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1.  The paraventricular nucleus of the thalamus is differentially recruited by stimuli conditioned to the availability of cocaine vs. palatable food 
Addiction biology  2015;10.1111/adb.12280.
The paraventricular nucleus of the thalamus (PVT) is not traditionally considered part of the brain addiction neurocircuitry but has received growing attention with regard to a role in the modulation of drug-seeking behavior. This study sought to establish the pattern of neural activation induced by a response-reinstating discriminative stimulus (SD) conditioned to either cocaine (COC) or a conventional reinforcer using a palatable food substance, sweetened condensed milk (SCM). Male Wistar rats were trained to associate one SD (S+; COC or SCM availability) and a distinctly different SD (S−; non-reward; i.e., the availability of saline or the absence of SCM). Following extinction of COC- and SCM-reinforced responding, rats were presented with the respective S+ or S− alone and tested for the reinstatement of reward seeking. The COC S+ and SCM S+ elicited identical reinstatement, whereas the non-reward S− was behaviorally ineffective. PVT sections were obtained following completion of the reinstatement tests and labeled for Fos. The number of Fos+ neurons was compared among rats that were presented with the COC S+, SCM S+, or S−. Rats that were presented with the COC S+ exhibited a significant increase in Fos expression compared with rats that were presented with the S−. Moreover, Fos expression was significantly correlated with the number of reinstatement responses that were induced by the COC S+. In contrast, the SCM S+ and S− produced identical increases in Fos expression, without behaviorally relevant correlations. The findings implicate the PVT as an important site that is selectively recruited during COC-seeking behavior.
PMCID: PMC4788574  PMID: 26096647
cocaine; discriminative stimulus; reinstatement
2.  Model-Free Functional Connectivity and Impulsivity Correlates of Alcohol Dependence: A Resting-State Study 
Addiction biology  2015;10.1111/adb.12272.
Alcohol dependence is characterized by impulsiveness toward consumption despite negative consequences. Although neuroimaging studies have implicated some regions underlying this disorder, there is little information regarding its large-scale connectivity pattern. This study investigated the within- and between-network functional connectivity (FC) in alcohol dependence and examined its relationship with clinical impulsivity measures.
Using Probabilistic Independent Component Analysis (PICA) on resting-state fMRI (rs-fMRI) data from 25 alcohol dependent (AD) and 26 healthy control (HC) participants, we compared the within- and between-network FC between AD and HC. Then, the relationship between FC and impulsiveness as measured by the Barratt Impulsiveness Scale (BIS-11), the UPPS-P Impulsive Scale and the delay-discounting task (DDT) was explored.
Compared to HC, AD exhibited increased within-network FC in salience (SN), default-mode (DMN), orbitofrontal cortex (OFCN), left executive control (LECN) and amygdala-striatum (ASN) networks. Increased between-network FC was found among LECN, ASN and SN. Between-network FC correlations were significantly negative between Negative-Urgency and OFCN pairs with RECN, anterior DMN (aDMN), and posterior DMN (pDMN) in AD. DDT was significantly correlated with the between-network FC among the LECN, aDMN and SN in AD.
These findings add evidence to the concept of altered within-network FC and also highlight the role of between-network FC in the pathophysiology of AD. Additionally, this study suggests differential neurobiological bases for different clinical measures of impulsivity that may be used as a systems-level biomarker for alcohol dependence severity and treatment efficacy.
PMCID: PMC4669235  PMID: 26040546
fMRI; Functional Connectivity; Resting state; Impulsivity; Alcohol dependence; ICA
3.  Transient CNS responses to repeated binge ethanol treatment 
Addiction biology  2015;21(6):1199-1216.
Adaptive changes occur in response to repeated exposure to drugs. Although ethanol (EtOH) is known to induce pharmacokinetic tolerance, the effects of EtOH on in vivo, magnetic resonance (MR)-detectable brain measures across repeated exposures have not previously been reported. Of 28 rats weighing 341±22g at baseline, 15 were assigned to the EtOH group and 13 to the control (Ctrl) group. EtOH animals were exposed to 5 cycles of 4-days of EtOH treatment followed by 10 days of recovery. Rats in both groups had structural MR imaging (MRI) scans and whole brain MR spectroscopy (MRS) at baseline, immediately following each binge period, and after each recovery period (total=11 MR scans per rat).
Average blood alcohol levels (BALs) across each of the 5, 4-day binge periods were 298, 300, 301, 312, 318 mg/dL. Cerebrospinal fluid (CSF) volumes of the lateral ventricles and cisterns showed enlargement with each binge EtOH exposure but recovery with each abstinence period. Similarly, changes to MRS metabolites were transient: levels of N-acetyl aspartate (NAA) and total creatine (tCr) decreased, while those of choline-containing compounds (Cho) and glutamate/glutamine (Glx) increased with each binge EtOH exposure cycle, but also recovered during each abstinence period. The directionality of changes in response to EtOH were in expected directions based on previous, single-binge EtOH exposure experiments, but the current results do not provide support for accruing pathology with repeated binge EtOH exposure.
