Matrix metalloproteinase-9 overexpression in the hippocampus reduces alcohol-induced conditioned-place preference by regulating synaptic plasticity in mice.

Extracellular matrix proteins appear to be necessary for the synaptic plasticity that underlies addiction memory. In the brain, matrix metalloproteinases (MMPs), especially matrix metalloproteinase-9 (MMP-9), have been recently implicated in processes involving alcohol reward and memory. Here, we showed for the first time, the positive effects of MMP-9 on alcohol-induced conditioned place preference (CPP) behavior and hippocampal neuron plasticity in C57BL/6 mice. Using recombinant adeno-associated viruses to overexpress MMP-9 in the hippocampus, we investigated the NMDAR, PSD-95, and cellular cytoskeleton proteins F-actin/G-actin in the modulation of alcohol reward behavior in mice exposed to CPP. We found that hippocampal infusions of MMP-9 decreased alcohol-induced place preference suggesting a reduction in alcohol reward. Western blot analysis demonstrated that protein expression of NMDA receptors (GluN1, GluN2A and GluN2B) in the hippocampus of alcohol-exposed mice were higher than that of the saline group. Further, the expression of these proteins was decreased in MMP-9 overexpressing mice. MMP-9 also regulated the ratio of F-actin/G-actin (dendritic spines cytoskeleton proteins), which might be the key mediator for behavioral changes in mice. Consequently, our results highlight new evidence that MMP-9 may play an important role in the molecular mechanism underlying alcohol reward and preference.

A social contextual review of the effects of alcohol on emotion.

Drinking and drinking problems are complex phenomena. Understanding the etiology of alcohol use disorder requires consideration of biological, psychological, and social processes. It is our view that the last of these dimensions is just beginning to receive adequate scrutiny. In this selective review, we discuss the concept of a biopsychosocial analysis of the effects of alcohol. After briefly addressing biological and psychological research on alcohol's emotional effects, we bid to make a case for the vital role that social processes play in understanding why people drink. The bulk of the paper describes research illustrating the contributions that a social psychological perspective can make to advance understanding of the rewarding effects of alcohol. Overall, studies incorporating social contexts have revealed reliable evidence that alcohol enhances emotional experience in many social environments and have identified socio-contextual variables that moderate responses to alcohol. Further, these studies have broadened the scope of constructs thought to be socially rewarding, including social bonding, relationship functioning, and humor enjoyment. Our analysis concludes by identifying research areas we believe would profit from additional research.

Behavioral economics indices predict alcohol use and consequences in young men at 4-year follow-up.

BACKGROUND AND AIMS: The alcohol purchase task (APT), which presents a scenario and asks participants how many drinks they would purchase and consume at different prices, generates indices of alcohol reward value that have shown robust associations with alcohol-related outcomes in numerous studies. The aim was to test its prospective validity at 4-year follow-up. DESIGN: Prospective cohort study. SETTING: General population sample of young Swiss men. PARTICIPANTS: A total of 4594 Swiss young men (median age = 21, 25th - 75th quartiles = 20.5 - 21.5) completed baseline questionnaires; among those, 4214 (91.7%) were successfully followed-up 4 years later. MEASUREMENTS: Alcohol reward value parameters (i.e. intensity, the planned consumption when drinks are free; breakpoint, the price at which consumption would be suppressed; Omax , the maximum alcohol expenditure; Pmax , the price associated with Omax ; and elasticity, the relative change in alcohol consumption as a function of the relative change in price) were derived from the APT at baseline and used to predict self-reported weekly drinking amount, monthly binge drinking, alcohol-related consequences and DSM-5 alcohol use disorder criteria. FINDINGS: Regression analyses, adjusting for the baseline alcohol measure, age, linguistic region and socio-economic indicators showed that intensity, breakpoint, Omax and elasticity significantly predicted all tested outcomes in the expected direction (e.g. standardized incidence rate ratio [95% confidence interval] = 1.11 [1.07-1.15], 1.07 [1.03-1.10], 1.08 [1.04-1.11], and 0.92 [0.89-0.95], respectively, for weekly drinking amount, all P < 0.001). Pmax did not significantly predict any outcomes. Non-adjusted correlations, baseline adjusted regression and ancillary analyses using (1) latent alcohol variables, (2) multiple imputation for missing data and (3) replications in training and testing subsamples to evaluate predictive accuracy provided consistent findings. CONCLUSIONS: The alcohol purchase task demand curve measures of alcohol reward value are useful in characterizing alcohol-related risk in young men and have long-term predictive utility.

