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CDAP > Center for Drug and Alcohol Programs Faculty Publications
Center for Drug and Alcohol Programs Faculty Publications

Books 

Addiction Research Methods

Miller, P.G., Strang, J., & Miller, P.M. (Eds.) (2010). Oxford, England: Wiley-Blackwell.
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Evidence-Based Addiction Treatment

Miller, P. M. (Ed.) Evidence-Based Addiction Treatment (2009). San Diego Academic Press

With the addictions treatment field becoming the subject of increased scrutiny, there is greater emphasis being placed on treatment accountability and cost effectiveness. Substance abuse treatment programs are now required to provide evidence-based treatments, with funding and insurance reimbursement dependent upon compliance with these guidelines. Evidence-Based Addiction Treatment presents detailed descriptions of assessments and treatment practices that have proven to be effective. It provides a comprehensive and practical guide to evidence based practices for students, clinicians, and substance abuse counselors.

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Journal Articles

The Alcohol Clinical Trials Initiative (ACTIVE): Purpose and Goals for Assessing Important and Salient Issues for Medications Development in Alcohol Use Disorders

Although progress has been made in the treatment of alcohol use disorders, more effective treatments are needed. In the last 15 years, several medications have been approved for use in alcohol dependence but have only limited effectiveness and clinical acceptance. While academics have developed some 'standards' for the performance of clinical trials for alcohol dependence, they vary considerably, in the type of populations to be studied, the length of trials, salient outcome measures, and data analyses to be used (especially in the treatment of missing data). This variability impedes the commercial development of medications to treat alcohol dependence. Using a model similar to that used to develop an expert consensus for medications to improve cognitive aspects of schizophrenia (MATRICS) and in the treatment of pain (IMMPACT), a workgroup has been formed under the auspices of ACNP, known as the ACTIVE (Alcohol Clinical Trials Initiative) group, to evaluate data from completed clinical trials to develop a consensus on key issues in the conduct of clinical trials in alcohol dependence. ACTIVE consists of academic experts, industry representatives, and staff from the Food and Drug Administration, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Drug Abuse. This paper describes the rationale behind the effort, its history and organization, and initial key questions that have been identified as the primary focus of the workgroup. Future papers will focus on knowledge gained from the re-analysis of completed trials and provide consensus opinions regarding the performance of clinical trials that might be undertaken in the future.

Anton RF, Litten RZ, Falk DE, Palumbo JM, Bartus RT, Robinson RL, Kranzler HR, Kosten TR, Meyer RE, O'Brien CP, Mann K & Meulien D. The Alcohol Clinical Trials Initiative (ACTIVE): Purpose and Goals for Assessing Important and Salient Issues for Medications Development in Alcohol Use Disorders. Neuropsychopharmacology 37(2):402-411, 2012.

To read the full publication of this study's findings, visit the journal website.


Animal models of excessive alcohol consumption in rodents

Numerous animal models have been developed to study excessive alcohol consumption in rodents. Use of such models has played a valuable role in elucidating biological underpinnings and environmental factors that mediate/promote excessive levels of alcohol drinking. A major obstacle in this work has been the need to overcome the natural tendency of rodents to either avoid alcohol or consume it in limited amounts that typically do not produce overt signs of intoxication. A variety of experimental approaches that entail modifying genetic and/or environmental factors have been employed to address this general problem and demonstrate excessive levels of alcohol consumption. Five different approaches that characterize animal models of excessive alcohol consumption are described: models that involve (a) scheduled access to alcohol; (b) scheduled periods of alcohol deprivation; (c) scheduled intermittent access to alcohol; (d) scheduled-induced polydipsia; and (e) dependence and withdrawal experience. Each of the models possesses unique experimental features that engender excessive levels of alcohol consumption. Both advantages and disadvantages for each model are described along with discussion of future challenges to be considered in developing more optimal models. Ultimately, the validity and usefulness of these models will lie in their ability to serve as a platform for studying biological underpinnings and environmental influences that drive increased motivation for alcohol seeking and consumption, as well as evaluation of treatment strategies that effectively reduce excessive levels of alcohol consumption.