PMCID: PMC4801670  PMID: 26283309
repeated withdrawals; alcohol; binge; MRI; MRS; ventricles; glutamate
4.  The monoamine stabilizer (−)‐OSU6162 counteracts downregulated dopamine output in the nucleus accumbens of long‐term drinking Wistar rats 
Addiction Biology  2015;21(2):438-449.
We recently established that the monoamine stabilizer (−)‐OSU6162 (OSU6162) decreased voluntary alcohol‐mediated behaviors, including alcohol intake and cue/priming‐induced reinstatement, in long‐term drinking rats, while blunting alcohol‐induced dopamine output in the nucleus accumbens (NAc) of alcohol‐naïve rats. Therefore, we hypothesized that OSU6162 attenuates alcohol‐mediated behaviors by blunting alcohol's rewarding effects. Here, we evaluated the effects of long‐term drinking and OSU6162 treatment (30 mg/kg, sc) on basal and alcohol‐induced (2.5 g/kg, ip) NAc dopamine outputs in Wistar rats after 10 months of intermittent access to 20% alcohol. The results showed that basal and alcohol‐induced NAc dopamine outputs were significantly lower in long‐term drinking rats, compared with alcohol‐naïve rats. In the long‐term drinking rats, OSU6162 slowly increased and maintained the dopamine output significantly elevated compared with baseline for at least 4 hours. Furthermore, OSU6162 pre‐treatment did not blunt the alcohol‐induced output in the long‐term drinking rats, a finding that contrasted with our previous results in alcohol‐naïve rats. Finally, OSU6162 did not induce conditioned place preference (CPP) in either long‐term drinking or alcohol‐naïve rats, indicating that OSU6162 has no reinforcing properties. To verify that the CPP results were not due to memory acquisition impairment, we demonstrated that OSU6162 did not affect novel object recognition. In conclusion, these results indicate that OSU6162 attenuates alcohol‐mediated behaviors by counteracting NAc dopamine deficits in long‐term drinking rats and that OSU6162 is not rewarding on its own. Together with OSU6162's beneficial side‐effect profile, the present study merits evaluation of OSU6162's clinical efficacy to attenuate alcohol use in alcohol‐dependent patients.
PMCID: PMC5057338  PMID: 26464265
Alcohol dependence; condition place preference; ethanol; medication development; microdialysis
5.  The glucagon‐like peptide 1 receptor agonist liraglutide attenuates the reinforcing properties of alcohol in rodents 
Addiction Biology  2015;21(2):422-437.
The incretin hormone, glucagon‐like peptide 1 (GLP‐1), regulates gastric emptying, glucose‐dependent stimulation of insulin secretion and glucagon release, and GLP‐1 analogs are therefore approved for treatment of type II diabetes. GLP‐1 receptors are expressed in reward‐related areas such as the ventral tegmental area and nucleus accumbens, and GLP‐1 was recently shown to regulate several alcohol‐mediated behaviors as well as amphetamine‐induced, cocaine‐induced and nicotine‐induced reward. The present series of experiments were undertaken to investigate the effect of the GLP‐1 receptor agonist, liraglutide, on several alcohol‐related behaviors in rats that model different aspects of alcohol use disorder in humans. Acute liraglutide treatment suppressed the well‐documented effects of alcohol on the mesolimbic dopamine system, namely alcohol‐induced accumbal dopamine release and conditioned place preference in mice. In addition, acute administration of liraglutide prevented the alcohol deprivation effect and reduced alcohol intake in outbred rats, while repeated treatment of liraglutide decreased alcohol intake in outbred rats as well as reduced operant self‐administration of alcohol in selectively bred Sardinian alcohol‐preferring rats. Collectively, these data suggest that GLP‐1 receptor agonists could be tested for treatment of alcohol dependence in humans.
PMCID: PMC5049632  PMID: 26303264
Addictive behaviours; dependence; reward
6.  Genetic variation of the growth hormone secretagogue receptor gene is associated with alcohol use disorders identification test scores and smoking 
Addiction Biology  2015;21(2):481-488.
The multifaceted gut‐brain peptide ghrelin and its receptor (GHSR‐1a) are implicated in mechanisms regulating not only the energy balance but also the reward circuitry. In our pre‐clinical models, we have shown that ghrelin increases whereas GHSR‐1a antagonists decrease alcohol consumption and the motivation to consume alcohol in rodents. Moreover, ghrelin signaling is required for the rewarding properties of addictive drugs including alcohol and nicotine in rodents. Given the hereditary component underlying addictive behaviors and disorders, we sought to investigate whether single nucleotide polymorphisms (SNPs) located in the pre‐proghrelin gene (GHRL) and GHSR‐1a gene (GHSR) are associated with alcohol use, measured by the alcohol use disorders identification test (AUDIT) and smoking. Two SNPs located in GHRL, rs4684677 (Gln90Leu) and rs696217 (Leu72Met), and one in GHSR, rs2948694, were genotyped in a subset (n = 4161) of a Finnish population‐based cohort, the Genetics of Sexuality and Aggression project. The effect of these SNPs on AUDIT scores and smoking was investigated using linear and logistic regressions, respectively. We found that the minor allele of the rs2948694 SNP was nominally associated with higher AUDIT scores (P = 0.0204, recessive model) and smoking (P = 0.0002, dominant model). Furthermore, post hoc analyses showed that this risk allele was also associated with increased likelihood of having high level of alcohol problems as determined by AUDIT scores ≥ 16 (P = 0.0043, recessive model). These convergent findings lend further support for the hypothesized involvement of ghrelin signaling in addictive disorders.
