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1.  Brain activation to cocaine cues and motivation/treatment status 
Addiction biology  2012;19(2):240-249.
Motivation to change is believed to be a key factor in therapeutic success in substance use disorders; however, the neurobiological mechanisms through which motivation to change impacts decreased substance use remain unclear. Existing research is conflicting, with some investigations supporting decreased and others reporting increased frontal activation to drug cues in individuals seeking treatment for substance use disorders. The present study investigated the relationship between motivation to change cocaine use and cue-elicited brain activity in cocaine-dependent individuals using two conceptualizations of “motivation to change:” 1) current treatment status (i.e., currently receiving vs. not receiving outpatient treatment for cocaine dependence) and 2) self-reported motivation to change substance use, using the Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES; Miller and Tonigan, 1996). Thirty-eight cocaine-dependent individuals (14 currently in treatment) completed a diagnostic assessment and an fMRI cocaine cue-reactivity task. Whole-brain analyses demonstrated that both treatment-seeking and motivated participants had lower activation to cocaine cues in a wide variety of brain regions in the frontal, occipital, temporal, and cingulate cortices relative to non-treatment-seeking and less motivated participants. Future research is needed to explain the mechanism by which treatment and/or motivation impacts neural cue-reactivity, as such work could potentially aid in the development of more effective therapeutic techniques for substance-dependent patients.
doi:10.1111/j.1369-1600.2012.00446.x
PMCID: PMC3390439  PMID: 22458561
cocaine dependence; cue reactivity; fMRI; motivation to change; SOCRATES; treatment seeking
2.  Methylphenidate and Cocaine Self-Administration Produce Distinct Dopamine Terminal Alterations 
Addiction biology  2012;19(2):145-155.
Methylphenidate (MPH) is a commonly abused psychostimulant prescribed for the treatment of attention deficit hyperactivity disorder. MPH has a mechanism of action similar to cocaine (COC) and is commonly characterized as a dopamine transporter (DAT) blocker. While there has been extensive work aimed at understanding dopamine (DA) nerve terminal changes following COC self-administration, very little is known about the effects of MPH self-administration on the DA system. We used fast scan cyclic voltammetry in nucleus accumbens core slices from animals with a five-day self-administration history of 40 injections/day of either MPH (0.56 mg/kg) or COC (1.5 mg/kg) to explore alterations in baseline DA release and uptake kinetics as well as alterations in the interaction of each compound with the DAT. Although MPH and COC have similar behavioral effects, the consequences of self-administration on DA system parameters were found to be divergent. We show that COC self-administration reduced DAT levels and maximal rates of DA uptake, as well as reducing electrically stimulated release, suggesting decreased DA terminal function. In contrast, MPH self-administration increased DAT levels, DA uptake rates, and DA release, suggesting enhanced terminal function, which was supported by findings of increased metabolite/DA tissue content ratios. Tyrosine hydroxylase mRNA, protein and phosphorylation levels were also assessed in both groups. Additionally, COC self-administration reduced COC-induced DAT inhibition, while MPH self-administration increased MPH-induced DAT inhibition, suggesting opposite pharmacodynamic effects of these two drugs. These findings suggest that the factors governing DA system adaptations are more complicated than simple DA uptake blockade.
doi:10.1111/j.1369-1600.2012.00456.x
PMCID: PMC3390453  PMID: 22458761
Cocaine; Dopamine; Dopamine Transporter; Methylphenidate; Nucleus Accumbens; Self-administration
3.  Differences in Regional Cerebral Blood Flow Response to a 5HT3 Antagonist in Early- and Late-Onset Cocaine Dependent Subjects 
Addiction biology  2012;19(2):250-261.
5-hydroxytryptamine 3 (5HT3) receptors are important modulators of mesostriatal dopaminergic transmission and have been implicated in the pathophysiology of cocaine reward, withdrawal, and self-administration. In addition, the 5HT3 antagonist ondansetron is effective in treating early-onset, but not late-onset, alcohol-dependent subjects. To explore the role of 5HT3 receptor systems in cocaine addiction using functioning imaging, we administered ondansetron to 23 abstinent, treatment-seeking cocaine-addicted and 22 sex-, age-, and race-matched healthy control participants. Differences between early- (first use before 20 years, n=10) and late-onset (first use after 20 years, n=10) cocaine-addicted subjects were also assessed. On two separate days, subjects were administered ondansetron (0.15 mg/kg intravenously over 15 min) or saline. Regional cerebral blood flow (rCBF) was measured following each infusion with single photon emission computed tomography (SPECT). No significant rCBF differences between the cocaine-addicted and control participants were observed following ondansetron relative to saline. Early-onset subjects, however, showed increased (p < 0.001) right posterior parahippocampal rCBF following ondansetron. In contrast, late-onset subjects showed decreased rCBF following ondansetron in an overlapping region of the right parahippocampal/hippocampal gyrus. Early-onset subjects also displayed increased rCBF in the left anterior insula and subthalamic nucleus following ondansetron; late-onset subjects showed decreased rCBF in the right anterior insula. These findings suggest that age of drug use onset is associated with serotonergic biosignatures in cocaine-addicted subjects. Further clarification of these alterations may guide targeted treatment with serotonergic medications similar to those successfully used in alcohol-dependent patients.
doi:10.1111/j.1369-1600.2012.00450.x
PMCID: PMC3643993  PMID: 22458709
4.  Selective serotonin re-uptake inhibitors potentiate gene blunting induced by repeated methylphenidate treatment: Zif268 vs. Homer1a 
Addiction biology  2013;19(6):986-995.