Becker HC. Animal models of excessive alcohol consumption in rodents. Curr Top Behav Neurosci 13:355-377, 2013.

To read the full publication of this study's findings, visit the journal website


Client attitudes toward alcohol use self-report

Because psychiatric illnesses and problematic alcohol use frequently co-occur and heavy alcohol use can exacerbate depression and anxiety, mental health clinicians should perform alcohol-use screenings. The aim of this study was to determine if psychiatric patients would be accepting of their mental health clinician screening them for heavy alcohol use. Using a written survey, patients rated their levels of agreement with 9 statements regarding opinions about alcohol screening by their mental-health providers. They also completed the Alcohol Use Disorders Identification Test-C (AUDIT-C), a screening instrument for heavy alcohol use. One hundred fifty-four patients were surveyed in 2 psychiatric outpatient clinics. Nearly 40% screened positively for heavy alcohol use on the AUDIT-C. Nearly 8 out of 10 psychiatric patients were in favor of being screened for alcohol use by either self-report or biomarkers, independent of AUDIT-C status and gender. Thus, mental health clinicians should not be deterred from alcohol screening by perceived negative attitudes from patients.

Book SW, Thomas SE, Stewart SH & Miller PM. Client attitudes toward alcohol use self-report. Subst Abus 33(2):124-129, 2012.

To read more about the research findings of this study, visit the journal website.


Chronic ethanol up-regulates the synaptic expression of the nuclear translational regulatory protein AIDA-1 in primary hippocampal neurons

Recent studies have identified synaptic proteins that undergo synapse-to-nucleus translocation in response to neuronal activity that modulate protein synthesis. One such translational regulatory protein of the postsynaptic density (PSD) is AIDA-1d, which binds to PSD-95 via its C-terminus. Activation of synaptic NMDA receptors induces the cleavage of AIDA-1d, and the N-terminus is then shuttled to nuclear Cajal bodies where it plays a role in regulating global protein synthesis. Chronic ethanol exposure has been shown to increase the synaptic clustering of NMDA receptors and PSD-95. Here, we tested the hypothesis that AIDA-1d regulates chronic ethanol-induced increases in synaptic NMDA receptor expression. As reported, we found that AIDA-1 was highly enriched in dendritic spines and co-localized with PSD-95. Acute NMDA treatment increased AIDA-1 colocalization with p80 coilin, a marker of Cajal bodies. Chronic treatment (4 day) of cultures with ethanol (25-100 mM) or with the NMDA receptor antagonist AP-V (50 muM) enhanced the clustering of AIDA-1 at synaptic sites. However, chronic ethanol treatment (50 mM) in the presence of the NMDA receptor agonist NMDA (2.5 muM) prevented this increase. Surprisingly, PSD-95 did not seem to play a role in the synaptic distribution of AIDA-1 as this distribution was not affected by declustering PSD-95 from synapses in response to inhibition of palmitoylation. We found that lentiviral knockdown of AIDA-1d did not affect protein expression levels of NMDA receptor subunits GluN1, GluN1 C2', or GluN2B. The results of this study demonstrate that synaptic AIDA-1 expression is enhanced by chronic ethanol exposure that can be prevented by concurrent stimulation of NMDA receptors. In addition, we found that the association of AIDA-1 with PSD-95 is not required for its localization to the PSD. Moreover, we found that AIDA-1 does not regulate protein expression levels or alternative splicing of the GluN1 subunit of NMDA receptors.
  

Mulholland PJ, Jordan BA & Chandler LJ. Chronic ethanol up-regulates the synaptic expression of the nuclear translational regulatory protein AIDA-1 in primary hippocampal neurons. Alcohol 46(6):569-576, 2012. PMCID: 3411901

To read more about the research findings of this study, visit the journal website.


