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1.  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.
PMCID: PMC4332883  PMID: 23763573
cocaine; cognitive enhancer; dopamine; gene expression; psychostimulant; SSRI antidepressant
2.  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.
PMCID: PMC4300855  PMID: 23231598
addiction; locomotion; opiate; Pavlovian; place conditioning; reward
3.  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.
PMCID: PMC3528793  PMID: 22943795
Brain volume; magnetic resonance imaging; cigarette smoking; alcohol dependence; brain reward system
4.  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.
PMCID: PMC3535502  PMID: 23017017
nucleus accumbens; self-administration; microdialysis
5.  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.
PMCID: PMC3762937  PMID: 23710649
mGluR5; dorsal striatum; nucleus accumbens; cocaine; abstinence; extinction; long-term depression; surface expression
6.  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.
PMCID: PMC3867542  PMID: 22500942
association study; heroin dependence; OPRD1; OPRK1; OPRM1
7.  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.
PMCID: PMC4110897  PMID: 23461423
CREB; AMPA receptor; nucleus accumbens; synapsin
8.  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.
PMCID: PMC4259254  PMID: 22126215
Alcoholism; self-administration; rodent model; ethanol; circadian rhythms; selective breeding
9.  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.
PMCID: PMC4242554  PMID: 22129527
Conditioned place preference; contextual conditioning; d-amphetamine; humans; sensitization; subjective effects
10.  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.
PMCID: PMC3465638  PMID: 22741619
11.  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.
PMCID: PMC3578002  PMID: 23145795
SSRI; Alcohol Dependence; 5-HTTLPR
12.  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.
PMCID: PMC4157587  PMID: 22070867
Alcohol dependence; brain reward system; cigarette smoking; cortical thickness; N-acetylaspartate; nicotine
13.  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.
PMCID: PMC4153606  PMID: 21812870
Alcohol dependence; alcohol withdrawal; brain regional adaptations; chronic intermittent alcohol exposure; gene expression profiling; microarray analysis
14.  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.
PMCID: PMC4151628  PMID: 18507735
Cold-pressor pain; dextromethorphan; electrical stimulation pain; hyperalgesia; methadone; opiods
15.  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.
PMCID: PMC3548058  PMID: 22823124
genetics; cannabis; heritability; association
16.  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.
PMCID: PMC3641159  PMID: 23363010
cathinone; reinforcement; stimulant; thermoregulation
17.  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.
PMCID: PMC3692583  PMID: 23448145
18.  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.
PMCID: PMC3883914  PMID: 23634951
allostatic theory; conditioned place aversions; conditioned place preferences; cocaine; drug self-administration; immunohistochemistry
19.  Reduced ethanol consumption and preference in cocaine- and amphetamine-regulated transcript (CART) knockout mice 
Addiction biology  2012;19(2):175-184.
Cocaine- and amphetamine-regulated transcript (CART) is a neuropeptide implicated in addiction to drugs of abuse. Several studies have characterized the role of CART in addiction to psychostimulants, but few have examined the role of CART in alcohol use disorders including alcoholism. The current study utilized a CART knockout (KO) mouse model to investigate the role of CART in ethanol appetitive behaviors. A two-bottle choice, unlimited-access paradigm was used to compare ethanol appetitive behaviors between CART wild type (WT) and KO mice. The mice were presented with an ethanol solution (3%-21%) and water, each concentration for four days, and their consumption was measured daily. Consumption of quinine (bitter) and saccharin (sweet) solutions were measured following the ethanol preference tests. In addition, ethanol metabolism rates and ethanol sensitivity were compared between genotypes. CART KO mice consumed and preferred ethanol less than their WT counterparts in both sexes. This genotype effect could not be attributed to differences in bitter or sweet taste perception or ethanol metabolism rates. There was also no difference in ethanol sensitivity in male mice; however, CART KO female mice showed a greater ethanol sensitivity than the WT females. Taken together, these data demonstrate a role for CART in ethanol appetitive behaviors and as a possible therapeutic drug target for alcoholism and abstinence enhancement.
PMCID: PMC4148419  PMID: 22823101
addiction; alcoholism; CART; Ethanol; Knock out; mouse
20.  Effects of adolescent nicotine exposure and withdrawal on intravenous cocaine self-administration during adulthood in male C57BL/6J mice 
Addiction biology  2012;19(1):37-48.
