Differential Effects of Nicotine, Alcohol, and Coexposure on Neuroimmune-Related Protein and Gene Expression in Corticolimbic Brain Regions of Rats.

Nicotine and alcohol co-use is extremely common and their use constitutes two of the most common causes of preventable death, yet the underlying biological mechanisms are largely understudied. Activation of neuroimmune toll-like receptors (TLRs) promotes the induction of proinflammatory cascades and increases alcohol intake in rodents, which further promotes TLRs in the brain; nicotine may decrease central proinflammatory signaling. The current studies sought to determine the effects of nicotine ± alcohol (alone or in combination) on circulating blood plasma and TLR protein/gene expression in addiction-associated corticolimbic brain regions, including the prefrontal cortex-prelimbic (mPFC-PL) and nucleus accumbens core (AcbC). Adult rats were treated with alcohol (0 or 2 g/kg, IG) and exposed to nicotine vapor (0 or 30 mg/mL solution) daily for 2, 14, or 28 days. Plasma studies indicated no effects of independent exposure or coexposure in males. Coexposure decreased plasma nicotine levels versus nicotine-only treated females, yet alcohol and cotinine concentrations were unchanged. By 28 days, the anti-inflammatory cytokine IL-13 was decreased in alcohol-only females. Divergent changes in TLR3 (but not TLR4) protein occurred for independent-drug exposed males (but not coexposure), with reductions in the mPFC-PL after 14 days and increases in the AcbC by 28 days. Gene expression following chronic coexposure suggests nicotine may regionally counteract alcohol-induced inflammation, including increased AcbC-TLR3/4/7 and several downstream markers in females and increased mPFC-PL-TLR3 and -STAT3 (but not IRF3) evident in males with exposure to either drug alone. These findings give further insight into the role of sex and the neuroimmune system in independent exposure and coexposure to nicotine ± alcohol.

Alcohol, nicotine, and COVID-19: A retrospective study of health outcomes in central Pennsylvania.

Individuals with substance abuse disorder are at increased risk for the development of severe disease following COVID-19 infection. Furthermore, individuals in rural populations where access to healthcare is limited and rates of substance abuse tend to be higher are at increased risk compared to other regions. The Penn State Health Network serves 29 counties in central Pennsylvania that are largely rural. The current study assessed the electronic medical records for individuals in this population that were reported as having alcohol dependence, nicotine dependence or both (co-users) in addition to individuals with no history of drug use and the rate of developing primary and secondary health outcomes following COVID-19 infection. All patients in this study were determined to be COVID+ while in care. We found that overall, risk for requiring ventilation, developing pneumonia, and mortality within 30 days of diagnosis all increased with any substance use history, across both males and females and across all age groups. Moreover, rates of these outcomes were considerably higher in patients that were both alcohol and nicotine dependent suggesting additive effects of co-use. Rates of secondary effects also increased substantially across all use categories with these patients showing greater risk of developing liver, kidney, and pancreas maladies compared to patients with no history of substance use. Taken together, these findings reinforce previous studies showing that substance use increases the risks of significant disease following COVID-19 infection, giving insights into the health disparities that exist in rural populations.

Adolescent alcohol disrupts development of noradrenergic neurons in the nucleus of the tractus solitarius and enhances stress behaviors in adulthood in mice in a sex specific manner.