There is a growing use of psychostimulants such as methylphenidate (Ritalin; dopamine reuptake inhibitor) for medical treatments and as cognitive enhancers in the healthy. Methylphenidate is known to produce some addiction-related gene regulation. Recent findings in animal models show that selective serotonin reuptake inhibitors (SSRIs) including fluoxetine can potentiate acute induction of gene expression by methylphenidate, thus indicating an acute facilitatory role for serotonin in dopamine-induced gene regulation. We investigated whether repeated exposure to fluoxetine in conjunction with methylphenidate in adolescent rats facilitated a gene regulation effect well-established for repeated exposure to illicit psychostimulants such as cocaine - blunting (repression) of gene inducibility. We measured, by in situ hybridization histochemistry, the effects of a 5-day repeated treatment with methylphenidate (5 mg/kg), fluoxetine (5 mg/kg) or a combination on the inducibility (by cocaine) of neuroplasticity-related genes (Zif268, Homer1a) in the striatum. Repeated methylphenidate treatment alone produced minimal gene blunting, while fluoxetine alone had no effect. In contrast, fluoxetine added to methylphenidate robustly potentiated methylphenidate-induced blunting for both genes. This potentiation was widespread throughout the striatum, but was most robust in the lateral, sensorimotor striatum, thus mimicking cocaine effects. For illicit psychostimulants, blunting of gene expression is considered part of the molecular basis of addiction. Our results thus suggest that SSRIs such as fluoxetine may increase the addiction liability of methylphenidate.
doi:10.1111/adb.12067
PMCID: PMC4332883  PMID: 23763573
cocaine; cognitive enhancer; dopamine; gene expression; psychostimulant; SSRI antidepressant
5.  The heritability of oxycodone reward and concomitant phenotypes in a LG/J × SM/J mouse advanced intercross line 
Addiction biology  2012;19(4):552-561.
The rewarding property of opioids likely contributes to their abuse potential. Therefore, determining the genetic basis of opioid reward could aid in understanding the neurobiological mechanisms of opioid addiction, provided that it is a heritable trait. Here, we characterized the rewarding property of the widely abused prescription opioid oxycodone (OXY) in the conditioned place preference (CPP) assay using LG/J and SM/J parental inbred mouse strains and 17 parent-offspring families of a LG/J × SM/J F47/F48 advanced intercross line (AIL). Following OXY training (5 mg/kg, i.p.), SM/J mice and AIL mice, but not LG/J mice, showed an increase in preference for the OXY-paired side, suggesting a genetic basis for OXY-CPP. SM/J mice showed greater locomotor activity than LG/J mice in response to both saline and OXY. LG/J, SM/J, and AIL mice all exhibited robust OXY-induced locomotor sensitization. Narrow-sense heritability (h2) estimates of the phenotypes using linear regression and maximum likelihood estimation showed good agreement (r = 0.91). OXY-CPP was clearly not a heritable trait whereas drug free- and OXY-induced locomotor activity and sensitization were significantly and sometimes highly heritable (h2 = 0.30–0.84). Interestingly, the number of transitions between the saline- and OXY-paired sides emerged as a reliably heritable trait following OXY training (h2 = 0.46–0.66) and could represent a genetic component of drug seeking behavior. Thus, although OXY-CPP does not appear to be amenable to genome-wide quantitative trait locus (QTL) mapping, this protocol will be useful for mapping other traits potentially relevant to opioid abuse.
doi:10.1111/adb.12016
PMCID: PMC4300855  PMID: 23231598
addiction; locomotion; opiate; Pavlovian; place conditioning; reward
6.  Interactive Effects of Chronic Cigarette Smoking and Age on Brain Volumes in Controls and Alcohol Dependent Individuals in Early Abstinence 
Addiction biology  2012;19(1):10.1111/j.1369-1600.2012.00492.x.
Chronic alcohol use disorders (AUD) have been shown to interact with normal age-related volume loss to exacerbate brain atrophy with increasing age. However, chronic cigarette smoking, a highly comorbid condition in AUD, and its influence on age-related brain atrophy has not been evaluated. We performed 1.5T quantitative MRI in non-smoking controls (nsCON; n=54), smoking light drinking controls (sCON, n=34), and 1-week-abstinent, treatment-seeking non-smoking alcohol dependent individuals (nsALC, n=35) and smoking ALC (sALC, n=43), to evaluate the independent and interactive effects of alcohol dependence and chronic smoking on regional cortical and subcortical brain volumes, emphasizing the brain reward/executive oversight system (BREOS),. nsCON and sALC showed greater age-related volume losses than nsALC in the dorsal prefrontal cortex (DPFC), total cortical BREOS, superior parietal lobule and putamen. nsALC and sALC demonstrated smaller volumes than nsCON in most cortical ROIs. sCON had smaller volumes than nsCON in the DPFC, insula, inferior parietal lobule, temporal pole/parahippocampal region and all global cortical measures. nsALC and sALC had smaller volumes than sCON in the DPFC, superior temporal gyrus, inferior and superior parietal lobules, precuneus and all global cortical measures. Volume differences between nsALC and sALC were observed only in the putamen. Alcohol consumption measures were not related to volumes in any ROI for ALC; smoking severity measures were related to corpus callosum volume in sCON and sALC. The findings indicate that consideration of smoking status is necessary for a better understanding of the factors contributing to regional brain atrophy in AUD.
doi:10.1111/j.1369-1600.2012.00492.x
PMCID: PMC3528793  PMID: 22943795
Brain volume; magnetic resonance imaging; cigarette smoking; alcohol dependence; brain reward system
7.  Modafinil Attenuates Reinstatement of Cocaine Seeking: Role for Cystine-Glutamate Exchange and Metabotropic Glutamate Receptors 
Addiction biology  2012;19(1):10.1111/j.1369-1600.2012.00506.x.
