Sex differences in associations between delay discounting and expectancies for alcohol analgesia.

Self-medication of pain with alcohol is prevalent, and expectancies for alcohol analgesia likely influence pain relief and alcohol consumption. Hazardous alcohol use has been associated with greater delay discounting rates; however, little is known about the relationship between delay discounting and expectancies for alcohol analgesia. Therefore, the present study examined sex differences in associations between delay discounting and expectancies for alcohol analgesia. Healthy drinkers without chronic pain (N = 53) completed measures of expectancies for alcohol analgesia, alcohol use, and alcohol outcome expectancies. A five-trial adjusting-delay discounting task (DDT) for monetary outcomes was also administered. Regression analyses revealed that sex moderated the relationship between delay discounting and expectancies for alcohol analgesia. Steeper delay discounting rates were associated with weaker expectancies for alcohol analgesia among men when adjusting for average alcohol consumption. Among women, nonsignificant associations between delay discounting rates and expectancies for alcohol analgesia were observed. These findings provide initial evidence of sex differences in associations between delay discounting and expectancies for alcohol analgesia. The directionality of these associations was unexpected and may have implications for patterns of self-medication with alcohol. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Acute Tolerance to the Analgesic Effects of Alcohol.

OBJECTIVE: The goal of this study was to determine whether the acute analgesic effects of alcohol intake are moderated by acute alcohol tolerance, characterized by differing subjective and neurobehavioral effects of a given blood alcohol concentration (BAC) depending on whether BAC is rising or falling. METHOD: Twenty-nine healthy drinkers (20 women) completed two laboratory sessions in which they consumed a study beverage: active alcohol (target BAC= .08 g/dl) and placebo. Acute alcohol tolerance was assessed by examining the main and interactive effects of beverage condition and assessment limb (ascending vs. descending) on quantitative sensory testing measures collected using slowly ramping heat stimuli and perceived relief ratings at comparable breath alcohol concentrations on the ascending and descending limbs. RESULTS: BAC limb moderated the effect of condition on pain threshold, such that the threshold was significantly elevated in the alcohol condition on the ascending limb. The alcohol condition produced greater ratings of perceived pain relief than the placebo condition, and pain relief ratings were greater on the ascending versus descending limb of the BAC curve. Alcohol intake did not significantly affect pain tolerance or aftersensation ratings on either BAC limb. CONCLUSIONS: This study provides initial experimental evidence that alcohol's analgesic and pain-relieving effects are subject to acute tolerance following acute alcohol intake. These findings suggest that self-medicating pain via alcohol intake may be associated with high-risk drinking topography, increasing the risk for alcohol-related consequences. Further research is needed to determine if these effects extend to the context of clinical and chronic pain.

Sex moderates the effects of experimentally induced musculoskeletal pain on alcohol demand in healthy drinkers.

BACKGROUND: Pain may serve as an antecedent for alcohol use, increasing risk for hazardous drinking and associated consequences. Delayed onset muscle soreness (DOMS) induction produces clinically relevant but time-limited musculoskeletal pain. This study was conducted to determine whether DOMS induction on the dominant elbow flexors influenced alcohol demand using the Alcohol Purchase Task (APT). We hypothesized DOMS would increase alcohol demand relative to a sham control. Based on existing studies of pain self-medication, we expected DOMS-related increases in alcohol demand would be greatest in men. METHODS: Participants (N = 53; 57 % women) were randomly assigned to a DOMS (eccentric exercise) or sham condition (concentric exercise). Participants completed the APT pre-exercise and 48 -hs post-exercise. Repeated measures GLM was used to characterize group by sex by time interactions on APT indices, including intensity, breakpoint, essential value (EV), Omax, and Pmax. RESULTS: The DOMS procedure significantly increased pain ratings at the elbow flexors. Men had significantly higher demand intensity than women across groups and time points. Significant interactive effects were detected for breakpoint and EV. From pre- to post-test, breakpoint significantly increased in men in the DOMS group. However, breakpoint and EV significantly decreased in women in the DOMS group. CONCLUSIONS: Increased alcohol demand in men in the DOMS group was consistent with epidemiological data suggesting men are at higher risk for self-medicating pain with alcohol than women. However, decreased demand in women was unexpected. Taken together, results indicate DOMS induction may be a useful means to characterize pain as an antecedent for alcohol use.