Alcohol use disorders (AUDs) are common mental health issues worldwide and can lead to other chronic diseases. Stress is a major factor in the development and continuation of AUDs, and adolescent alcohol exposure can lead to enhanced stress-responsivity and increased risk for AUD development in adulthood. The exact mechanisms behind the interaction between adolescence, stress, and alcohol are not fully understood and require further research. In this regard, the nucleus of the tractus solitarius (NTS) provides dense norepinephrine projections to the extended amygdala, providing a key pathway for stress-related alcohol behaviors. While NTS norepinephrine neurons are known to be alcohol sensitive, whether adolescent alcohol disrupts NTS-norepinephrine neuron development and if this is related to altered stress-sensitivity and alcohol preference in adulthood has not previously been examined. Here, we exposed male and female C57Bl/6J mice to the commonly used adolescent intermittent ethanol (AIE) vapor model during postnatal day 28-42 and examined AIE effects on: 1) tyrosine hydroxylase (TH) mRNA expression in the NTS across various ages (postnatal day 21-90), 2) behavioral responses to acute stress in the light/dark box test in adulthood, 3) NTS TH neuron responses to acute stress and ethanol challenges in adulthood, and 4) ethanol conditioned place preference behavior in adulthood. Overall the findings indicate that AIE alters NTS TH mRNA expression and increases anxiety-like behaviors following acute stress exposure in a sex-dependent manner. These mRNA expression and behavioral changes occur in the absence of AIE-induced changes in NTS TH neuron sensitivity to either acute stress or acute alcohol exposure or changes to ethanol conditioned place preference.

Ethanol inhibits pancreatic projecting neurons in the dorsal motor nucleus of the vagus.

Alcohol use disorder (AUD) is a rapidly growing concern in the United States. Current trending escalations of alcohol use are associated with a concurrent rise in alcohol-related end-organ damage, increasing risk for further diseases. Alcohol-related end-organ damage can be driven by autonomic nervous system dysfunction, however studies on alcohol effects on autonomic control of end-organ function are lacking. Alcohol intake has been shown to reduce insulin secretions from the pancreas. Pancreatic insulin release is controlled in part by preganglionic parasympathetic motor neurons residing in the dorsal motor nucleus of the vagus (DMV) that project to the pancreas. How these neurons are affected by alcohol exposure has not been directly examined. Here we investigated the effects of acute ethanol (EtOH) application on DMV pancreatic-projecting neurons with whole-cell patch-clamp electrophysiology. We found that bath application of EtOH (50 mM) for greater than 30 min significantly enhanced the frequency of spontaneous inhibitory post synaptic current (sIPSC) events of DMV pancreatic-projecting neurons suggesting a presynaptic mechanism of EtOH to increase GABAergic transmission. Thirty-minute EtOH application also decreased action potential firing of these neurons. Pretreatment of DMV slices with 20 µM fluoxetine, a selective serotonin reuptake inhibitor, also increased GABAergic transmission and decreased action potential firing of these DMV neurons while occluding any further effects of EtOH application, suggesting a critical role for serotonin in mediating EtOH effects in the DMV. Ultimately, decreased DMV motor output may lead to alterations in pancreatic secretions. Further studies are needed to fully understand EtOH's influence on DMV neurons as well as the consequences of changes in parasympathetic output to the pancreas.

Increased alcohol self-administration following repeated Toll-like receptor 3 agonist treatment in male and female rats.

Toll-like receptor (TLR) signaling may play an important role in the neuroimmune system's involvement in the development and maintenance of alcohol use disorder (AUD). In the present study we administered the TLR3 agonist poly(I:C) in male and female Long-Evans rats to determine whether TLR3 agonism can increase alcohol consumption on a daily 15% alcohol operant self-administration paradigm. We found few effects when poly(I:C) was given every-other-day at 0.3 or 1.0 mg/kg. However, when 1.0 mg/kg was given on consecutive days, alcohol intake increased in the days following injections specifically in females. In a second experiment, we found that this effect only emerged when rats had a history of multiple poly(I:C) injections. In the final experiment the poly(I:C) dose was increased to 3.0 mg/kg on consecutive days which resulted in significant reductions in alcohol intake on injection days in females that were not accompanied by subsequent increases. The poly(I:C) dose was increased to 9.0 mg/kg for one final pair of injections which led to reductions in intake in both males and females followed by a male specific delayed increase in alcohol intake. Overall, repeated poly(I:C) administration was able to increase subsequent alcohol consumption in both sexes, with females showing an increase at a lower dose than males. These findings support TLR3 agonism in contributing to increased alcohol consumption and add to the body of work identifying the neuroimmune system as a potential therapeutic target for AUD.