PMCID: PMC5033010  PMID: 26059200
Candidate gene association study; gastrointestinal hormones; substance use disorder
7.  Recent updates on incubation of drug craving: a mini-review 
Addiction biology  2014;20(5):872-876.
Cue-induced drug craving progressively increases after prolonged withdrawal from drug self-administration in laboratory animals, a behavioral phenomenon termed “incubation of drug craving.” Studies over the years have revealed several important neural mechanisms contributing to incubation of drug craving. In this mini-review, we first discuss three excellent Addiction Biology publications on incubation of drug craving in both human and laboratory animals. We then review several key publications from the past year on behavioral and mechanistic findings related to incubation of drug craving.
PMCID: PMC4451451  PMID: 25440081
Incubation; cocaine; glutamate; dopamine; addiction; relapse
8.  Serial longitudinal MRI data indicates non-linear regional gray matter volume recovery in abstinent alcohol dependent individuals 
Addiction biology  2014;20(5):956-967.
The trajectory of regional volume changes during the first year of sustained abstinence in those recovering from an alcohol use disorder is unclear because previous research typically employed only two assessment points. To better understand the trajectory of regional brain volume recovery in treatment-seeking alcohol dependent individuals (ALC), regional brain volumes were measured after 1-week, 1-month, and 7.5-months of sustained abstinence, via magnetic resonance imaging at 1.5 Tesla. ALC showed significant volume increases in frontal, parietal, and occipital gray matter (GM) and white matter (WM), total cortical GM and total lobar WM, thalamus and cerebellum, and decreased ventricular volume over 7.5-months of abstinence. Volume increases in regional GM were significantly greater over 1-week to 1-month than from 1-month to 7.5-months of abstinence, indicating a non-linear rate of change in regional GM over 7.5-months. Overall, regional lobar WM showed linear volume increases over 7.5-months. With increasing age, smoking ALC showed lower frontal and total cortical GM volume recovery than non-smoking ALC. Despite significant volume increases, ALC showed smaller GM volumes in all regions, except the frontal cortex, than controls after 7.5-months of abstinence. ALC and controls showed no regional WM volume differences at any assessment point. In non-smoking ALC only, increasing regional GM and WM volumes were related to improving processing speed. Findings may indicate a differential rate of recovery of cell types/cellular components contributing to GM and WM volume during early abstinence, and that GM volume deficits persist after 7.5-months of sustained sobriety in this ALC cohort.
PMCID: PMC4345147  PMID: 25170881
alcohol use disorders; brain volume; cigarette smoking; cognition; recovery
9.  Persistent palatable food preference in rats with a history of limited and extended access to methamphetamine self-administration 
Addiction biology  2015;20(5):913-926.
Recent studies have shown that when given a mutually exclusive choice between cocaine and palatable foods most rats prefer the non-drug rewards over cocaine. Here, we used a discrete choice procedure to assess whether palatable food preference generalizes to rats with a history of limited (3 hr/day) or extended (6 or 9 hr/day) access to methamphetamine self-administration. On different daily sessions, we trained rats to lever-press for either methamphetamine (0.1–0.2 mg/kg/infusion) or palatable food (5 pellets per reward delivery) for several weeks; regular food was freely available. We then assessed food-methamphetamine preference either during training, after priming methamphetamine injections (0.5–1.0 mg/kg), following a satiety manipulation (palatable food exposure in the home cage), or after 21 days of withdrawal from methamphetamine. We also assessed progressive ratio responding for palatable food and methamphetamine. We found that independent of the daily drug access conditions and the withdrawal period, the rats strongly preferred the palatable food over methamphetamine, even when they were given free access to the palatable food in the home cage. Intake of methamphetamine and progressive ratio responding for the drug, both of which increased or escalated over time, did not predict preference in the discrete choice test. Results demonstrate that most rats strongly prefer palatable food pellets over intravenous methamphetamine, confirming previous studies using discrete choice procedures with intravenous cocaine. Results also demonstrate that escalation of drug self-administration, a popular model of compulsive drug use, is not associated with a cardinal feature of human addiction of reduced behavioral responding for non-drug rewards.