CANUE: A Theoretical Model of Pain as an Antecedent for Substance Use.

BACKGROUND: Pain and substance use are frequently comorbid and have been shown to exert bidirectional effects. Self-medication of pain and distress via substance use is common and can be understood via negative reinforcement, ultimately strengthening the pathway between pain to substance use over time. As such, a testable model of the potentially modifiable candidate mechanisms that underlie the pain to substance use pathway is needed. PURPOSE: This review proposes a testable model of pain as an antecedent to substance use to guide future research and inform clinical practice. METHODS: An integrative review of current evidence regarding pain, substance use, and associated risk factors (i.e., negative affect, pain-related attitudes, negative urgency, and substance use outcome expectancies) was conducted. RESULTS: The Catastrophizing, Anxiety, Negative Urgency, and Expectancy (CANUE) model highlights modifiable risk factors for self-medicating pain with substance use, including increased negative affect and maladaptive pain-related attitudes (i.e., pain catastrophizing, pain anxiety, and fear of pain), negative urgency, and substance-related outcome expectancies for pain relief and enhanced pain coping. CONCLUSIONS: Targeted behavioral and psychological interventions that address these factors may facilitate more adaptive pain-coping responses, thereby reducing the impacts of pain on substance use. Systematic research is needed to evaluate the validity and clinical utility of this model.

A Rat Model of Cocaine-Alcohol Polysubstance Use Reveals Altered Cocaine Seeking and Glutamate Levels in the Nucleus Accumbens.

Preclinical models of cocaine use disorder are widely utilized to identify neuroadaptations underlying cocaine seeking and to screen medications to reduce seeking. However, while the majority of cocaine users engage in poly-substance use (PSU), a minority of preclinical studies employ PSU models. We previously reported that when rats consume alcohol after daily intravenous cocaine self-administration, nucleus accumbens (NA) core basal glutamate levels are reduced below those of rats that consumed only cocaine, and do not increase during cue + cocaine-primed reinstatement of cocaine-seeking. Here we used the same model of sequential cocaine and alcohol self-administration to test the hypothesis that a similar pattern of glutamate changes would be observed in the NA core prior to and during a cocaine-primed reinstatement test. Rats underwent intravenous cocaine self-administration followed by access to unsweetened alcohol in the home cage for 12 days. Rats underwent a minimum of 12 daily extinction sessions prior to a cocaine-primed reinstatement test conducted during microdialysis procedures. Contrary to our previous work using the same model, here we found that access to alcohol increased cocaine intake and increased responding during early extinction training. We found that as in our previous work, cocaine + alcohol-consuming rats displayed basal glutamate levels below those of rats that self-administered only cocaine. During the cocaine-primed reinstatement test, rats that consumed only cocaine displayed increased glutamate efflux in the NA core while those that consumed cocaine + alcohol did not. These results indicate that preclinical models of PSU should be utilized to develop experimental therapeutics for the reduction of cocaine seeking.

Acute Alcohol Intake Produces Widespread Decreases in Cortical Resting Signal Variability in Healthy Social Drinkers.

BACKGROUND: Acute alcohol intoxication has wide-ranging neurobehavioral effects on psychomotor, attentional, inhibitory, and memory-related cognitive processes. These effects are mirrored in disruption of neural metabolism, functional activation, and functional network coherence. Metrics of intraregional neural dynamics such as regional signal variability (RSV) and brain entropy (BEN) may capture unique aspects of neural functional capacity in healthy and clinical populations; however, alcohol's influence on these metrics is unclear. The present study aimed to elucidate the influence of acute alcohol intoxication on RSV and to clarify these effects with subsequent BEN analyses. METHODS: 26 healthy adults between 25 and 45 years of age (65.4% women) participated in 2 counterbalanced sessions. In one, participants consumed a beverage containing alcohol sufficient to produce a breath alcohol concentration of 0.08 g/dl. In the other, they consumed a placebo beverage. Approximately 35 minutes after beverage consumption, participants completed a 9-minute resting-state fMRI scan. Whole-brain, voxel-wise standard deviation was used to assess RSV, which was compared between sessions. Within clusters displaying alterations in RSV, sample entropy was calculated to assess BEN. RESULTS: Compared to the placebo, alcohol intake resulted in widespread reductions in RSV in the bilateral middle frontal, right inferior frontal, right superior frontal, bilateral posterior cingulate, bilateral middle temporal, right supramarginal gyri, and bilateral inferior parietal lobule. Within these clusters, significant reductions in BEN were found in the bilateral middle frontal and right superior frontal gyri. No effects were noted in subcortical or cerebellar areas. CONCLUSIONS: Findings indicate that alcohol intake produces diffuse reductions in RSV among structures associated with attentional processes. Within these structures, signal complexity was also reduced in a subset of frontal regions. Neurobehavioral effects of acute alcohol consumption may be partially driven by disruption of intraregional neural dynamics among regions involved in higher-order cognitive and attentional processes.