Modafinil may be useful for treating stimulant abuse, but the mechanisms by which it does so are unknown. Indeed, a primary effect of modafinil is to inhibit dopamine transport, which typically promotes rather than inhibits motivated behavior. Therefore, we examined the role of nucleus accumbens extracellular glutamate and the group II metabotropic glutamate receptor (mGluR2/3) in modafinil effects. One group of rats was trained to self-administer cocaine for 10 days and extinguished, then given priming injections of cocaine to elicit reinstatement. Modafinil (300 mg/kg, i.p.) inhibited reinstated cocaine-seeking (but did not alter extinction responding by itself), and this effect was prevented by pretreatment with bilateral microinjections of the mGluR2/3 antagonist LY-341495 (LY) into nucleus accumbens core. No reversal of modafinil effects was seen after unilateral accumbens core LY, or bilateral LY in the rostral pole of accumbens. Next, we sought to explore effects of modafinil on extracellular glutamate levels in accumbens after chronic cocaine. Separate rats were administered non-contingent cocaine, and after 3 weeks of withdrawal underwent accumbens microdialysis. Modafinil increased extracellular accumbens glutamate in chronic cocaine, but not chronic saline pretreated animals. This increase was prevented by reverse dialysis of cystine-glutamate exchange or voltage-dependent calcium channel antagonists. Voltage-dependent sodium channel blockade partly attenuated the increase in glutamate, but mGluR1 blockade did not. We conclude that modafinil increases extracellular glutamate in nucleus accumbens from glial and neuronal sources in cocaine-exposed rats, which may be important for its mGluR2/3-mediated anti-relapse properties.
doi:10.1111/j.1369-1600.2012.00506.x
PMCID: PMC3535502  PMID: 23017017
nucleus accumbens; self-administration; microdialysis
8.  The role of ventral and dorsal striatum mGluR5 in relapse to cocaine-seeking and extinction learning 
Addiction biology  2013;19(1):10.1111/adb.12061.
Cocaine addiction is a chronic, relapsing disease characterized by an inability to regulate drug-seeking behavior. Here we investigated the role of mGluR5 in the ventral and dorsal striatum in regulating cocaine-seeking following both abstinence and extinction. Animals underwent 2 weeks of cocaine self-administration followed by 3 weeks of home-cage abstinence. Animals were then reintroduced to the operant chamber for a context-induced relapse test, followed by 7–10 days of extinction training. Once responding was extinguished, cue-primed reinstatement test was conducted. Both drug-seeking tests were conducted in the presence of either the mGluR5 negative allosteric modulator, MTEP or vehicle infused into either the nucleus accumbens (NA) core or dorsolateral striatum (dlSTR). We found that MTEP infused in the NA core attenuated both context-induced relapse following abstinence and cue-primed reinstatement following extinction training. Blocking dlSTR mGluR5 had no effect on context- or cue-induced cocaine-seeking. However, the intra-dlSTR MTEP infusion on the context-induced relapse test day attenuated extinction learning for 4 days after the infusion. Furthermore, mGluR5 surface expression was reduced and LTD was absent in dlSTR slices of animals undergoing 3 weeks of abstinence from cocaine but not sucrose self-administration. LTD was restored by bath application of VU-29, a positive allosteric modulator of mGluR5. Bath application of MTEP prevented the induction of LTD in dSTR slices from sucrose animals. Taken together, this data indicates that dlSTR mGluR5 plays an essential role in extinction learning but not cocaine relapse, while NA core mGluR5 modulates drug-seeking following both extinction and abstinence from cocaine self-administration.
doi:10.1111/adb.12061
PMCID: PMC3762937  PMID: 23710649
mGluR5; dorsal striatum; nucleus accumbens; cocaine; abstinence; extinction; long-term depression; surface expression
9.  Association of OPRD1 Polymorphisms with Heroin Dependence in a Large Case-control Series 
Addiction biology  2012;19(1):10.1111/j.1369-1600.2012.00445.x.
Genes encoding the opioid receptors (OPRM1, OPRD1, and OPRK1) are obvious candidates for involvement in risk for heroin dependence. Prior association studies commonly had samples of modest size, included limited single nucleotide polymorphism (SNP) coverage of these genes, and yielded inconsistent results. Participants for the current investigation included 1459 heroin dependent cases ascertained from maintenance clinics in New South Wales, Australia, 1495 unrelated individuals selected from an Australian sample of twins and siblings as not meeting DSM-IV criteria for lifetime alcohol or illicit drug dependence (non-dependent controls), and 531 controls ascertained from economically-disadvantaged neighborhoods in proximity to the maintenance clinics. A total of 136 OPRM1, OPRD1, and OPRK1 SNPs were genotyped in this sample. After controlling for admixture with principal components analysis, our comparison of cases to non-dependent controls found 4 OPRD1 SNPs in fairly high linkage disequilibrium for which adjusted p values remained significant (e.g., rs2236857; OR 1.25; p=2.95 × 10−4) replicating a previously reported association. A post-hoc analysis revealed that the two-SNP (rs2236857 and rs581111) GA haplotype in OPRD1 is associated with greater risk (OR 1.68; p=1.41 × 10−5). No OPRM1 or OPRK1 SNPs reached more than nominal significance. Comparisons of cases to neighborhood controls reached only nominal significance. Our results replicate a prior report providing strong evidence implicating OPRD1 SNPs and, in particular, the two SNP (rs2236857 and rs581111) GA haplotype in liability for heroin dependence. Support was not found for similar association involving either OPRM1 or OPRK1 SNPs.
doi:10.1111/j.1369-1600.2012.00445.x
PMCID: PMC3867542  PMID: 22500942
association study; heroin dependence; OPRD1; OPRK1; OPRM1
10.  Relapse to Cocaine-seeking after Abstinence Is Regulated by cAMP-dependent Protein Kinase A in the Prefrontal Cortex 
Addiction biology  2013;19(1):77-86.