PMCID: PMC4499505  PMID: 25582886
psychostimulants; palatable food; discrete choice; preference; self-administration; extended access; limited access; progressive ratio; drug priming; food satiety
10.  Heritability of compulsive Internet use in adolescents 
Addiction Biology  2015;21(2):460-468.
Over the past decades, Internet use has grown substantially, and it now serves people as a supportive tool that is used regularly and—in large parts of the world—inevitably. Some people develop problematic Internet use, which may lead to addictive behavior and it is becoming important to explore the risk factors for compulsive Internet use. Data were analyzed on compulsive Internet use [with the Compulsive Internet Use Scale (CIUS)] from 5247 monozygotic (MZ) and dizygotic (DZ) adolescent twins registered with the Netherlands Twin Register. The participants form a sample that is informative for genetic analyses, allowing the investigation of the causes of individual differences in compulsive Internet use. The internal consistency of the instrument was high and the 1.6‐year test–retest correlation in a subsample (n = 902) was 0.55. CIUS scores increased slightly with age. Remarkably, gender did not explain variation in CIUS scores, as mean scores on the CIUS were the same in boys and girls. However, the time spent on specific Internet activities differed: boys spent more time on gaming, whereas girls spent more time on social network sites and chatting. The heritability estimates were the same for boys and girls: 48 percent of the individual differences in CIUS score were influenced by genetic factors. The remaining variance (52 percent) was due to environmental influences that were not shared between family members. Because a life without Internet is almost impossible nowadays, it is important to further explore the determinants of compulsive Internet use, including genetic risk factors.
PMCID: PMC5006854  PMID: 25582809
Addictive behavior; adolescents; compulsive Internet use; heritability; Internet addiction
Addiction biology  2015;21(1):3-22.
Given the strong evidence for neurological alterations at the basis of drug dependence, functional magnetic resonance imaging (fMRI) represents an important tool in the clinical neuroscience of addiction. fMRI cue-reactivity paradigms represent an ideal platform to probe the involvement of neurobiological pathways subserving the reward/motivation system in addiction and potentially offer a translational mechanism by which interventions and behavioral predictions can be tested. Thus, this review summarizes the research that has applied fMRI cue-reactivity paradigms to the study of adult substance use disorder treatment responses. Studies utilizing fMRI cue-reactivity paradigms for the prediction of relapse, and as a means to investigate psychosocial and pharmacological treatment effects on cue-elicited brain activation are presented within four primary categories of substances: alcohol, nicotine, cocaine, and opioids. Lastly, suggestions for how to leverage fMRI technology to advance addiction science and treatment development are provided.
PMCID: PMC4986996  PMID: 26435524
addiction; cue-reactivity; fMRI; medication development; substance use disorder; treatment
12.  Ghrelin system in alcohol-dependent subjects: role of plasma ghrelin levels in alcohol drinking and craving 
Addiction biology  2011;17(2):452-464.
Animal studies suggest that the gut-brain peptide ghrelin plays an important role in the neurobiology of alcohol dependence (AD). Human studies show an effect of alcohol on ghrelin levels and a correlation between ghrelin levels and alcohol craving in alcoholics.
This investigation consisted of two studies. Study 1 was a 12-week study with alcohol-dependent subjects, where plasma ghrelin determinations were assessed four times (T0-T3) and related to alcohol intake and craving [Penn Alcohol Craving Score (PACS) and Obsessive Compulsive Drinking Scale (OCDS)]. Serum growth hormone (GH) levels and assessment of the nutritional/metabolic status were also performed. Study 2 was a pilot case-control study to assess ghrelin gene polymorphisms (Arg51Gln and Leu72Met) in alcohol-dependent individuals. Study 1 showed no significant differences in ghrelin levels in the whole sample, while there was a statistical difference for ghrelin between non-abstinent and abstinent subjects. Baseline ghrelin levels were significantly and positively correlated with the PACS score at T1 and with all craving scores both at T2 and T3 (PACS, OCDS, obsessive and compulsive OCDS subscores). In Study 2, although there was a higher frequency of the Leu72Met ghrelin gene polymorphism in alcohol-dependent individuals, the distribution between healthy controls and alcohol dependent individuals was not statistically significant.
This investigation suggests that ghrelin is potentially able to affect alcohol-seeking behaviors, such as alcohol drinking and craving, representing a new potential neuropharmacological target for AD.
PMCID: PMC4974482  PMID: 21392177
ghrelin; alcohol dependence; alcohol drinking; craving
13.  MT-7716, a potent NOP receptor agonist, preferentially reduces ethanol seeking and reinforcement in post-dependent rats 
Addiction biology  2014;20(4):643-651.