Low-dose alcohol: Interoceptive and molecular effects and the role of dentate gyrus in rats.

Alcohol abuse and dependence are world-wide health problems. Most research on alcohol use focuses on the consequences of moderate to high levels of alcohol. However, even at low concentrations, alcohol is capable of producing effects in the brain that can ultimately affect behavior. The current studies seek to understand the effects of low-dose alcohol (blood alcohol levels of ≤10mM). To do so, these experiments utilize a combination of behavioral and molecular techniques to (1) assess the ability of the interoceptive effects of a low dose of alcohol to gain control over goal-tracking behavior in a Pavlovian discrimination task, (2) determine brain regional differences in cellular activity via expression of immediate early genes (IEGs), and (3) assess the role of the dentate gyrus in modulating sensitivity to the interoceptive effects of a low dose of alcohol. Here, we show that intragastric administration of a dose of 0.8 g/kg alcohol produces blood alcohol levels ≤10mM in both male and female Long-Evans rats and can readily be trained as a Pavlovian interoceptive drug cue. In rats trained on this procedure, this dose of alcohol also modulates expression of the IEGs c-Fos and Arc in brain regions known to modulate expression of alcohol interoceptive effects. Finally, pharmacological inactivation of the dentate gyrus with GABA agonists baclofen and muscimol disrupted the ability of a low dose of alcohol to serve as an interoceptive cue. Together, these findings demonstrate behavioral and molecular consequences of low-dose alcohol.

Acute and chronic bupropion treatment does not prevent morphine-induced conditioned place preference in mice.

A substantial barrier to the treatment of Opioid Use Disorder (OUD) is the elevated relapse rates in affected patients, and a significant contributor to these events of relapse is exposure to cues and contexts that are intensely associated with prior drug abuse. The neurotransmitter dopamine plays a key role in reward-related behaviors, and previous studies have illustrated that dopamine hypofunction in periods of abstinence serves to prompt drug craving and seeking. We hypothesized that restoration of dopaminergic signaling could attenuate drug-seeking behaviors. Therefore, we investigated whether use of an FDA-approved drug, bupropion, an inhibitor of the dopamine transporter (DAT), or a dopamine uptake inhibitor with high affinity for DAT, JHW 007, was able to decrease preference for a drug-paired context. In these experiments, mice underwent 5 days of non-contingent morphine (10 mg/kg) exposure in a conditioned place preference (CPP) paradigm. We found that systemic injection of bupropion (20 mg/kg, i. p.) or intracranial injection of JHW 007 into the nucleus accumbens shell did not prevent the expression of morphine CPP. We then investigated whether chronic bupropion treatment (via implanted osmotic pumps) would influence morphine CPP. We observed that chronic bupropion treatment for 21 days following morphine conditioning did not attenuate the prolonged preference for morphine-paired contexts. Overall, with our dose and paradigm, neither acute nor chronic bupropion diminishes morphine CPP. Continued studies should address FDA-approved medications and their potential for recovery in OUD patients.

Opioid and Dopamine Genes Interact to Predict Naltrexone Response in a Randomized Alcohol Use Disorder Clinical Trial.