Abstinence from cocaine self-administration (SA) is associated with neuroadaptations in the prefrontal cortex (PFC) and nucleus accumbens (NAc) that are implicated in cocaine-induced neuronal plasticity and relapse to drug-seeking. Alterations in cAMP-dependent protein kinase A (PKA) signaling are prominent in medium spiny neurons in the NAc after repeated cocaine exposure but it is unknown whether similar changes occur in the PFC. Because cocaine SA induces disturbances in glutamatergic transmission in the PFC-NAc pathway, we examined whether dysregulation of PKA-mediated molecular targets in PFC-NAc neurons occurs during abstinence and, if so, whether it contributes to cocaine seeking. We measured the phosphorylation of CREB (Ser133) and GluA1 (Ser845) in the dorsomedial (dm) PFC and the presynaptic marker, synapsin I (Ser9, Ser62/67, Ser603), in the NAc after 7 days of abstinence from cocaine SA with or without cue-induced cocaine-seeking. We also evaluated whether infusion of the PKA inhibitor, 8-bromo-Rp-cyclic adenosine 3′, 5′-monophosphorothioate (Rp-cAMPs), into the dmPFC after abstinence would affect cue-induced cocaine-seeking and PKA-regulated phosphoprotein levels. Seven days of forced abstinence increased the phosphorylation of CREB and GluA1 in the dmPFC and synapsin I (Ser9) in the NAc. Induction of these phosphoproteins was reversed by a cue-induced relapse test of cocaine-seeking. Bilateral intra-dmPFC Rp-cAMPs rescued abstinence-elevated PKA-mediated phosphoprotein levels in the dmPFC and NAc and suppressed cue-induced relapse. Thus, by inhibiting abstinence-induced PKA molecular targets, relapse reverses abstinence-induced neuroadaptations in the dmPFC that are responsible, in part, for the expression of cue-induced cocaine-seeking.
doi:10.1111/adb.12043
PMCID: PMC4110897  PMID: 23461423
CREB; AMPA receptor; nucleus accumbens; synapsin
11.  Ventral midbrain correlation between genetic variation and expression of the dopamine transporter gene in cocaine-abusing versus non-abusing subjects 
Addiction biology  2011;19(1):10.1111/j.1369-1600.2011.00391.x.
Altered activity of the human dopamine transporter gene (hDAT) is asssociated with several common and severe brain disorders including cocaine abuse. However, there is little a priori information on whether such alteration was due to nature (genetic variantion) or nurture (human behaviors such as cocaine abuse). This study investigated the correlation between seven markers throughout hDAT and its mRNA levels in postmortem ventral midbrain tissues from 18 cocaine abusers and 18 strictly matched drug-free controls in the African American population. Here we show that one major haplotype with same frequency in cocaine abusers versus drug-free controls displays a 37.1%-reduction of expression levels in cocaine abusers, compared to matched controls (P = 0.0057). The most studied genetic marker, variable number tandem repeats (VNTR) located in Exon 15 (3′VNTR), is not correlated with hDAT mRNA levels. A 5′ upstream VNTR (rs70957367) has repeat numbers positively correlated with expression levels in controls (r2 0.9536, P = 0.0235) but this positive correlation disappears in cocaine abusers. The findings suggest that varying hDAT activity is attributed to both genetics and cocaine abuse.
doi:10.1111/j.1369-1600.2011.00391.x
PMCID: PMC3270208  PMID: 22026501
Addiction; DAT; expressional variation; pharmacogenomics; postmortem; epigenetics
12.  Baclofen effects on alcohol seeking, self-administration and extinction of seeking responses in a within-session design in baboons 
Addiction biology  2012;19(1):10.1111/j.1369-1600.2012.00448.x.
Baclofen, a GABAB receptor agonist, is currently under investigation as a potential treatment to prevent relapse to drinking in alcohol dependent persons. In the current study, two groups of baboons were trained under a chained schedule of reinforcement (CSR), with 3 linked components, which were each correlated with different response requirements and cues. Fulfilling the requirement in the 2nd link initiated the 3rd link where either alcohol (n=4) or a preferred non-alcoholic beverage (Tang, n=5) was available for self-administration; failure to complete the response requirement in Link 2 ended the session (no access to alcohol or Tang). Seeking responses in Link 2 were used as indices of the motivational processes thought to be involved in relapse. The effects of baclofen (0.1 – 2.4 mg/kg) were examined under conditions with alcohol or Tang access and under extinction. Under the CSR baclofen (1.8 and 2.4 mg/kg) significantly decreased (p<0.05) alcohol self-administration responses and total g/kg alcohol intake. In contrast, only the highest dose of baclofen (2.4 mg/kg) reduced Tang self-administration and consumption. Under within-session extinction conditions, baclofen (1.8 and 2.4 mg/kg) facilitated extinction of responding for both alcohol and Tang, particularly during the first 10 min of extinction. Baclofen may be effective in reducing craving and alcohol drinking, although the facilitation of extinction and suppression of both alcohol and Tang self-administration by baclofen suggests these effects may be related to a more general suppression of consummatory and conditioned behaviors.
doi:10.1111/j.1369-1600.2012.00448.x
PMCID: PMC3394930  PMID: 22458648
alcohol; baclofen; drug-seeking; extinction; nonhuman primate; reinforcement
13.  Binge-Like Ethanol Consumption Increases Corticosterone Levels and Neurodegneration whereas occupancy of Type II Glucocorticoid Receptors with Mifepristone is Neuroprotective 
Addiction biology  2012;19(1):10.1111/j.1369-1600.2012.00451.x.