Dysregulation of the nociceptin (N/OFQ) system has been implicated in alcohol abuse and alcoholism and growing evidence suggests that targeting this system may be beneficial for treating alcoholism. To further explore the treatment target potential of the N/OFQ system, the novel non-peptide, small-molecule N/OFQ (NOP) agonist MT-7716, (R)-2-{3-[1-(Acenaphthen-1-yl)piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-N-methylacetamide hydrochloride hydrate, was examined for its effects on ethanol self-administration and stress induced reinstatement of alcohol seeking in non-dependent and post-dependent rats. Male Wistar rats were trained to self-administer ethanol and then made ethanol dependent via repeated intragastric ethanol intubation. The effects of MT-7716 (0.3 and 1 mg/kg; PO) on alcohol self-administration were determined two weeks following dependence induction, when baseline self-administration was restored. Effects of MT-7716 on stress-induced reinstatement were tested in separate cohorts of rats, one and three weeks post-withdrawal. MT-7716 reduced alcohol self-administration and stress-induced reinstatement of alcohol seeking in post-dependent rats, but was ineffective in non-dependent animals. Moreover, the prevention of stress-induced reinstatement by MT-7716 was more pronounced at 3 weeks post-dependence. The results further confirm treatment target potential for the NOP receptor and identify non-peptide NOP agonists as promising potential treatment drugs for alcohol abuse and relapse prevention. The findings also support dysregulation of the N/OFQ system as a factor in alcohol seeking and reinforcement.
PMCID: PMC4268094  PMID: 24930632
MT-7716; Addiction; Alcohol; Nociceptin/orphanin FQ; self-administration; reinstatement; stress
14.  Effects of childhood maltreatment on the neural correlates of stress- and drug cue-induced cocaine craving 
Addiction biology  2014;20(4):820-831.
Childhood adversity negatively influences all stages of the addiction process and is associated with persistent alterations in neuroendocrine, autonomic and brain responses to stress. We sought to characterize the impact of childhood abuse and neglect on the neural correlates of stress- and drug cue-induced drug craving associated with cocaine addiction. Cocaine-dependent men with (n=20) and without (n=18) moderate to severe childhood maltreatment histories underwent fMRI during script-guided mental imagery of personalized stress, drug use, and neutral experiences. Compared to the neutral script, the stress and drug use scripts activated striatal, prefrontal, posterior cingulate, temporal and cerebellar regions consistent with prior studies of induced states of stress and drug craving. For the stress script, maltreated men exhibited reduced activation of the anterior precuneus and supplementary motor area (SMA); the interaction of maltreatment severity and stress-induced craving responses predicted lesser rostral anterior cingulate cortex activation. For the drug use script, maltreated men exhibited greater left dorsolateral prefrontal cortex activation. The interaction of maltreatment severity and craving responses was associated with greater activation of the visual cortex and SMA, whereas a maltreatment-by-anxiety interaction effect included lesser ventromedial prefrontal cortex activation. The outcomes indicate an association of childhood maltreatment with a heightened appetitive anticipatory response to drug cues and a diminished engagement of regulatory and controlled action selection processes in response to stress- or drug cue-induced drug craving and anxiety responses for cocaine-dependent men. These findings provide novel insights into possible brain mechanisms by which childhood maltreatment heightens risk for relapse in drug-dependent individuals.
PMCID: PMC4362751  PMID: 25214317
addiction; childhood maltreatment; cocaine; drug cues; fMRI; stress
15.  Effect of yohimbine on reinstatement of operant responding in rats is dependent on cue contingency but not food reward history 
Addiction biology  2014;20(4):690-700.
Yohimbine is an alpha-2 adrenoceptor antagonist that has been used in numerous studies as a pharmacological stressor in rodents, monkeys, and humans. Recently, yohimbine has become the most common stress manipulation in studies on reinstatement of drug and food seeking. However, the wide range of conditions under which yohimbine promotes reward seeking is significantly greater than that of stressors like intermittent footshock. Here we addressed two fundamental questions regarding yohimbine’s effect on reinstatement of reward seeking: (1) whether the drug’s effect on operant responding is dependent on previous reward history or cue contingency, and (2) whether yohimbine is aversive or rewarding under conditions typically used in reinstatement studies. We also used in vivo microdialysis to determine yohimbine’s effect on dopamine levels in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC).
We found that the magnitude of yohimbine-induced (0.5, 1.0, 2.0 mg/kg) operant responding during the reinstatement tests was critically dependent on the contingency between lever-pressing and discrete tone-light cue delivery but not the previous history with food reward during training. We also found that yohimbine (2 mg/kg) did not cause conditioned place aversion. Finally, we found that yohimbine modestly increased dopamine levels in mPFC but not NAc.
Results suggest that yohimbine’s effects on operant responding in reinstatement studies are likely independent of the history of contingent self-administration of food or drug rewards and may not be related to the commonly assumed stress-like effects of yohimbine.
PMCID: PMC4308573  PMID: 25065697
Conditioned place preference/aversion; dopamine; reinstatement; stress; sensory seeking; yohimbine
16.  Methods for inducing alcohol craving in individuals with comorbid alcohol dependence and posttraumatic stress disorder: Behavioral and physiological outcomes 
Addiction biology  2014;20(4):733-746.