Regional increases in brain signal variability are associated with pain intensity reductions following repeated eccentric exercise bouts.

BACKGROUND: Traditional pain interventions limit fluctuations in pain sensation, which may paradoxically impair endogenous pain modulatory systems (EPMS). However, controlled exposures to clinically relevant pain (e.g. delayed onset muscle soreness [DOMS]) may build capacity in the EPMS. Emerging evidence suggests that regional signal variability (RSV) may be an important indicator of efficiency and modulatory capacity within brain regions. This study sought to determine the role of RSV in both susceptibility to and trainability of pain response following repeated DOMS inductions. METHODS: Baseline and follow-up resting-state fMRI was performed on 12 healthy volunteers ~40 days apart. Between scanning visits, participants received four weekly DOMS inductions in alternating elbow flexors and were supplied seven days of post-induction pain ratings. Voxel-wise standard deviation of signal intensity was calculated to measure RSV. Associations among DOMS-related pain and RSV were assessed with regression. Relationships among baseline and change measurements were probed (i.e. susceptibility to DOMS; trainability following multiple inductions). RESULTS: Significant association between baseline RSV in left middle frontal gyrus (MFG) and right cerebellum and reductions in DOMS-related pain unpleasantness were detected. Furthermore, increases in RSV were associated with reduced DOMS pain intensity (left lingual gyrus, right MTG, left MTG, left precuneus) and unpleasantness (left MTG, right SFG). DISCUSSION: Findings suggest that RSV may be an indicator of EPMS resilience and responsivity to training, as well as an indicator that is responsive to training. Involved regions underlie cognitive, affective and representation processes. Results further clarify the potential role of RSV as an indicator of pain modulation and resilience. SIGNIFICANCE: Regional signal variability may be an important indicator of endogenous pain modulatory system responsivity to training following repeated bouts of clinically relevant pain and may in fact be responsive to training itself.

Simultaneous edited MRS of GABA, glutathione, and ethanol.

The aim of this work was to develop simultaneous edited MRS of γ-aminobutyric acid (GABA), glutathione (GSH), and ethanol (EtOH) using Hadamard encoding and reconstruction of MEGA-edited spectroscopy (HERMES) at 3T. Density-matrix simulations of HERMES were carried out and compared with phantom experiments. In vivo experiments were performed in six healthy volunteers about 30 min after alcohol consumption. Simulations of HERMES showed GABA-, GSH-, and EtOH-edited spectra with low levels of crosstalk and excellent agreement with phantom spectra. In vivo experiments showed well edited GABA signals at 3.0 ppm, GSH at 2.95 ppm, and EtOH at 1.18 ppm in the respective Hadamard combination spectra. Measured integral ratios were 0.082 ± 0.012 for GABA/Cr, 0.037 ± 0.006 for GSH/Cr, and 0.305 ± 0.129 for EtOH/Cr. Simulated, phantom, and in vivo measurements of HERMES show excellent separation of GABA-, GSH-, and EtOH-edited signals with negligible levels of crosstalk. HERMES allows a threefold acceleration of editing while maintaining spectral quality compared with sequentially acquired MEGA-PRESS measurements.

Acute alcohol intake alters resting state functional connectivity of nucleus accumbens with pain-related corticolimbic structures.