Excessive ethanol (EtOH) use leads to impaired memory and cognition. Using a rat model of binge-like intoxication, we tested whether elevated corticosterone (Cort) levels contribute to the neurotoxic consequences of EtOH exposure. Rats were adrenalectomized (Adx) and implanted with cholesterol pellets, or cholesterol pellets containing basal, medium or high Cort. Intragastric EtOH or an isocaloric control solution was given 3 times daily for 4 days to achieve blood alcohol levels (BALs) ranging between 200-350 mg/dl. Mean 24 hour (24-hr) plasma Cort levels were ~110 ng/ml and ~40 ng/ml in intact EtOH treated and intact control, respectively. Basal Cort replacement in EtOH-treated Adx animals animals did not exacerbate alcohol-induced neurodegeneration in the hippocampal dentate gyrus (DG) or the entorhinal cortex (EC) as observed by amino-cupric silver staining. In contrast, Cort replacement resulting in levels 2-fold higher (medium) than normal, or higher (high) in Adx-Cort-EtOH animals increased neurodegeneration. In separate experiments, pharmacological blockade of the Type II glucocortocoid (GC) receptor was initiated with mifepristone (RU38486; 0, 5, 15 mg/kg/day, i.p.). At the higher dose, mifepristone decreased the number of degenerating hippocampal DG cells in binge-EtOH treated intact animals, whereas, only a trend for reduction was observed in 15 mg/kg/day mifepristone treated animals in the EC, as determined by Fluoro Jade B staining. These results suggest that Cort in part mediates EtOH-induced neurotoxicity in the brain through activation of Type II GC receptors.
doi:10.1111/j.1369-1600.2012.00451.x
PMCID: PMC3561503  PMID: 22500955
ethanol; corticosterone; neurodegeneration; mifepristone. dentate gyrus; Fluoro Jade B; RU38486; entorhinal cortex
14.  Pharmacologically Relevant Intake During Chronic, Free-Choice Drinking Rhythms in Selectively Bred High Alcohol Preferring Mice 
Addiction biology  2011;18(6):921-929.
Multiple lines of High Alcohol Preferring (HAP) mice were selectively bred for their intake of 10% ethanol (v/v) during 24-h daily access over a four-week period, with the highest drinking lines exhibiting intakes in excess of 20 g/kg/day. We observed circadian drinking patterns and resulting blood ethanol concentrations in the HAP lines. We also compared the drinking rhythms and corresponding blood ethanol concentrations (BEC) of the highest drinking HAP lines to those of the C57BL/6J (B6) inbred strain. Adult male and female crossed HAP (cHAP), HAP replicate lines 1, 2, 3, and B6 mice had free-choice access to 10% ethanol and water for 3 weeks prior to bi-hourly assessments of intake throughout the dark portion of the light-dark cycle. All HAP lines reached and maintained a rate of alcohol intake above the rate at which HAP1 mice metabolize alcohol, and BECs were consistent with this finding. Further, cHAP and HAP1 mice maintained an excessive level of intake throughout the dark portion of the cycle, accumulating mean BEC levels of 261.5 ± 18.09 and 217.9 ± 25.02 mg/dl, respectively. B6 mice drank comparatively modestly, and did not accumulate high BEC levels (53.63 + 8.15 mg/dl). Free-choice drinking demonstrated by the HAP1 and cHAP lines may provide a unique opportunity for modeling the excessive intake that often occurs in alcohol-dependent individuals, and allow for exploration of predisposing factors for excessive consumption, as well as the development of physiological, behavioral, and toxicological outcomes following alcohol exposure.
doi:10.1111/j.1369-1600.2011.00412.x
PMCID: PMC4259254  PMID: 22126215
Alcoholism; self-administration; rodent model; ethanol; circadian rhythms; selective breeding
15.  Contextual conditioning enhances the psychostimulant and incentive properties of d-amphetamine in humans 
Addiction biology  2011;18(6):985-992.
Learned associations between drugs and the places they are used are critical to the development of drug addiction. Contextual conditioning has long been studied in animals as an indirect measure of drug reward, but little is known about the process in humans. Here, we investigated de novo contextual conditioning with d-amphetamine in healthy humans (n = 34). Volunteers underwent four conditioning sessions conducted in two testing rooms with double-blind, alternating d-amphetamine (20 mg) and placebo administration. Before conditioning procedures began, they rated the two rooms to examine pre-existing preferences. One group (Paired, n = 19) always received d-amphetamine in their least preferred room and placebo in the other during conditioning sessions. Another group (Unpaired, n = 15) received d-amphetamine and placebo in both rooms. Subjective drug effects were monitored at repeated times. At a separate re-exposure test, preference ratings for the drug-associated room were increased among the Paired group only, and more subjects in the Paired than the Unpaired group switched their preference to their initially least preferred room. Also, ratings of d-amphetamine drug liking independently predicted room liking at test among the Paired group only. Further, Paired group subjects reported greater stimulation and drug craving after d-amphetamine on the second administration, relative to the first. This study supports preliminary findings that humans, like animals, develop a preference for a place associated with d-amphetamine that is related to its subjective effects. These findings also suggest that experiencing d-amphetamine in a consistent environment produces context-dependent changes in its subjective effects, including an enhanced rewarding efficacy and abuse potential.
doi:10.1111/j.1369-1600.2011.00416.x
PMCID: PMC4242554  PMID: 22129527
Conditioned place preference; contextual conditioning; d-amphetamine; humans; sensitization; subjective effects
16.  A human laboratory study investigating the effects of quetiapine on marijuana withdrawal and relapse in daily marijuana smokers 
Addiction biology  2012;18(6):10.1111/j.1369-1600.2012.00461.x.