Alcohol addiction is a chronic relapsing disorder that presents a substantial public health problem, and is frequently comorbid with posttraumatic stress disorder (PTSD). Craving for alcohol is a predictor of relapse to alcohol use, and is triggered by cues associated with alcohol and trauma. Identification of reliable and valid laboratory methods for craving induction is an important objective for alcoholism and PTSD research.
The present study compares two methods for induction of craving via stress and alcohol cues in individuals with comorbid alcohol dependence (AD) and PTSD: the combined Trier Social Stress Test and cue reactivity paradigm (Trier/CR), and a guided imagery (Scripts) paradigm. Outcomes include self-reported measures of craving, stress, and anxiety as well as endocrine measures.
Subjects were 52 individuals diagnosed with comorbid AD and PTSD seeking treatment at the NIAAA inpatient research facility. They participated in a four week inpatient study of the efficacy of a NK1 antagonist to treat comorbid AD and PTSD, and which included the two challenge procedures.
Both the Trier/CR and Scripts induced craving for alcohol, as well as elevated levels of subjective distress and anxiety. The Trier/CR yielded significant increases in ACTH and cortisol, while the Scripts did not.
Both paradigms are effective laboratory means of inducing craving for alcohol. Further research is warranted to better understand the mechanisms behind craving induced by stress vs. alcohol cues, as well as to understand the impact of comorbid PTSD and AD on craving.
PMCID: PMC4224641  PMID: 24806358
Alcoholism; cortisol; craving; neuroendocrine; stress; PTSD
17.  Abuse Potential of Intranasal Buprenorphine versus Buprenorphine/Naloxone in Buprenorphine-Maintained Heroin Users 
Addiction biology  2014;20(4):784-798.
In spite of the clinical utility of buprenorphine, parenteral abuse of this medication has been reported in several laboratory investigations and in the real world. Studies have demonstrated lower abuse liability of the buprenorphine/naloxone combination relative to buprenorphine alone. However, clinical research has not yet examined the utility of the combined formulation to deter intranasal use in a buprenorphine-maintained population. Heroin-using volunteers (n = 12) lived in the hospital for 8–9 weeks and were maintained on each of three sublingual buprenorphine doses (2, 8, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intranasal doses of buprenorphine (8, 16 mg), buprenorphine/naloxone (8/2, 8/8, 8/16, 16/4 mg) and controls (placebo, heroin 100 mg, naloxone 4 mg) were assessed. Intranasal buprenorphine alone typically produced increases in positive subjective effects and the 8 mg dose was self-administered above the level of placebo. The addition of naloxone dose-dependently reduced positive subjective effects and increased aversive effects. No buprenorphine/naloxone combination dose was self-administered significantly more than placebo. These data suggest that within a buprenorphine-dependent population, intranasal buprenorphine/naloxone has reduced abuse potential in comparison to buprenorphine alone. These data strongly argue in favor of buprenorphine/naloxone rather than buprenorphine alone as the more reasonable option for managing the risk of buprenorphine misuse.
PMCID: PMC4305506  PMID: 25060839
Abuse Liability; Buprenorphine; Intranasal; Opioids; Self-administration
18.  The Galanin Receptor Agonist, Galnon, Attenuates Cocaine-Induced Reinstatement and Dopamine Overflow in the Frontal Cortex 
Addiction biology  2014;20(4):701-713.
Relapse represents one of the most significant problems in the long-term treatment of drug addiction. Cocaine blocks plasma membrane monoamine transporters and increases dopamine (DA) overflow in the brain, and DA is critical for the motivational and primary reinforcing effects of the drug as well as cocaine-primed reinstatement of cocaine seeking in rats, a model of relapse. Thus, modulators of the DA system may be effective for the treatment of cocaine dependence. The endogenous neuropeptide galanin inhibits DA transmission, and both galanin and the synthetic galanin receptor agonist, galnon, interfere with some rewarding properties of cocaine. The purpose of this study was to further assess the effects of galnon on cocaine-induced behaviors and neurochemistry in rats. We found that galnon attenuated cocaine-induced motor activity, reinstatement, and DA overflow in the frontal cortex at a dose that did not reduce baseline motor activity, stable self-administration of cocaine, baseline extracellular DA levels, or cocaine-induced DA overflow in the nucleus accumbens (NAc). Similar to cocaine, galnon had no effect on stable food self-administration but reduced food-primed reinstatement. These results indicate that galnon can diminish cocaine-induced hyperactivity and relapse-like behavior, possibly in part by modulating DA transmission in the frontal cortex.
PMCID: PMC4305031  PMID: 25053279
cocaine; cortex; dopamine; galanin; galnon; reinstatement
19.  Interaction Between Early Life Stress and Alcohol Dependence on Neural Stress Reactivity 
Addiction biology  2014;20(3):523-533.