Repeated cycles of chronic intermittent ethanol exposure leads to the development of tolerance to aversive effects of ethanol in C57BL/6J mice

Repeated cycles of chronic intermittent ethanol (CIE) exposure lead to increased voluntary ethanol (EtOH) intake in C57BL/6J mice. This study evaluates the development of tolerance to EtOH's aversive effects in CIE exposure. METHODS: Adult male C57BL/6J mice were trained to drink 15% EtOH (vs. water) in a limited access procedure and then exposed to CIE (EtOH mice) or air (control [CTL] mice) for 5 cycles alternating with weekly access to EtOH drinking. Following the 4th CIE cycle, the aversive effects of EtOH were evaluated using a conditioned taste aversion (CTA) paradigm with 1% saccharin as the conditioned stimulus. Several doses of EtOH (0, 1, 2, and 3 g/kg) and LiCl (0.4 M, 0.02 ml/g) served as unconditioned stimuli. Finally, mice underwent a 5th CIE cycle to measure blood and brain concentrations following a 2 g/kg EtOH dose. RESULTS: CIE exposure increased EtOH drinking in EtOH mice while drinking in CTL mice remained stable. The lowest EtOH dose (1 g/kg) did not induce CTA in either group, but the highest dose (3 g/kg) produced CTA in both groups (49% reduction for CTL vs. 25% reduction for EtOH) although the group differences were not statistically significant. However, the 2 g/kg EtOH dose induced a significant aversion in CTL mice (27% reduction) but not in EtOH mice (20% increase), indicating tolerance to EtOH's aversive effects. LiCl caused a similar aversion in CTL and EtOH mice (50% reduction). Finally, blood and brain ethanol concentrations were not different between CTL and EtOH mice following a 2 g/kg EtOH dose. CONCLUSIONS: The data indicate that CIE exposure produces tolerance to the aversive effects of 2 g/kg EtOH. This effect does not appear to be related to a learning deficit or altered EtOH pharmacokinetics. These data support the notion that tolerance to EtOH's aversive effects may contribute to excessive EtOH drinking in EtOH-dependent mice.

Lopez MF, Griffin WC, 3rd, Melendez RI & Becker HC. Repeated cycles of chronic intermittent ethanol exposure leads to the development of tolerance to aversive effects of ethanol in C57BL/6J mice. Alcoholism Clinical & Experimental Research 36(7):1180-1187, 2012. PMCID: 3527904

To read more about the research findings in this study, visit the journal website.


Glutamatergic medications for the treatment of drug and behavioral addictions

Historically, most pharmacological approaches to the treatment of addictive disorders have utilized either substitution-based methods (i.e., nicotine replacement or opioid maintenance) or have targeted monoaminergic or endogenous opioidergic neurotransmitter systems. However, substantial evidence has accumulated indicating that ligands acting on glutamatergic transmission are also of potential utility in the treatment of drug addiction, as well as various behavioral addictions such as pathological gambling. The purpose of this review is to summarize the pharmacological mechanisms of action and general clinical efficacy of glutamatergic medications that are currently approved or are being investigated for approval for the treatment of addictive disorders. Medications with effects on glutamatergic transmission that will be discussed include acamprosate, N-acetylcysteine, d-cycloserine, gabapentin, lamotrigine, memantine, modafinil, and topiramate. We conclude that manipulation of glutamatergic neurotransmission is a relatively young but promising avenue for the development of improved therapeutic agents for the treatment of drug and behavioral addictions.

Olive MF, Cleva RM, Kalivas PW & Malcolm RJ. Glutamatergic medications for the treatment of drug and behavioral addictions. Pharmacology Biochemistry & Behavior 100(4):801-810, 2012. PMCID: 3154511

To read more about the research findings in this study, visit the journal website.


Interacting Effects of Naltrexone and OPRM1 and DAT1 Variation on the Neural Response to Alcohol Cues