BACKGROUND: While the opiate antagonist, naltrexone, is approved for treating alcohol use disorder (AUD), not everyone who receives the medication benefits from it. This study evaluated whether the OPRM1 SNP rs1799971 interacts with the dopamine transporter gene DAT1/SLC6A3 VNTR rs28363170 or the catechol-O-methyltransferase (COMT) gene SNP rs4680 in predicting naltrexone response. METHODS: Individuals who met DSM-IV alcohol dependence were randomly assigned to naltrexone (50 mg/d) or placebo based on their OPRM1 genotype (75 G-allele carriers and 77 A-allele homozygotes) and also genotyped for DAT1 VNTR (9 vs. 10 repeats) or COMT SNP (val/val vs. met carriers). Heavy drinking days (%HDD) were evaluated over 16 weeks and at the end of treatment. Effect sizes (d) for naltrexone response were calculated based on genotypes. RESULTS: Naltrexone, relative to placebo, significantly reduced %HDD among OPRM1 G carriers who also had DAT1 10/10 (p = 0.021, d = 0.72) or COMT val/val genotypes (p = 0.05, d = 0.80), and to a lesser degree in those OPRM1 A homozygotes who were also DAT1 9-repeat carriers (p = 0.09, d = 0.70) or COMT met carriers (p = 0.03, d = 0.63). All other genotype combinations showed no differential response to naltrexone. Diarrhea/abdominal pain was more prominent in OPRM1 A homozygotes who were also DAT 9 or COMT met carriers. CONCLUSIONS: These results suggest that individuals with AUD with a more opioid-responsive genotype (OPRM1 G carriers) respond better to naltrexone if they have genotypes indicating normal/less dopamine tone (DAT1 10,10 or COMT val,val), while those with a less responsive opioid-responsive genotype (OPRM1 A homozygotes) respond better to naltrexone if they have genotypes indicating greater dopamine tone (DAT1 9-repeat or COMT met carriers). These results could lead to more personalized AUD treatments.

"You Have to Separate the Sinner From the Sin": Clinician's Approaches to Psychological Assessments With Men who Have Sexually Offended.

Men who have sexually offended are often referred for presentence psychological assessments to determine factors which contributed to offending, identify risk of recidivism, and develop treatment recommendations. The accuracy of assessments is largely reliant on the cooperation of the assessee. Despite the significant legal and emotional consequences, how clinicians approach these assessments, attempt to engage assessees, and overcome resistance have not been investigated. This research sought to develop an understanding of the clinicians' experience of conducting the assessment. How clinicians approach interviews with men who have sexually offended and the techniques they use were explored. Six interviews were conducted with qualified psychologists, at a private practice, whose role included conducting psychological assessments across a range of forensic matters. The findings, reached using Interpretative Phenomenological Analysis, highlighted the relational/social nature of the interaction and the clinicians' experience of a somewhat blurred line in practice between forensic assessments and therapeutic endeavours.

Considering Drug-Associated Contexts in Substance Use Disorders and Treatment Development.

Environmental contexts that are reliably associated with the use of pharmacologically active substances are hypothesized to contribute to substance use disorders. In this review, we provide an updated summary of parallel preclinical and human studies that support this hypothesis. Research conducted in rats shows that environmental contexts that are reliably paired with drug use can renew extinguished drug-seeking behavior and amplify responding elicited by discrete, drug-predictive cues. Akin to drug-associated contexts, interoceptive drug stimuli produced by the psychopharmacological effects of drugs can also influence learning and memory processes that play a role in substance use disorders. Findings from human laboratory studies show that drug-associated contexts, including social stimuli, can have profound effects on cue reactivity, drug use, and drug-related cognitive expectancies. This translationally relevant research supports the idea that treatments for substance use disorders could be improved by considering drug-associated contexts as a factor in treatment interventions. We conclude this review with ideas for how to integrate drug-associated contexts into treatment-oriented research based on 4 approaches: pharmacology, brain stimulation, mindfulness-based relapse prevention, and cognitive behavioral group therapy. Throughout, we focus on alcohol- and tobacco-related research, which are two of the most prevalent and commonly misused drugs worldwide for which there are known treatments.

Role of mPFC and nucleus accumbens circuitry in modulation of a nicotine plus alcohol compound drug state.