Stress-response biologic systems are altered in alcohol-dependent individuals. Early life stress (ELS) is associated with a heightened risk of alcohol-dependence, presumably due to stress-induced neuroplastic changes. This study was designed to assess the contribution of ELS to a stress-induced neural response in alcohol-dependent participants. Fifteen alcohol-dependent men abstinent for 3–5 weeks and 15 age- and race-matched healthy controls were studied. Anticipatory anxiety was induced by a conditioned stimulus paired with an uncertain physically painful unconditioned stressor. Neural response was assessed with functional magnetic resonance imaging. ELS was assessed with the Childhood Adversity Interview (CAI). There was a significant interaction between ELS and group on Blood Oxygen Level-Dependent (BOLD) amplitude during anticipatory anxiety in the right amygdala and bilateral orbitofrontal cortex, posterior putamen, and insula. Higher ELS scores were associated with decreased BOLD amplitude during anticipatory anxiety in alcohol-dependent, but not control, participants. These findings suggest that ELS interacts with alcohol dependence to induce a muted cortico-striatal response to high threat stimuli. Allostatic changes due to both ELS and excessive alcohol use may jointly induce persistent changes in the neural response to acute stressors.
PMCID: PMC4893323  PMID: 24602036
alcoholism; brain imaging; childhood adversity; maltreatment; functional magnetic resonance imaging; striatum
20.  Inflated Reward Value in Early Opiate Withdrawal 
Addiction biology  2014;21(2):221-233.
Through incentive learning the emotional experience of a reward in a relevant need state (e.g., hunger for food) sets the incentive value that guides the performance actions that earn that reward when the need state is encountered again. Opiate withdrawal has been proposed as a need state in which, through experience, opiate value can be increased resulting in escalated opiate self-administration. Endogenous opioid transmission plays anatomically dissociable roles in the positive emotional experience of reward consumption and incentive learning. We, therefore, sought to determine if chronic opiate exposure and withdrawal produces a disruption in the fundamental incentive learning process such that reward seeking, even for non-opiate rewards, can become maladaptive, inconsistent with the emotional experience of reward consumption and irrespective of need. Rats trained to earn sucrose or water on a reward-seeking chain were treated with morphine (10-30 mg/k.g., s.c.) daily for 11 d prior to testing in withdrawal. Opiate withdrawn rats showed elevated reward-seeking actions, but only after they experienced the reward in withdrawal, an effect that was strongest in early (1-3 d), as opposed to late (14-16 d) withdrawal. This was sufficient to overcome a negative reward value change induced by sucrose experience in satiety and, in certain circumstances, was inconsistent with the emotional experience of reward consumption. Lastly, we found that early opiate withdrawal-induced inflation of reward value was blocked by inactivation of basolateral amygdala mu opioid receptors. These data suggest that in early opiate withdrawal the incentive learning process is disrupted resulting in maladaptive reward seeking.
PMCID: PMC4312551  PMID: 25081350
Opiate withdrawal; incentive learning; instrumental conditioning; reward; chronic morphine
21.  Anti-addiction drug ibogaine inhibits hERG channels: a cardiac arrhythmia risk! 
Addiction biology  2012;19(2):237-239.
Ibogaine, an alkaloid derived from the African shrub Tabernanthe iboga, has shown promising anti-addictive properties in animals. Anecdotal evidence suggests that ibogaine is also anti-addictive in humans. Thus, it alleviates drug craving and impedes relapse of drug use. Although not licensed as therapeutic drug, and despite evidence that ibogaine may disturb the rhythm of the heart, this alkaloid is currently used as an anti-addiction drug in alternative medicine. Here we report that therapeutic concentrations of ibogaine reduce currents through human ERG potassium channels. Thereby, we provide a mechanism by which ibogaine may generate life-threatening cardiac arrhythmias.
PMCID: PMC4888945  PMID: 22458604
Anti-addiction drug; cardiac arrhythmias; hERG potassium channels; ibogaine; indole alkaloid
22.  Polygenic risk for alcohol dependence associates with alcohol consumption, cognitive function and social deprivation in a population‐based cohort 
Addiction Biology  2015;21(2):469-480.
Alcohol dependence is frequently co‐morbid with cognitive impairment. The relationship between these traits is complex as cognitive dysfunction may arise as a consequence of heavy drinking or exist prior to the onset of dependence. In the present study, we tested the genetic overlap between cognitive abilities and alcohol dependence using polygenic risk scores (PGRS). We created two independent PGRS derived from two recent genome‐wide association studies (GWAS) of alcohol dependence (SAGE GWAS: n = 2750; Yale‐Penn GWAS: n = 2377) in a population‐based cohort, Generation Scotland: Scottish Family Health Study (GS:SFHS) (n = 9863). Data on alcohol consumption and four tests of cognitive function [Mill Hill Vocabulary (MHV), digit symbol coding, phonemic verbal fluency (VF) and logical memory] were available. PGRS for alcohol dependence were negatively associated with two measures of cognitive function: MHV (SAGE: P = 0.009, β = −0.027; Yale‐Penn: P = 0.001, β = −0.034) and VF (SAGE: P = 0.0008, β = −0.036; Yale‐Penn: P = 0.00005, β = −0.044). VF remained robustly associated after adjustment for education and social deprivation; however, the association with MHV was substantially attenuated. Shared genetic variants may account for some of the phenotypic association between cognitive ability and alcohol dependence. A significant negative association between PGRS and social deprivation was found (SAGE: P = 5.2 × 10−7, β = −0.054; Yale‐Penn: P = 0.000012, β = −0.047). Individuals living in socially deprived regions were found to carry more alcohol dependence risk alleles which may contribute to the increased prevalence of problem drinking in regions of deprivation. Future work to identify genes which affect both cognitive impairment and alcohol dependence will help elucidate biological processes common to both disorders.