Variation at a single nucleotide polymorphism in the mu-opioid receptor gene (OPRM1), A118G (Asn40Asp), may moderate naltrexone (NTX) effects in alcohol dependence. Both NTX and A118G variation have also been reported to affect alcohol cue-elicited brain activation. This study investigated whether sub-acute NTX treatment and A118G genotype interacted in their effects on cue-elicited activation of the ventral striatum (VS), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). Secondarily, variation at a variable number tandem repeat polymorphism in the dopamine transporter gene (DAT1/SLC6A3), which has been associated with increased reward-related activation in VS, was analyzed as a moderator of medication and A118G effects. Seventy-four non-treatment-seeking alcohol-dependent individuals, half preselected to carry at least one copy of the A118G G (Asp) allele, were randomized to NTX (50 mg) or placebo for 7 days, and performed an fMRI alcohol cue reactivity task on day 6. Region-of-interest analyses indicated no main effects of medication or A118G genotype. However, these factors interacted in their effects on OFC activation, such that, among NTX-treated individuals, G-allele carriers had less activation than A-allele homozygotes. DAT1 variation also moderated medication/A118G effects. There was a three-way interaction between medication and A118G and DAT1 genotypes on VS activation, such that, among G-allele carriers who received NTX, DAT1 10-repeat-allele (10R) homozygotes had less activation than 9-repeat-allele (9R) carriers. Further, 10R homozygotes who received NTX had less mPFC activation than 9R carriers. Polymorphic variation in OPRM1 and DAT1 should be considered in future studies of NTX, particularly regarding its effects on reward processing.Neuropsychopharmacology advance online publication, 3 October 2012; doi:10.1038/npp.2012.195.

Schacht JP, Anton RF, Voronin KE, Randall PK, Li X, Henderson S & Myrick H. Interacting Effects of Naltrexone and OPRM1 and DAT1 Variation on the Neural Response to Alcohol Cues. Neuropsychopharmacology 2012.

To read more about the research findings in this study, visit the journal website.


Ethanol inhibition of up-states in prefrontal cortical neurons expressing the genetically encoded calcium indicator GCaMP3

he prefrontal cortex (PFC) is critically involved in working memory, cognition, and decision making; processes significantly affected by ethanol (EtOH). During quiet restfulness or sleep, PFC neurons show synaptically evoked oscillations in membrane potential between hyperpolarized down-states and depolarized up-states. Previous studies from this laboratory used whole-cell electrophysiology and demonstrated that in individual neurons, EtOH inhibited PFC up-states at concentrations associated with behavioral impairment. Although those studies monitored activity in 1 or 2 neurons at a time, it is likely that in vivo, larger networks of neurons participate in the complex functions of the PFC. In the present study, we used imaging and a genetically encoded calcium sensor to examine the effects of EtOH on the activity of multiple neurons simultaneously during up-states. METHODS: Slice cultures of mouse PFC were infected with an AAV virus encoding the calcium indicator GCaMP3 whose expression was driven by the neuron-specific synapsin promoter. After 2 to 3 weeks in culture, a fast CCD-camera imaging system was used to capture changes in GCaMP3 fluorescence before, during, and after exposure to EtOH. RESULTS: PFC neurons displayed robust and reproducible changes in GCaMP3 fluorescence during evoked and spontaneous up-states. Simultaneous whole-cell patch-clamp recording and GCaMP3 imaging verified that neurons transitioned into and out of up-states together. Acute application of EtOH reliably depressed up-state calcium signals with lower doses having a greater effect on up-state duration than amplitude. These effects of EtOH on up-state parameters were reversed during washout. CONCLUSIONS: The results of the present study indicate that EtOH has profound effects on up-state activity in prefrontal neurons and suggest that this action may underlie some of the cognitive impairment associated with acute alcohol intoxication.

Woodward JJ & Pava M. Ethanol inhibition of up-states in prefrontal cortical neurons expressing the genetically encoded calcium indicator GCaMP3. Alcoholism Clinical & Experimental Research 36(5):780-787, 2012. PMCID: 3297730

To read more about the research findings in this study, visit the journal website.






  

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"I felt at all times that the staff I encountered were very interested in helping me. I never felt like a 'number.' "-CEL

" I did not feel judged or less of a person because of my alcohol issues. It has been a very positive experience...I also now realize this is a forever problem that I have to address on a daily basis."-Bobby

"This was an excellent experience. I learned a lot about alcohol dependence, coping strategies and other health related issues as they involve alcohol consumption. Most importantly my personal and family life have improved dramatically. Thank you, thank you, thank you!" -James