Combined use of nicotine and alcohol constitute a significant public health risk. An important aspect of drug use and dependence are the various cues, both external (contextual) and internal (interoceptive) that influence drug-seeking and drug-taking behavior. The present experiments employed the use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and complementary Pavlovian drug discrimination procedures (feature-positive and feature-negative training conditions) in order to examine whether medial prefrontal cortex (prelimbic; mPFC-PL) projections to the nucleus accumbens core (AcbC) modulate sensitivity to a nicotine + alcohol (N + A) interoceptive cue. First, we show neuronal activation in mPFC-PL and AcbC following treatment with N + A. Next, we demonstrate that chemogenetic silencing of projections from mPFC-PL to nucleus accumbens core decrease sensitivity to the N + A interoceptive cue, while enhancing sensitivity to the individual components, suggesting an important role for this specific projection. Furthermore, we demonstrate that clozapine-N-oxide (CNO), the ligand used to activate the DREADDs, had no effect in parallel mCherry controls. These findings contribute important information regarding our understanding of the cortical-striatal circuitry that regulates sensitivity to the interoceptive effects of a compound N + A cue.

Effects of nicotine conditioning history on alcohol and methamphetamine self-administration in rats.

BACKGROUND: Smoking constitutes a significant public health risk. Alcohol and methamphetamine use disorders are also highly co-morbid with smoking, further increasing negative health outcomes. An important question in determining the underlying neurobiology of nicotine poly-drug use is understanding whether having a positive history with nicotine effects alters later drug-taking behavior. METHODS: The current experiments sought to elucidate whether having an appetitive nicotine conditioning history would affect later alcohol or methamphetamine self-administration. Adult male and female Long-Evans rats were first trained on a discriminated goal-tracking task in which the interoceptive effects of nicotine predicted sucrose reinforcement. As a control, pseudo-conditioned groups were included that had equated nicotine and sucrose experience. Rats were then shifted to either alcohol self-administration or methamphetamine self-administration. RESULTS: Nicotine conditioning history had no effect on acquisition or maintenance of alcohol self-administration in males or females. In contrast, an appetitive nicotine conditioning history decreased methamphetamine self-administration in female rats, but not males. CONCLUSIONS: In female, but not male, rats, an appetitive conditioning history with nicotine decreases methamphetamine, but not alcohol, self-administration. This dissociation suggests that the effects may be due to a specific increase in the reinforcing value of methamphetamine. This may have implications for better understanding the progression of drug use from nicotine to methamphetamine.

The Toll-Like Receptor 3 Agonist Poly(I:C) Induces Rapid and Lasting Changes in Gene Expression Related to Glutamatergic Function and Increases Ethanol Self-Administration in Rats.

BACKGROUND: Growing evidence suggests that neuroimmune signaling via Toll-like receptors (TLRs) alters brain circuitry related to alcohol use disorders. Both ethanol (EtOH) exposure and the TLR3 agonist, poly(I:C), increase brain TLR3 expression in neurons and glia. Furthermore, previous studies have shown that cortical TLR3 expression is correlated with lifetime EtOH intake in humans. METHODS: The current experiments investigated the consequences of poly(I:C) treatment on gene expression in 2 brain regions contributing to alcohol reinforcement, the insular cortex (IC) and nucleus accumbens (Acb) and on operant EtOH self-administration, in Long Evans rats. RESULTS: TLR3 activation increased mRNA levels of neuroimmune genes (TLR3, COX2), glutamatergic genes (mGluR2, mGluR3, GLT1), and the trophic factor BDNF in Acb and IC. Furthermore, increases in each of these genes were correlated with increases in TLR3 mRNA, suggesting that TLR3 induction of these genes may impact excitatory transmission in IC and Acb. TLR3 activation also increased EtOH self-administration 18 days postinjection and enhanced the effects of the mGluR2/3 agonist LY379268 to reduce EtOH self-administration following poly(I:C). CONCLUSIONS: Together, these findings suggest lasting consequences of TLR3 activation on gene expression including increases in Group II mGluRs in the Acb. Furthermore, we show an important role for TLR3 signaling in EtOH intake, and a functional involvement of Group II mGluRs.