Studies of adolescent drug use show (1) a pattern in which the use of tobacco precedes the use of other drugs and (2) a positive relationship between adolescent tobacco use and later drug use. These observations have led to the hypothesis that a causal relationship exists between early exposure to nicotine and the later use of hard drugs such as cocaine. Using male C57BL/6J mice, we tested the hypothesis that nicotine exposure in adolescence leads to increased intravenous self-administration (IVSA) of cocaine in adulthood. Using miniature osmotic pumps, we exposed mice and their littermate controls to nicotine (24 mg/kg/day) or vehicle, respectively, over the entire course of adolescence [postnatal days (P) 28–56]. Nicotine exposure was terminated on P56 and mice were not exposed to nicotine again during the experiment. On P73, mice were allowed to acquire cocaine IVSA (1.0 mg/kg/infusion) and a dose–response curve was generated (0.18, 0.32, 0.56, 1.0, 1.8 mg/kg/infusion). Lever pressing during extinction conditions was also evaluated. All mice rapidly learned to lever press for the combination of cocaine infusions and non-drug stimuli. Analysis of the dose–response curve revealed that adolescent nicotine-exposed mice self-administered significantly more (P < 0.05) cocaine than controls at all but the highest dose. No significant differences were observed between adolescent nicotine-exposed and control mice during the acquisition or extinction stages. These results indicate that adolescent nicotine exposure can increase cocaine IVSA in mice, which suggests the possibility of a causal link between adolescent tobacco use and later cocaine use in humans.
PMCID: PMC4084694  PMID: 22978678
Cocaine; gateway effect; mouse; nicotine; osmotic pump; self-administration
21.  Blockade of Dopamine D3 Receptors in the Nucleus Accumbens and Central Amygdala Inhibits Incubation of Cocaine Craving in Rats 
Addiction biology  2012;18(4):665-677.
Cue-induced drug seeking progressively increases over time of withdrawal from drug self-administration in rats, a phenomenon called “incubation of craving”. The underlying mechanisms have been linked to increased expression of brain-derived neurotrophic factor (BDNF) and GluR2-lacking AMPA receptors in the mesolimic dopamine (DA) system, and also to increased extracellular signal-regulated kinase (ERK) activation in the central amygdala (CeA). However, it remains unclear whether any DA mechanism is also involved in incubation of craving. Recent research demonstrates that cue-induced cocaine seeking appears to parallel increased DA D3, but not D1 or D2, receptor expression in the nucleus accumbens (NAc) of rats over time of withdrawal, suggesting possible involvement of D3 receptors (D3R) in incubation of cocaine craving. Here we report that systemic or local administration of SB-277011A, a highly selective D3R antagonist, into the NAc (core and shell) or the CeA, but not the dorsal striatum or basolateral amygdala, significantly inhibits expression of incubation of cocaine craving in rats after 2–30 days of withdrawal from previous cocaine self-administration, but had no effect on sucrose-seeking behavior in rats after 10–30 days of withdrawal. These data suggest that DA D3Rs in both the NAc and the CeA plays an important role in incubation of cocaine craving in rats, and supports the potential utility of D3R antagonists in the treatment of cocaine addiction.
PMCID: PMC3509252  PMID: 22913325
Cocaine; dopamine; D3 receptor; SB-277011A; incubation; craving; relapse; drug-seeking
22.  Volitional Reduction of Anterior Cingulate Cortex Activity Produces Decreased Cue Craving in Smoking Cessation: A Preliminary Real-Time fMRI Study 
Addiction biology  2012;18(4):739-748.
Numerous research groups are now using analysis of blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) results and relaying back information about regional activity in their brains to participants in the scanner in “real time”. In this study, we explored the feasibility of self-regulation of frontal cortical activation using real time fMRI (rtfMRI) neurofeedback in nicotine-dependent cigarette smokers during exposure to smoking cues. Ten cigarette smokers were shown smoking-related visual cues in a 3 Tesla MRI scanner to induce their nicotine craving. Participants were instructed to modify their craving using rtfMRI feedback with two different approaches. In a “reduce craving” paradigm, participants were instructed to “reduce” their craving, and decrease the anterior cingulate cortex (ACC) activity. In a separate “increase resistance” paradigm, participants were asked to increase their resistance to craving and to increase middle prefrontal cortex (mPFC) activity. We found that participants were able to significantly reduce the BOLD signal in the ACC during the “reduce craving” task (p=0.028). There was a significant correlation between decreased ACC activation and reduced craving ratings during the “reduce craving” session (p=0.011). In contrast, there was no modulation of the BOLD signal in mPFC during the “increase resistance” session. These preliminary results suggest that some smokers may be able to use neurofeedback via rtfMRI to voluntarily regulate ACC activation and temporarily reduce smoking cue-induced craving. Further research is needed to determine the optimal parameters of neurofeedback rtfMRI, and whether it might eventually become a therapeutic tool for nicotine dependence.
PMCID: PMC3389595  PMID: 22458676
nicotine dependence; smoking cessation; real-time fMRI; neurofeedback; anterior cingulate cortex; cue-induced craving
23.  CYP2B6 SNPs are associated with methadone dose required for effective treatment of opioid addiction 
Addiction biology  2011;18(4):709-716.