BACKGROUND: The nucleus accumbens (NAc) is a ventral striatal structure underlying reward, reinforcement, and motivation, with extensive anatomic and functional connections to a wide range of affective processing structures (medial prefrontal cortex (mPFC), amygdala, and insula). Characterizing how acute alcohol intake affects resting state functional connectivity (rsFC) between the nucleus accumbens (NAc) and these regions will improve mechanistic understanding of alcohol's neurobehavioral effects, including the neural overlap between acute alcohol effects and pain processing. METHODS: Fifteen healthy social drinkers (10 women; age: 25-45 years) were included in the study. Participants completed one session in which they consumed an alcohol dose targeting a breath alcohol concentration of 0.08 g/dL, and in a second a placebo beverage. Nine-minute resting state fMRI scans were acquired 30-35 min after beverage administration during each session. rsFC between NAc and a priori corticolimbic regions of interest (mPFC, amgydala, and insula), were compared between beverage conditions. We also conducted an exploratory whole-brain seed-to-voxel analysis of NAc FC. RESULTS: Alcohol intake reduced rsFC between NAc and mPFC, as well as NAc and amygdala. Alcohol also reduced rsFC between NAc and a 97-voxel cluster including bilateral paracingulate cortex and anterior cingulate cortex. CONCLUSIONS: Findings suggest that acute alcohol intake reduces rsFC between NAc and several structures, including mPFC, amygdala, and rostral ACC in healthy social drinkers. These structures underlie reward, motivated behavior, and emotion regulation, and may provide mechanistic insight to how alcohol affects related processes, including pain.

Sequential cocaine-alcohol self-administration produces adaptations in rat nucleus accumbens core glutamate homeostasis that are distinct from those produced by cocaine self-administration alone.

There are currently no FDA-approved medications to reduce cocaine relapse. The majority of preclinical studies aimed at identifying the neurobiology underlying relapse involve the self-administration of cocaine alone, whereas many, if not a majority, of cocaine users engage in polysubstance use. Here we developed a rat model of sequential cocaine and alcohol self-administration to test the hypothesis that this combination produces distinct neuroadaptations relative to those produced by cocaine alone. Male rats underwent intravenous cocaine self-administration (2 h/day) followed by 6 h access to unsweetened alcohol (20% v/v) for 12 days. After extinction training, we assessed surface expression of the glutamate transporter GLT-1 and glutamate efflux in the nucleus accumbens (NA) core during the reinstatement of cocaine-seeking. We also tested the ability of ceftriaxone to attenuate the reinstatement of cocaine-seeking and assessed reinstatement-induced Fos expression in several regions critical for reinstatement. Alcohol consumption did not alter cocaine intake, nor did access to cocaine alter alcohol consumption. However, we noted significant changes in glutamate homeostasis in the NA core of cocaine + alcohol rats relative to rats consuming cocaine alone, such as increased surface GLT-1 expression and a lack of increase in glutamate efflux during reinstatement of cocaine-seeking. A history of cocaine + alcohol also altered patterns of reinstatement-induced Fos expression. These changes likely account for the inability of ceftriaxone to attenuate cocaine relapse in cocaine + alcohol rats, while it does so in rats consuming only cocaine. As such glutamate neuroadaptations are targeted by medications to reduce cocaine relapse, preclinical models should consider polysubstance use.

Ceftriaxone reduces alcohol intake in outbred rats while upregulating xCT in the nucleus accumbens core.