Silencing the insular-striatal circuit decreases alcohol self-administration and increases sensitivity to alcohol.

Internal drug states/cues can impact drug taking, as pretreatment with a moderate to high alcohol dose (i.e., loading dose) can decrease subsequent alcohol self-administration, alcohol-seeking, and relapse-like drinking. The insular cortex (IC) is implicated in processing information about internal states and findings show that silencing the IC and its projections to the nucleus accumbens core (AcbC) enhance sensitivity to the interoceptive effects of alcohol. Therefore, the goal of the present work was to determine the functional role of IC-AcbC projections in modulating the effects of alcohol pretreatment on operant alcohol self-administration. Long-Evans rats were trained to self-administer a sweetened alcohol solution (15% alcohol (v/v) + 2% sucrose (w/v)) and on test sessions received pretreatment with an alcohol loading dose. A chemogenetic strategy (i.e., hM4D Designer Receptors Exclusively Activated by Designer Drugs [DREADDs]) was implemented to silence the IC-AcbC projections and test the functional role of the insular-striatal circuitry in regulating self-administration following the alcohol loading doses. Alcohol self-administration decreased following pre-session treatment with alcohol, confirming titration of alcohol drinking following a loading dose of alcohol. Chemogenetic silencing of IC-AcbC projections decreased alcohol self-administration under baseline conditions (i.e., water loading dose) and the reduction in self-administration of an alcohol loading dose, implicating a role for this circuit in the maintenance of alcohol self-administration and suggesting increased sensitivity to the alcohol loading dose. These findings provide evidence for the critical nature of insular-striatal circuitry in ongoing alcohol self-administration, and specifically in relation to interoceptive/internal cues that can impact alcohol drinking.

Nicotine-Use/Smoking Is Associated with the Efficacy of Naltrexone in the Treatment of Alcohol Dependence.

BACKGROUND: The opioid antagonist naltrexone is not efficacious for every alcohol treatment seeker. However, various individual factors, such as genetic differences and nicotine-use/smoking status, have been suggested as predictors of naltrexone response. In a randomized clinical trial, we previously reported that nicotine-use/smoking status might be a stronger predictor of naltrexone efficacy than OPRM1 A118G single nucleotide polymorphism (SNP) genotype. In this report, we further characterize the nicotine-users in that trial, examine other drinking outcomes, examine the influence of smoking change on naltrexone effects on drinking, and validate the result in smokers with disialo carbohydrate-deficient transferrin (%dCDT) change as an independent biomarker of response. METHODS: Individuals (n = 146) meeting DSM-IV criteria for alcohol dependence who were genotyped for the OPRM1 A118G SNP and who did, or did not, use nicotine/cigarettes were randomized, in a balanced fashion, to naltrexone (50 mg/d) or placebo and provided medical management (MM) over a 16-week clinical trial. Alcohol use and smoking during the trial were assessed and analyzed. RESULTS: Nicotine-use/smoking status significantly interacted with medication in reducing percent heavy drinking days (PHDD) during the trial (p = 0.003), such that nicotine-users/smokers showed significantly lower PHDD on naltrexone versus placebo (p = 0.0001, Cohen's d = 0.89), while nonusers showed no significant difference between naltrexone and placebo (p = 0.95, Cohen's d = 0.02). Similar effects were shown for drinks per day and percent days drinking. The superiority of naltrexone over placebo on PHDD reduction in nicotine-users/smokers was confirmed with %dCDT (Cohen's d range 0.3 to 0.9 over the study). Naltrexone did not significantly change cigarette use in smokers, and change in use did not influence naltrexone's effect on PHDD. CONCLUSIONS: These data confirm past findings that naltrexone is more efficacious in those who use nicotine/cigarettes. Compared to previous work on the OPRM1 A118G SNP, it appears that nicotine-use might be a more salient predictor of naltrexone treatment response. While naltrexone did not change cigarette use during the study, and smoking change was not related to alcohol reduction, it should be noted that participants were not seeking smoking cessation and MM did not address this issue.