PMCID: PMC4600406  PMID: 25865819
Alcohol dependence; cognition; environment; genetics; polygenic; social deprivation
23.  Susceptibility to ethanol withdrawal seizures is produced by BK channel gene expression 
Addiction biology  2012;19(3):332-337.
Alcohol withdrawal seizures are part of the symptomatology of severe alcohol dependence and are believed to originate from long-term neural adaptations that counter the CNS depressant effects of alcohol. Upon alcohol withdrawal however, the increased neural excitability that was adaptive in the presence of alcohol, becomes counteradaptive and produces an imbalanced hyperactive nervous system. For some individuals, the uncovering of this imbalance by alcohol abstention can be sufficient to generate a seizure. Using the Drosophila model organism, we demonstrate a central role for the BK-type Ca2+-activated K+ channel gene slo in the production of alcohol withdrawal seizures.
PMCID: PMC4860885  PMID: 22734584
Addiction; Alcohol dependence; Drosophila; KCNMA1; Ion channels
24.  Anterior thalamic paraventricular nucleus is involved in intermittent access ethanol drinking: Role of orexin receptor 2 
Addiction biology  2014;20(3):469-481.
The paraventricular nucleus of the thalamus (PVT) has been shown to participate in hedonic feeding and is thought to influence drug seeking. This understudied nucleus contains anterior (aPVT) and posterior (pPVT) subregions, which receive dense projections from hypothalamic orexin/hypocretin (OX) but exhibit anatomical and functional differences. This study sought to characterize in Long-Evans rats the involvement of these PVT subregions and their OX receptor activity in consumption of the drug, ethanol. Compared to those maintained on water and chow only (Water Group), rats trained to drink pharmacologically-relevant levels of ethanol (Ethanol Group) showed increased neuronal activation in the PVT, specifically the aPVT but not pPVT, as indicated by c-Fos-immunoreactivity. Similar results were obtained in rats administered ethanol via oral gavage, indicating that this site-specific effect was due to ethanol exposure. In support of the involvement of OX, the Ethanol group also showed increased mRNA levels of this neuropeptide in the hypothalamus and of OX 2 receptor (OX2R) but not OX 1 receptor (OX1R), again in the aPVT but not pPVT. Similarly, ethanol gavage increased double-labeling of c-Fos with OX2R but not OX1R, specifically in the aPVT. Evidence directly supporting a role for aPVT OX2R in ethanol consumption was provided by results with local injections, showing ethanol intake to be enhanced by OX-A or OX-B in the aPVT but not pPVT and reduced by a local antagonist of OX2R but not OX1R. These results focus attention on the aPVT and specifically its OX2R in mediating a positive-feedback relationship with ethanol intake.
PMCID: PMC4192116  PMID: 24712379
c-Fos; emotional behavior; immunohistochemistry; intermittent access; microinjection; rat
25.  Association of substance dependence phenotypes in the COGA sample 
Addiction biology  2014;20(3):617-627.
Alcohol and drug use disorders are individually heritable (50%). Twin studies indicate that alcohol and substance use disorders share common genetic influences, and therefore may represent a more heritable form of addiction and thus be more powerful for genetic studies. This study utilized data from 2,322 subjects from 118 European-American families in the COGA sample to conduct genomewide association analysis of a binary and a continuous index of general substance dependence liability. The binary phenotype (ANYDEP) was based on meeting lifetime criteria for any DSM-IV dependence on alcohol, cannabis, cocaine or opioids. The quantitative trait (QUANTDEP) was constructed from factor analysis based on endorsement across the 7 DSM-IV criteria for each of the 4 substances. Heritability was estimated to be 54% for ANYDEP and 86% for QUANTDEP. One SNP, rs2952621 in the uncharacterized gene LOC151121 on chromosome 2, was associated with ANYDEP (p=1.8×10−8), with support from surrounding imputed SNPs and replication in an independent sample (SAGE; p=0.02). One SNP, rs2567261 in ARHGAP28 (Rho GTPase activating protein 28), was associated with QUANTDEP (p=3.8×10−8), and supported by imputed SNPs in the region, but did not replicate in an independent sample (SAGE; p=0.29). The results of this study provide evidence that there are common variants that contribute to the risk for a general liability to substance dependence.
PMCID: PMC4233207  PMID: 24832863
alcohol dependence; cannabis dependence; cocaine dependence; common genetic liability; drug dependence; opioid dependence

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