Alcohol addiction is a chronic disease characterized by an inability to regulate drinking. A critical brain region involved in alcohol consumption is the nucleus accumbens (NA). Glutamate transmission in this region regulates alcohol consumption and relapse to alcohol-seeking. Across multiple alcohol-administration rodent models, basal extracellular glutamate levels are increased in the NA during early withdrawal. Glutamate transporter 1 (GLT-1) and system xC-, containing the subunit xCT, regulate NA glutamate levels. Ceftriaxone (Cef) increases expression and function of both transporters following extinction from cocaine self-administration and here we sought to determine if Cef would similarly decrease alcohol consumption while increasing xCT and GLT-1 in the NA core. We used the intermittent access to alcohol (IAA) paradigm to induce drinking in outbred Sprague-Dawley rats; this paradigm permits rats access to alcohol (20%v/v) for 24-h without water deprivation, followed by 24-h of abstinence. Following 17 24-h drinking sessions, Cef treatment (200mg/kg IP) was initiated and continued for 5days while a control group received vehicle (0.9% saline IP). Alcohol consumption was assessed for two 24-h periods during Cef and two 24-h periods after cessation of Cef treatment. In a separate cohort of rats, Cef's ability to alter blood alcohol levels (BALs) after a non-contingent alcohol injection (1g/kg) was assessed. We found that Cef decreased alcohol consumption during the period of Cef treatment and on the two days following injections, and this was accompanied by an increase in NA core xCT expression. Furthermore, a history of alcohol consumption did not alter xCT and GLT-1 expression relative to alcohol-naïve controls. Cef did not alter BALs, indicating that the reduction in alcohol consumption was not caused by altered alcohol clearance. These results indicate that while Cef reduces alcohol consumption in outbred rats, its ability to do so is not associated with an increase in GLT-1 expression.

Alcohol consumption increases basal extracellular glutamate in the nucleus accumbens core of Sprague-Dawley rats without increasing spontaneous glutamate release.

Glutamate neurotransmission in the nucleus accumbens core (NAc) mediates ethanol consumption. Previous studies using non-contingent and voluntary alcohol administration in inbred rodents have reported increased basal extracellular glutamate levels in the NAc. Here, we assessed basal glutamate levels in the NAc following intermittent alcohol consumption in male Sprague-Dawley rats that had access to ethanol for 7 weeks on alternating days. We found increased basal NAc glutamate at 24 h withdrawal from ethanol and thus sought to identify the source of this glutamate. To do so, we employed a combination of microdialysis, slice electrophysiology and western blotting. Reverse dialysis of the voltage-gated sodium channel blocker tetrodotoxin did not affect glutamate levels in either group. Electrophysiological recordings in slices made after 24 h withdrawal revealed a decrease in spontaneous excitatory postsynaptic current (sEPSC) frequency relative to controls, with no change in sEPSC amplitude. No change in metabotropic glutamate receptor 2/3 (mGlu2/3) function was detected as bath application of the mGlu2/3 agonist LY379268 decreased spontaneous and miniature EPSC frequency in slices from both control and ethanol-consuming rats. The increase in basal glutamate was not associated with changes in the surface expression of GLT-1, however, a decrease in slope of the no-net-flux dialysis function was observed following ethanol consumption, indicating a potential decrease in glutamate reuptake. Taken together, these findings indicate that the increase in basal extracellular glutamate occurring after chronic ethanol consumption is not mediated by an increase in action potential-dependent glutamate release or a failure of mGlu2/3 autoreceptors to regulate such release.

Neurotensin agonist attenuates nicotine potentiation to cocaine sensitization.

Tobacco usage typically precedes illicit drug use in adolescent and young adult populations. Several animal studies suggest nicotine increases the risk for subsequent cocaine abuse, and may be a negative prognostic factor for treatment of cocaine addiction; i.e., a "gateway drug". Neurotensin (NT) is a 13-amino acid neuropeptide that modulates dopamine, acetylcholine, glutamate, and GABA neurotransmission in brain reward pathways. NT69L, a NT(8-13) analog, blocks behavioral sensitization (an animal model for psychostimulant addiction) to nicotine, and nicotine self-administration in rats. The present study tested the effect of NT69L on the potentiating effects of nicotine on cocaine-induced locomotor sensitization. Male Wistar rats were injected daily for seven days with nicotine or saline (control) followed by four daily injections of cocaine. NT69L was administered 30 min prior to the last cocaine injection. Behavior was recorded with the use of activity chambers. Subchronic administration of nicotine enhanced cocaine-induced behavioral sensitization in Wistar rats, consistent with an hypothesized gateway effect. These behavioral effects of cocaine were attenuated by pretreatment with NT69L. The effect of the neurotensin agonist on cocaine sensitization in the nicotine treated group indicated a possible therapeutic effect for cocaine addiction, even in the presence of enhanced behavioral sensitization induced by nicotine.