Prenatal opioid exposure reprograms the behavioural response to future alcohol reward.

As the opioid crisis has continued to grow, so has the number of infants exposed to opioids during the prenatal period. A growing concern is that prenatal exposure to opioids may induce persistent neurological changes that increase the propensity for future addictions. Although alcohol represents the most likely addictive substance that the growing population of prenatal opioid exposed will encounter as they mature, no studies to date have examined the effect of prenatal opioid exposure on future sensitivity to alcohol reward. Using a recently developed mouse model of prenatal methadone exposure (PME), we investigated the rewarding properties of alcohol and alcohol consumption in male and female adolescent PME and prenatal saline exposed (PSE) control animals. Conditioned place preference to alcohol was disrupted in PME offspring in a sex-dependent manner with PME males exhibiting resistance to the rewarding properties of alcohol. Repeated injections of alcohol revealed enhanced sensitivity to the locomotor-stimulating effects of alcohol specific to PME females. PME males consumed significantly more alcohol over 4 weeks of alcohol access relative to PSE males and exhibited increased resistance to quinine-adulterated alcohol. Further, a novel machine learning model was developed to employ measured differences in alcohol consumption and drinking microstructure to reliably predict prenatal exposure. These findings indicate that PME alters the sensitivity to alcohol reward in adolescent mice in a sex-specific manner and suggests prenatal opioid exposure may induce persistent effects on reward neurocircuitry that can reprogram offspring behavioural response to alcohol later in life.

Acute alcohol rewarding effects as a risk factor for hangover frequency.

BACKGROUND/PURPOSE: Acute subjective alcohol effects appear to play an important role in predicting alcohol hangover. However, no studies have used a laboratory-based alcohol challenge to examine the concurrent or longitudinal effects of subjective alcohol responses on hangover frequency. As such, we investigated the direct and indirect effects of alcohol stimulation, sedation, liking and wanting, as measured in a controlled setting, on hangover frequency over five years. METHOD: Participants were 294 young adult light-to-heavy social drinkers (aged 21-35 years, 42% female) enrolled in the Chicago Social Drinking Project. The study utilized a placebo-controlled, double blind, laboratory alcohol challenge and a battery of measures including the Biphasic Alcohol Effects Scale, Drug Effects Questionnaire, Hangover Symptom Scale, and alcohol use Quantity-Frequency Interview, with the latter two re-administered after five years. RESULTS: Through the use of a path analysis, the present study found significant direct effects from alcohol liking to hangover frequency at initial testing. In addition, there were multiple significant indirect effects from greater alcohol liking and wanting to greater alcohol use quantity-frequency and, in turn, greater hangover frequency at initial testing and 5-year follow-up. Last, there were significant indirect effects from greater alcohol sedation to less alcohol use quantity-frequency and, in turn, less hangover frequency at initial testing and 5-year follow-up. CONCLUSION: This study highlights the role of the hedonic reward and motivational salience of alcohol as potential mechanisms of alcohol-related consequences (i.e., hangover) among light-to-heavy social drinking young adults.

Predator odor stress blunts alcohol conditioned aversion.