Marijuana withdrawal contributes to the high relapse rates in individuals seeking treatment for marijuana-use disorders. Quetiapine, an atypical antipsychotic, reduces characteristic symptoms of marijuana withdrawal in a variety of psychiatric conditions including mood lability, sleep disruption, and anorexia. This human laboratory study investigated the effectiveness of quetiapine to decrease marijuana withdrawal and relapse to marijuana use in nontreatment seeking marijuana smokers. Volunteers were maintained on placebo or quetiapine (200 mg/day) in this double-blind, counter-balanced, within-subject study consisting of two 15-day medication phases, the last 8 days of which were inpatient. On the first inpatient day, active marijuana (6.2% delta (9)-tetrahydrocannabinol [THC]) was repeatedly smoked under controlled conditions. For the next 3 days, inactive marijuana (0.0% THC) was available for self-administration (withdrawal). On the subsequent 4 days, active marijuana (6.2% THC) was available for self-administration (relapse). Volunteers (n = 14) who smoked an average of 10 marijuana cigarettes/day, 7 days/week completed the study. Under placebo, withdrawal was marked by increased subjective ratings of negative mood, decreased sleep quality, decreased caloric intake, and weight loss. Compared to placebo, quetiapine improved sleep quality, increased caloric intake, and decreased weight loss. However, quetiapine increased marijuana craving and marijuana self-administration during the relapse phase. These data do not suggest that quetiapine shows promise as a potential treatment for marijuana dependence.
doi:10.1111/j.1369-1600.2012.00461.x
PMCID: PMC3465638  PMID: 22741619
17.  5-HTTLPR Genotype and Daily Negative Mood Moderate the Effects of Sertraline on Drinking Intensity 
Addiction biology  2012;18(6):10.1111/adb.12007.
We previously reported moderating effects of age of onset of alcohol dependence (AD) and a functional polymorphism (5-HTTLPR) in the gene encoding the serotonin transporter protein in a sample of 134 individuals participating in a 12-week, placebo-controlled trial of sertraline (Kranzler et al. 2011). To understand more fully the effects seen in that study, we examined moderation by negative moods reported each evening, with nighttime drinking intensity (i.e., the number of standard drinks consumed at night) as the dependent variable. We found a daily anxiety × age of onset × 5-HTTLPR polymorphism × medication interaction, which reflected a daily anxiety × medication group effect for early-onset individuals homozygous for the high-expression (L’) allele, but not others. Specifically, on days characterized by relatively high levels of anxiety, early-onset L’ homozygotes receiving placebo reduced their drinking intensity significantly. In contrast, early-onset L’ homozygotes treated with sertraline non-significantly increased their drinking intensity. These findings implicate anxiety as a key moderator of the observed effects pharmacogenetic effects. These findings have important implications because of the high prevalence of AD and the frequency with which SSRIs and other antidepressants are prescribed for a variety of psychiatric disorders.
doi:10.1111/adb.12007
PMCID: PMC3578002  PMID: 23145795
SSRI; Alcohol Dependence; 5-HTTLPR
18.  Cannabinoid-1 receptor antagonist rimonabant (SR141716) increases striatal dopamine D2 receptor availability 
Addiction biology  2011;18(6):10.1111/j.1369-1600.2011.00369.x.
The cannabinoid 1 (CB1) receptor antagonist rimonabant (SR141716) alters rewarding properties and intake of food and drugs. Additionally, striatal dopamine D2 receptor (DRD2) availability has been implicated in reward function. This study shows that chronic treatment of rats with rimonabant (1.0 and 3.0 mg/kg/day) dose-dependently increased DRD2 availability in the dorsal striatum (14% and 23%) compared to vehicle. High-dose rimonabant also increased DRD2 availability in the ventral striatum (12%) and reduced weight gain. Thus, upregulation of striatal DRD2 by chronic rimonabant administration may be an underlying mechanism of action and confirms the interactions of the endocannabinoid and dopaminergic systems.
doi:10.1111/j.1369-1600.2011.00369.x
PMCID: PMC3252421  PMID: 21955259
cannabinoid 1 receptor; dopamine D2 receptor; IBZM; nucleus accumbens; rimonabant; striatum
19.  Chronic cigarette smoking in alcohol dependence: associations with cortical thickness and N-acetylaspartate levels in the extended brain reward system 
Addiction biology  2011;18(2):379-391.