Adequate methadone dosing in methadone maintenance treatment (MMT) for opioid addiction is critical for therapeutic success. One of the challenges in dose determination is the inter-individual variability in dose response. Methadone metabolism is attributed primarily to cytochrome P450 enzymes CYP3A4, CYP2B6, and CYP2D6. The CYP2B6*6 allele [SNPs 785A>G (rs2279343) and 516G>T (rs3745274)] was associated with slow methadone metabolism. To explore the effects of CYP2B6*6 allele on methadone dose requirement, it was genotyped in a well-characterized sample of 74 Israeli former heroin addicts in MMT. The sample is primarily of Middle Eastern/European ancestry, based on ancestry informative markers (AIMs). Only patients with no major co-medication that may affect methadone metabolism were included. The stabilizing daily methadone dose in this sample ranges between 13-260 mg (mean 140±52 mg). The mean methadone doses required by subjects homozygous for the variant alleles of the CYP2B6 SNPs 785A>G and 516G>T (88, 96 mg, respectively) were significantly lower than those of the heterozygotes (133, 129 mg, respectively) and the non-carriers (150, 151 mg, respectively) (nominal P = 0.012, 0.048, respectively). The results remain significant after controlling for age, sex and the ABCB1 SNP 1236C>T (rs1128503), that was previously shown to be associated with high methadone dose requirement in this population (P = 0.006, 0.030, respectively). An additional 77 CYP2B6, CYP3A4 and CYP2D6 SNPs were genotyped. Of these, 24 SNPs were polymorphic and none showed significant association with methadone dose. Further studies are necessary to replicate these preliminary findings in additional subjects and other populations.
PMCID: PMC3735354  PMID: 21790905
CYP2B6; Israel; methadone; opioid addiction; pharmacogenomics
24.  Expression of HIV gp120 protein increases sensitivity to the rewarding properties of methamphetamine in mice 
Addiction biology  2012;10.1111/adb.12023.
Methamphetamine abuse and human immunodeficiency virus (HIV) infection induce neuropathological changes in corticolimbic brain areas involved in reward and cognitive function. Little is known about the combined effects of methamphetamine and HIV infection on cognitive and reward processes. The HIV/gp120 protein induces neurodegeneration in mice, similar to HIV-induced pathology in humans. We investigated the effects of gp120 expression on associative learning, preference for methamphetamine and non-drug reinforcers, and sensitivity to the conditioned rewarding properties of methamphetamine in transgenic (tg) mice expressing HIV/gp120 protein (gp120-tg). gp120-tg mice learned the operant response for food at the same rate as non-tg mice. In the two-bottle choice procedure with restricted access to drugs, gp120-tg mice exhibited greater preference for methamphetamine and saccharin than non-tg mice, whereas preference for quinine was similar between genotypes. Under conditions of unrestricted access to methamphetamine, the mice exhibited a decreased preference for increasing methamphetamine concentrations. However, male gp120-tg mice showed a decreased preference for methamphetamine at lower concentrations than non-tg male mice. gp120-tg mice developed methamphetamine-induced conditioned place preference at lower methamphetamine doses compared with non-tg mice. No differences in methamphetamine pharmacokinetics were found between genotypes. These results indicate that gp120-tg mice exhibit no deficits in associative learning or reward/motivational function for a natural reinforcer. Interestingly, gp120 expression resulted in increased preference for methamphetamine and a highly palatable non-drug reinforcer (saccharin) and increased sensitivity to methamphetamine-induced conditioned reward. These data suggest that HIV-positive individuals may have increased sensitivity to methamphetamine, leading to high methamphetamine abuse potential in this population.
PMCID: PMC3608835  PMID: 23252824
Conditioned place preference; food-maintained responding; oral self-administration; pharmacokinetics; quinine; saccharin
25.  Association of Smoking with Mu- Opioid Receptor Availability Before and During Naltrexone Blockade in Alcohol-Dependent Subjects 
Addiction biology  2012;10.1111/adb.12022.
Persons with a history of alcohol dependence are more likely to use tobacco and to meet criteria for nicotine dependence compared to social drinkers or nondrinkers. The high levels of comorbidity of nicotine and alcohol use and dependence are thought to be related to interactions between nicotinic, opioid and dopamine receptors in mesolimbic regions. The current study examined whether individual differences in regional mu-opioid receptor (MOR) availability were associated with tobacco use, nicotine dependence, and level of nicotine craving in 25 alcohol dependent (AD) subjects. AD subjects completed an inpatient protocol, which included medically supervised alcohol withdrawal, monitored alcohol abstinence, transdermal nicotine maintenance (21 mg/day), and Positron Emission Tomography (PET) imaging using the MOR agonist [11C]-carfentanil (CFN) before (basal scan) and during treatment with 50 mg/day naltrexone (naltrexone scan). Subjects who had higher scores on the Fagerström Nicotine Dependence Test had significantly lower basal scan binding potential (BPND) across mesolimbic regions including the amygdala, cingulate, globus pallidus, thalamus and insula. Likewise, the number of cigarettes per day was negatively associated with basal scan BPND in mesolimbic regions Higher nicotine craving was significantly associated with lower BPND in amygdala, globus pallidus, putamen, thalamus and ventral striatum. Although blunted during naltrexone treatment, the negative association was maintained for nicotine dependence and cigarettes per day, but not for nicotine craving. These findings suggest that intensity of cigarette smoking and severity of nicotine dependence symptoms are systematically related to reduced BPND across multiple brain regions in AD subjects.
PMCID: PMC3638047  PMID: 23252742
mu opioid receptors; nicotine; alcoholism; dependence; PET imaging; humans

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