Alcohol use disorder is highly co-morbid with traumatic stress disorders in humans, and dually diagnosed individuals cite negative affective symptoms as a primary reason for drinking alcohol. Therefore, it is reasonable to hypothesize that traumatic stress history increases the rewarding properties and/or blunts the aversive properties of alcohol. We used a place conditioning procedure to test the rewarding/aversive properties of alcohol in adult male Wistar rats with or without a traumatic stress (i.e., predator odor exposure) history, and with or without an alcohol drinking history. Because extended amygdala regions have documented roles in stress, reward, and stress-induced changes in reward, we also tested the effect of acute alcohol on CREB phosphorylation (pCREB) and striatal-enriched protein tyrosine phosphatase (STEP) expression in central amygdala (CeA) and bed nucleus of stria terminalis (BNST). Our results show that a moderate alcohol dose (1.0 g/kg) produces conditioned place aversion (CPA) that is blunted by stress history but is not affected by alcohol drinking history, and this effect differed in pair-housed versus single-housed rats. Stress history reduced pCREB expression in BNST of rats with and without an alcohol drinking history. Finally, acute alcohol effects on pCREB and STEP expression in CeA were positively associated with preference for the alcohol-paired chamber. These data suggest that stress history reduces the aversive properties of moderate alcohol doses, and that alcohol aversion is associated with acute alcohol effects on pCREB and STEP expression in the extended amygdala.

Effect of caffeine on alcohol consumption and alcohol-induced conditioned place preference in rodents.

Background The aim of the study was to determine the effect of caffeine on alcohol consumption with or without deprivation and alcohol-induced conditioned place preference. Methods In the present study, we examined the effects of caffeine (2.5, 5 and 10 mg/kg) on alcohol consumption in Wistar rats with or without periods of deprivation in an unlimited-access, two-bottle, free choice drinking procedure after a stable baseline alcohol consumption was established. Conditioned place preference (CPP) was established by intraperitoneal injections of alcohol (2 g/kg) in a 12-day conditioning schedule in mice. The effect of caffeine (3 mg/kg) on CPP expression was determined by a final post-conditioning test following 12 conditioning sessions with alcohol. The effect of caffeine (3 mg/kg) on the reinstatement of alcohol-induced CPP was determined in a final post-conditioning test following 12 conditioning sessions with alcohol and the extinction of alcohol-induced CPP. Results Alcohol deprivation for 3 days did not result in alcohol deprivation effect (ADE). While caffeine (10 mg/kg) caused a significant (p<0.05) reduction in alcohol consumption compared with the baseline following a period of alcohol deprivation, it did not cause a change in alcohol consumption compared with the baseline in the study without alcohol deprivation phase. Caffeine significantly (p<0.05) reduced the expression of alcohol-induced CPP compared to saline and blocked the reinstatement of alcohol-induced CPP following the injection of a priming dose (0.4 g/kg) of alcohol. Conclusions Given that caffeine is an adenosine receptor antagonist, our findings suggest a role for adenosine receptors in the alcohol reward and alcohol-seeking behaviour.

A Novel and Selective Nociceptin Receptor (NOP) Agonist (1-(1-((cis)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methanol (AT-312) Decreases Acquisition of Ethanol-Induced Conditioned Place Preference in Mice.