Dopaminergic Genetic Variation Influences Aripiprazole Effects on Alcohol Self-Administration and the Neural Response to Alcohol Cues in a Randomized Trial.

Dopamine (DA) signaling regulates many aspects of Alcohol Use Disorder (AUD). However, clinical studies of dopaminergic medications, including the DA partial agonist aripiprazole (APZ), have been inconsistent, suggesting the possibility of a pharmacogenetic interaction. This study examined whether variation in DA-related genes moderated APZ effects on reward-related AUD phenotypes. The interacting effects of APZ and a variable number tandem repeat (VNTR) polymorphism in DAT1/SLC6A3 (the gene encoding the DA transporter (DAT)) were tested. In addition, interactions between APZ and a genetic composite comprising the DAT1 VNTR and functional polymorphisms in catechol-O-methyltransferase (COMT), DRD2, and DRD4 were evaluated. Ninety-four non-treatment-seeking individuals with AUD were genotyped for these polymorphisms, randomized to APZ (titrated to 15 mg) or placebo for 8 days, and underwent an fMRI alcohol cue-reactivity task (day 7; n=81) and a bar lab paradigm (day 8). Primary outcomes were alcohol cue-elicited ventral striatal (VS) activation and the number of drinks consumed in the bar lab. DAT1 genotype significantly moderated medication effects, such that APZ, relative to placebo, reduced VS activation and bar-lab drinking only among carriers of the DAT1 9-repeat allele, previously associated with lower DAT expression and greater reward-related brain activation. The genetic composite further moderated medication effects, such that APZ reduced the primary outcomes more among individuals who carried a larger number of DAT1, COMT, DRD2, and DRD4 alleles associated with higher DA tone. Taken together, these data suggest that APZ may be a promising AUD treatment for individuals with a genetic predisposition to higher synaptic DA tone.

Functional role for cortical-striatal circuitry in modulating alcohol self-administration.

The cortical-striatal brain circuitry is heavily implicated in drug-use. As such, the present study investigated the functional role of cortical-striatal circuitry in modulating alcohol self-administration. Given that a functional role for the nucleus accumbens core (AcbC) in modulating alcohol-reinforced responding has been established, we sought to test the role of cortical brain regions with afferent projections to the AcbC: the medial prefrontal cortex (mPFC) and the insular cortex (IC). Long-Evans rats were trained to self-administer alcohol (15% alcohol (v/v)+2% sucrose (w/v)) during 30 min sessions. To test the functional role of the mPFC or IC, we utilized a chemogenetic technique (hM4Di-Designer Receptors Activation by Designer Drugs) to silence neuronal activity prior to an alcohol self-administration session. Additionally, we chemogenetically silenced mPFC→AcbC or IC→AcbC projections, to investigate the role of cortical-striatal circuitry in modulating alcohol self-administration. Chemogenetically silencing the mPFC decreased alcohol self-administration, while silencing the IC increased alcohol self-administration, an effect absent in mCherry-Controls. Interestingly, silencing mPFC→AcbC projections had no effect on alcohol self-administration. In contrast, silencing IC→AcbC projections decreased alcohol self-administration, in a reinforcer-specific manner as there was no effect in rats trained to self-administer sucrose (0.8%, w/v). Additionally, no change in self-administration was observed in the mCherry-Controls. Together these data demonstrate the complex role of the cortical-striatal circuitry while implicating a role for the insula-striatal circuit in modulating ongoing alcohol self-administration.

Predictors of Naltrexone Response in a Randomized Trial: Reward-Related Brain Activation, OPRM1 Genotype, and Smoking Status.

This corrects the article DOI: 10.1038/npp.2017.74.

Aripiprazole Suppression of Drinking in a Clinical Laboratory Paradigm: Influence of Impulsivity and Self-Control.

