blood stream. Over the same time window, improved gene-transfer technology has made it possible to deliver such enzymes by endogenous gene transduction at high levels for periods of a year or longer after a single treatment. This article reviews recent advances in this field and considers prospects for development of a robust therapy aimed at aiding recovering drug users avoid addiction relapse.

Future Med Chem. 2012 Feb; 4(2): 137-50
Narasimhan D, Woods JH, Sunahara RK

Cocaine is highly addictive and there are no pharmacotherapeutic drugs available to treat acute cocaine toxicity or chronic abuse. Antagonizing an inhibitor such as cocaine using a small molecule has proven difficult. The alternative approach is to modify cocaine's pharmacokinetic properties by sequestering or hydrolyzing it in serum and limiting access to its sites of action. We took advantage of a bacterial esterase (CocE) that has evolved to hydrolyze cocaine and have developed it as a therapeutic that rapidly and specifically clears cocaine from the subject. Native enzyme was unstable at 37°C, thus limiting CocE's potential. Innovative computational methods based on the protein's structure helped elucidate its mechanism of destabilization. Novel protein engineering methodologies were applied to substantially improve its stability in vitro and in vivo. These improvements rendered CocE as a powerful and efficacious therapeutic to treat cocaine intoxication and lead the way towards developing a therapy for addiction.