BACKGROUND: Nociceptin/orphanin FQ, the endogenous peptide agonist for the opioid receptor-like receptor (also known as NOP or the nociceptin receptor), has been shown to block the acquisition and expression of ethanol (EtOH)-induced conditioned place preference (CPP). Here, we report the characterization of a novel small-molecule NOP ligand AT-312 (1-(1-((cis)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methanol) in receptor binding and GTPγS functional assays in vitro. We then investigated the effect of AT-312 on the rewarding action of EtOH in mice using the CPP paradigm. Further, using mice lacking the NOP receptor and their wild-type controls, we also examined the involvement of NOP in the effect of AT-312. Motivational effects of AT-312 alone were also assessed in the CPP paradigm. METHODS: Female mice lacking NOP and/or their wild-type controls received conditioning in the presence or absence of the NOP agonist [AT-312 (1, 3, and 10 mg/kg) or the control NOP agonist SCH221510 (10 mg/kg)] followed by saline/EtOH for 3 consecutive days (twice daily) and tested for CPP in a drug-free state on the next day. RESULTS: Our in vitro data showed that AT-312 is a high-affinity, selective NOP full agonist with 17-fold selectivity over the mu opioid receptor and >200-fold selectivity over the kappa opioid receptor. The results of our in vivo studies showed that AT-312 reduced EtOH CPP at the lowest dose (1 mg/kg) tested but completely abolished EtOH CPP at higher doses (3 or 10 mg/kg) compared to their vehicle-treated control group. AT-312 (3 mg/kg) did not alter EtOH-induced CPP in mice lacking NOP, confirming that AT-312 reduced EtOH CPP through its action at the NOP receptor. AT-312 (3 mg/kg) did not induce reward or aversion when administered alone, showing that the novel small-molecule NOP agonist shows efficacy in blocking EtOH-induced CPP via the NOP receptor. CONCLUSIONS: Together, these data suggest that small-molecule NOP agonists have the potential to reduce alcohol reward and may be promising as medications to treat alcohol addiction.

Alcohol preference and consumption are controlled by the caudal linear nucleus in alcohol-preferring rats.

The neuroanatomical and neurochemical basis of alcohol drinking has been extensively studied, but the neural circuitry mediating alcohol reinforcement has not been fully delineated. In the present experiments, we used both neuroimaging and pharmacological tools to identify neural systems associated with alcohol preference and high voluntary alcohol drinking in alcohol-preferring AA (Alko Alcohol) rats. First, we compared the basal brain activity of AA rats with that of heterogeneous Wistar rats with manganese-enhanced magnetic resonance imaging (MEMRI). Briefly, alcohol-naïve rats were implanted with subcutaneous osmotic minipumps delivering 120 mg/kg MnCl2 over a 7-day period, and were then imaged using a three-dimensional rapid acquisition-relaxation enhanced pulse sequence. MEMRI analysis revealed that the most conspicuous subcortical activation difference was located in the caudal linear nucleus of raphe (CLi), with AA rats displaying significantly lower T1 signal in this region compared to Wistar rats. However, following long-term alcohol drinking, CLi activity was increased in AA rats. In the second experiment, the CLi was targeted with pharmacological tools. AA rats trained to drink 10% alcohol during 2-h sessions were implanted with guide cannulas aimed at the CLi and were given injections of the GABAA receptor agonist muscimol into the CLi before drinking sessions. Muscimol dose-dependently increased alcohol drinking, and co-administration of the gamma aminobutyric acid (GABA)A antagonist bicuculline blocked muscimol's effect. These findings suggest that the mediocaudal region of the ventral tegmental area, particularly the CLi, is important for the propensity for high alcohol drinking and controls alcohol reward via GABAergic transmission.

Change in delay discounting and substance reward value following a brief alcohol and drug use intervention.

The present study examined (1) the impact of a brief substance use intervention on delay discounting and indices of substance reward value (RV), and (2) whether baseline values and posttreatment change in these behavioral economic variables predict substance use outcomes. Participants were 97 heavy drinking college students (58.8% female, 41.2% male) who completed a brief motivational intervention (BMI) and then were randomized to one of two conditions: a supplemental behavioral economic intervention that attempted to increase engagement in substance-free activities associated with delayed rewards (SFAS) or an Education control (EDU). Demand intensity, and Omax, decreased and elasticity significantly increased after treatment, but there was no effect for condition. Both baseline values and change in RV, but not discounting, predicted substance use outcomes at 6-month follow-up. Students with high RV who used marijuana were more likely to reduce their use after the SFAS intervention. These results suggest that brief interventions may reduce substance reward value, and that changes in reward value are associated with subsequent drinking and drug use reductions. High RV marijuana users may benefit from intervention elements that enhance future time orientation and substance-free activity participation.