BACKGROUND: Aspects of impulsivity have been implicated in the development, or maintenance, of alcohol use disorder (AUD). The brain dopamine system is implicated in both reward processing/memory (typically subcortical) and in brain inhibitory control mechanisms (typically cortical). Using a validated clinical laboratory paradigm, the dopamine/serotonin "stabilizing" drug, aripiprazole was evaluated in non-treatment-seeking AUD individuals based on their level of impulsivity/self-control. METHODS: Ninety-nine individuals (77% male; mean age 27; 7.5 drinks per day; 83% heavy drinking days) meeting DSM-IV criteria for alcohol dependence were randomized to aripiprazole (N = 47 evaluable) or placebo (N = 48 evaluable) based on their Barratt Impulsiveness Scale (BIS-11) score (above or below 68). Aripiprazole, or similar placebo, was titrated to 15 mg over 8 days. Drinking was recorded over 6 days under natural conditions. On Day 8, after 1 day of required abstinence, individuals participated in a bar laboratory paradigm that included a priming drink (breath alcohol concentration [BAC] target 0.02 to 0.03 g/dl) and free-choice consumption of up to 8 drinks (max BAC 0.1 g/dl) in exchange for a "bar credit" of $2 per drink (max $16). End points were drinks per day under natural conditions and drinks consumed in the bar laboratory after the priming drink. RESULTS: There was no significant main effect of aripiprazole or interaction with BIS-11 score during the natural drinking period. However, there was a main effect of aripiprazole on bar laboratory drinking (p = 0.04) and aripiprazole reduced the total number of drinks consumed more among individuals with low self-control (p = 0.034) and increased latency to consume those drinks (p = 0.045) more among those with high impulsivity. Relative to placebo, aripiprazole caused more side effects and increased alcohol-induced sedation, but neither significantly influenced its interaction with impulsivity/self-control scores on drinking. CONCLUSIONS: This paradigm forced a choice between immediate drinking reward and delayed monetary reward. In those with high impulsivity and/or low self-control, aripiprazole shifts the balance away from immediate drinking toward a later reward. Medications targeting cortical dopamine/serotonin balance might show clinical benefit of reduced drinking, among individuals with impulsivity/low self-control.

Predictors of Naltrexone Response in a Randomized Trial: Reward-Related Brain Activation, OPRM1 Genotype, and Smoking Status.

Naltrexone reduces drinking among individuals with alcohol use disorders (AUDs), but it is not effective for everyone. Variability in its effects on reward-related brain activation, genetic variation, and/or cigarette smoking may account for this mixed response profile. This randomized clinical trial tested the effects of naltrexone on drinking and alcohol cue-elicited brain activation, evaluated whether OPRM1 A118G genotype or smoking moderated these effects, and explored whether the effects of medication on cue-elicited activation predicted subsequent drinking. One hundred and fifty-two treatment-seeking individuals with alcohol dependence, half preselected to carry at least one A118G G (Asp) allele, were randomized to naltrexone (50 mg) or placebo for 16 weeks and administered an fMRI alcohol cue reactivity task at baseline and after 2 weeks of treatment. Naltrexone, relative to placebo, significantly reduced alcohol cue-elicited activation of the right ventral striatum (VS) between baseline and week 2 and reduced heavy drinking over 16 weeks. OPRM1 genotype did not significantly moderate these effects, but G-allele carriers who received naltrexone had an accelerated return to heavy drinking after medication was stopped. Smoking moderated the effects of medication on drinking, such that naltrexone was superior to placebo only among smokers. The degree of reduction in right VS activation between scans interacted with medication in predicting subsequent drinking, such that individuals with greater reduction in activation who received naltrexone, but not placebo, experienced the least heavy drinking during the following 14 weeks. These data replicate previous findings that naltrexone reduces heavy drinking and reward-related brain activation among treatment-seeking individuals with AUDs, and indicate that smoking and the magnitude of reduction in cue-elicited brain activation may predict treatment response.