Chronic smoking in alcohol dependence is associated with abnormalities in brain morphology and metabolite levels in large lobar regions (e.g. frontal lobe). Here, we evaluated if these abnormalities are specifically apparent in several cortical and select subcortical components of the extended brain reward system (BRS), a network that is critically involved in the development and maintenance of all forms of addictive disorders. We studied 33 non-smoking and 43 smoking alcohol-dependent individuals (ALC) with 1 week of abstinence and 42 non-smoking Controls. At 1.5 Tesla, we obtained regional measures of cortical thickness and N-acetylaspartate (NAA; a surrogate marker of neuronal integrity) concentration in major components of the BRS as well as the corresponding measures throughout the cortex. Smoking ALC and non-smoking ALC demonstrated decreased thickness compared with Controls in the dorsolateral prefrontal cortex (DLPFC), insula, orbitofrontal cortex (OFC), the total BRS, total frontal cortex and global cortex. Smoking ALC had significantly decreased thickness compared to non-smoking ALC in the ACC, insula, the total BRS and total frontal cortex. Smoking ALC had also lower NAA concentrations than both non-smoking ALC and Controls in the DLPFC, insula, superior corona radiata and the total BRS. Alcohol consumption and common medical and psychiatric co-morbidities did not mediate differences between smoking and non-smoking ALC. This dual modality magnetic resonance (MR) study indicated that chronic smoking in ALC was associated with significant cortical thinning and NAA abnormalities in anterior brain regions that are implicated in the development and maintenance of addictive disorders.
doi:10.1111/j.1369-1600.2011.00407.x
PMCID: PMC4157587  PMID: 22070867
Alcohol dependence; brain reward system; cigarette smoking; cortical thickness; N-acetylaspartate; nicotine
20.  Brain region-specific gene expression changes after chronic intermittent ethanol exposure and early withdrawal in C57BL/6J mice 
Addiction biology  2011;17(2):351-364.
Neuroadaptations that participate in the ontogeny of alcohol dependence are likely a result of altered gene expression in various brain regions. The present study investigated brain region-specific changes in the pattern and magnitude of gene expression immediately following chronic intermittent ethanol (CIE) exposure and 8 hours following final ethanol exposure [i.e. early withdrawal (EWD)]. High-density oligonucleotide microarrays (Affymetrix 430A 2.0, Affymetrix, Santa Clara, CA, USA) and bioinformatics analysis were used to characterize gene expression and function in the prefrontal cortex (PFC), hippocampus (HPC) and nucleus accumbens (NAc) of C57BL/6J mice (Jackson Laboratories, Bar Harbor, ME, USA). Gene expression levels were determined using gene chip robust multi-array average followed by statistical analysis of microarrays and validated by quantitative real-time reverse transcription polymerase chain reaction and Western blot analysis. Results indicated that immediately following CIE exposure, changes in gene expression were strikingly greater in the PFC (284 genes) compared with the HPC (16 genes) and NAc (32 genes). Bioinformatics analysis revealed that most of the transcriptionally responsive genes in the PFC were involved in Ras/MAPK signaling, notch signaling or ubiquitination. In contrast, during EWD, changes in gene expression were greatest in the HPC (139 genes) compared with the PFC (four genes) and NAc (eight genes). The most transcriptionally responsive genes in the HPC were involved in mRNA processing or actin dynamics. Of the few genes detected in the NAc, the most representatives were involved in circadian rhythms. Overall, these findings indicate that brain region-specific and time-dependent neuroadaptive alterations in gene expression play an integral role in the development of alcohol dependence and withdrawal.
doi:10.1111/j.1369-1600.2011.00357.x
PMCID: PMC4153606  PMID: 21812870
Alcohol dependence; alcohol withdrawal; brain regional adaptations; chronic intermittent alcohol exposure; gene expression profiling; microarray analysis
21.  Lack of effect of chronic dextromethorphan on experimental pain tolerance in methadone-maintained patients 
Addiction biology  2008;13(0):393-402.
Good evidence exists to suggest that individuals on opioid maintenance for the treatment of addiction (i.e. methadone) are less tolerant of experimental pain than are matched controls or ex-opioid addicts, a phenomenon theorized to reflect opioid-induced hyperalgesia (OIH). Agonist activity at the excitatory ionotropic N-methyl-D-aspartate (NMDA) receptor on dorsal horn neurons has been implicated in the development of both OIH and its putative expression at the clinical level—opioid tolerance. The aim of this study was to evaluate the potential utility of the NMDA-receptor antagonist, dextromethorphan (DEX), to reverse or treat OIH in methadone-maintenance (MM) patients. Utilizing a clinical trial design and double-blind conditions, changes in pain threshold and tolerance [cold pressor (CP) and electrical stimulation (ES)] following a 5-week trial of DEX (titrated to 480 mg/day) in comparison with placebo was evaluated in a well-characterized sample of MM patients. The sample (n = 40) was 53% male and ethnically diverse (53% Latino, 28% African American, 10% White, 9% other), with a mean age of 48.0 years (SD = 6.97). Based on t-test analyses, no difference was found between groups on CP pain threshold, CP pain tolerance, ES pain threshold or ES pain tolerance, both pre- and postmedication. Notably, DEX-related changes significantly differed by gender, with women tending to show diminished tolerance for pain with DEX therapy. These results support that chronic high-dose NMDA antagonism does not improve tolerance for pain in MM patients, although a gender effect on DEX response is suggested.
doi:10.1111/j.1369-1600.2008.00112.x
PMCID: PMC4151628  PMID: 18507735
Cold-pressor pain; dextromethorphan; electrical stimulation pain; hyperalgesia; methadone; opiods
22.  The genetic etiology of cannabis use initiation: a meta-analysis of genome-wide association studies and a SNP-based heritability estimation 
Addiction biology  2012;18(5):846-850.
While initiation of cannabis use is around 40% heritable, not much is known about the underlying genetic etiology. Here, we meta-analysed two genome-wide association studies of initiation of cannabis use with (>10,000 individuals). None of the genetic variants reached genome-wide significance. We also performed a gene-based association test, which also revealed no significant effects of individual genes. Finally, we estimated that only approximately 6.0% of the variation in cannabis initiation is due to common genetic variants. Future genetic studies using larger sample sizes and different methodologies (including sequencing) might provide more insight in the complex genetic etiology of cannabis use.
doi:10.1111/j.1369-1600.2012.00478.x
PMCID: PMC3548058  PMID: 22823124
genetics; cannabis; heritability; association
23.  Mephedrone (4-methylmethcathinone) supports intravenous self-administration in Sprague-Dawley and Wistar rats 
Addiction biology  2013;18(5):786-799.
Recreational use of the drug 4-methylmethcathinone (mephedrone; 4-MMC) became increasingly popular in the United Kingdom in recent years, spurred in part by the fact it was not criminalized until April of 2010. Although several fatalities have been associated with consumption of 4-MMC and cautions for recreational users about its addictive potential have appeared on Internet forums, very little information about abuse liability for this drug is available. This study was conducted to determine if 4-MMC serves as a reinforcer in a traditional intravenous self-administration model. Groups of male Wistar and Sprague-Dawley rats were prepared with intravenous catheters and trained to self-administer 4-MMC in one hour sessions. Per infusion doses of 0.5 and 1.0 mg/kg were consistently self-administered resulting in greater than 80% discrimination for the drug-paired lever and mean intakes of about 2–3 mg/kg/hr. Dose-substitution studies after acquisition demonstrated that the number of responses and/or the total amount of drug self-administered varied as a function of dose. In addition, radiotelemetry devices were employed to show that self-administered 4-MMC was capable of increasing locomotor activity (Wistar) and decreasing body temperature (Sprague-Dawley). Pharmacokinetic studies found the T1/2 of 4-MMC was about an hour in vivo in rat plasma and 90 minutes using in vitro liver microsomal assays. This study provides evidence of stimulant-typical abuse liability for 4-MMC in the traditional preclinical self-administration model.
doi:10.1111/adb.12038
PMCID: PMC3641159  PMID: 23363010
cathinone; reinforcement; stimulant; thermoregulation
24.  MeCP2 regulates ethanol sensitivity and intake 
Addiction biology  2013;19(5):791-799.
We have investigated the expression of chromatin regulating genes in the prefrontal cortex and in the shell subdivision of the nucleus accumbens during protracted withdrawal in mice with increased ethanol drinking after chronic intermittent ethanol vapor exposure (CIE) and in mice with a history of non-dependent drinking. We observed that the methyl-CpG binding protein 2 (MeCP2) was one of the few chromatin-regulating genes to be differentially regulated by a history of dependence. As MeCP2 has the potential of acting as a broad gene regulator, we investigated sensitivity to ethanol and ethanol drinking in MeCP2308/Y mice, which harbor a truncated MeCP2 allele but have a milder phenotype than MeCP2 null mice. We observed that MeCP2308/Y mice were more sensitive to ethanol’s stimulatory and sedative effects than wild-type mice, drank less ethanol in a limited access 2 bottle choice (2BC) paradigm, and did not show increased drinking after induction of dependence with exposure to chronic intermittent ethanol vapors (CIE). Alcohol metabolism did not differ in MeCP2308/Y and wild-type (WT) mice. Additionally, MeCP2308/Y mice did not differ from WT mice in ethanol preference in a 24 hr paradigm nor in their intake of graded solutions of saccharin or quinine, suggesting that the MeCP2308/Y mutation did not alter taste function. Lastly, using the Gene Set Enrichment Analysis (GSEA) algorithm we found a significant overlap in the genes regulated by alcohol and by MeCP2. Together, these results suggest that MeCP2 contributes to the regulation of ethanol sensitivity and drinking.
doi:10.1111/adb.12047
PMCID: PMC3692583  PMID: 23448145
25.  Prior extended daily access to cocaine elevates the reward threshold in a Conditioned Place Preference test 
Addiction biology  2013;19(5):826-837.
We have previously shown that extended-access subjects exhibit heightened motivation for cocaine in the runway model, as reflected by reduced number of retreats (Ben-Shahar et al., 2008). This heightened motivation could reflect either an increase in cocaine-induced reward or a decrease in cocaine-induced aversion. The current experiment was therefore devised to assess the cocaine-induced reward and aversion in extended access rats using a place conditioning test. Rats trained to lever-press for IV cocaine (0.25 mg/infusion) were provided 6-h daily access to the drug over 10 days. Lever-pressing in control subjects produced IV infusions of saline. Following drug self-administration, subjects underwent place conditioning for the immediate or delayed effects of cocaine (1.0 mg/kg or 2.5 mg/kg, IV). In control subjects, the immediate effects of the low dose of cocaine produced conditioned places preferences (CPPs) while the delayed effects produced conditioned place aversions (CPAs). In contrast, the 6-h animals receiving the low cocaine dose, exhibited place aversions but not preferences; an effect that was reversed when the dose of cocaine was increased. Additionally, in the 6-h group, delayed conditioning was associated with a reduction in zif-268 immunoreactivity in the medial prefrontal cortex and nucleus accumbens shell while immediate conditioning was associated with an increase in zif-268-positive cells in the central nucleus of the amygdala. Collectively, these data suggest that extended daily access to cocaine produces a shift in the subject’s perceived reward threshold that is paralleled by alterations in the activity of both the reward and stress pathways.
doi:10.1111/adb.12053
PMCID: PMC3883914  PMID: 23634951
allostatic theory; conditioned place aversions; conditioned place preferences; cocaine; drug self-administration; immunohistochemistry

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