Reward Regions Research Articles

Functional Organization of Auditory and Reward Systems in Aging.

The intrinsic organization of functional brain networks is known to change with age, and is affected by perceptual input and task conditions. Here, we compare functional activity and connectivity during music listening and rest between younger (n = 24) and older (n = 24) adults, using whole-brain regression, seed-based connectivity, and ROI-ROI connectivity analyses. As expected, activity and connectivity of auditory and reward networks scaled with liking during music listening in both groups. Younger adults show higher within-network connectivity of auditory and reward regions as compared with older adults, both at rest and during music listening, but this age-related difference at rest was reduced during music listening, especially in individuals who self-report high musical reward. Furthermore, younger adults showed higher functional connectivity between auditory network and medial prefrontal cortex that was specific to music listening, whereas older adults showed a more globally diffuse pattern of connectivity, including higher connectivity between auditory regions and bilateral lingual and inferior frontal gyri. Finally, connectivity between auditory and reward regions was higher when listening to music selected by the participant. These results highlight the roles of aging and reward sensitivity on auditory and reward networks. Results may inform the design of music-based interventions for older adults and improve our understanding of functional network dynamics of the brain at rest and during a cognitively engaging task.

The activity-regulated cytoskeleton-associated protein, Arc, functions in the nucleus accumbens shell to limit multiple triggers of cocaine-seeking behaviour.

Use of addictive substances like cocaine produces enduring associations between the drug experience and cues in the drug-taking environment. In individuals with a substance use disorder (SUD) and attempting to remain abstinent, these powerful drug-cue associations can trigger a return to active drug use, but the molecular mechanisms regulating drug-cue associations remain poorly understood. The activity-regulated cytoskeleton-associated protein (Arc) is induced by cocaine in the nucleus accumbens (NAc), an important brain reward region, but Arc's NAc function in SUD-related behaviour remains unclear. We show here that cocaine self-administration (SA) in rats produced a significant upregulation of Arc protein in both the core and shell subregions of the NAc. Subregion-specific Arc reduction (shRNA) in the medial NAc Shell enhanced both context-associated and cue-reinstated cocaine seeking, but without altering the motivation to work for cocaine, the sensitivity to the reinforcing effects of cocaine or the ability of cocaine priming to reinstate drug seeking. In contrast, we observed no effects of Arc knockdown in the NAc core on any aspect of cocaine SA, extinction or reinstated cocaine seeking, suggesting that Arc functions within the medial NAc shell, but not NAc core, to limit the strength of drug-context and drug-cue associations that promote cocaine-seeking behaviour.

UAV Anti-Jamming Communications With Power and Mobility Control

Unmanned aerial vehicle (UAV)-enabled air-ground integrated communication systems are vulnerable to jamming attack, mainly due to the high probability with line-of-sight wireless channel conditions. Although a few UAV anti-jamming transmission schemes have been recently proposed, the fundamental performance limits by simultaneously considering the UAV and jammer’s mobility have not yet been reported. These observations motivate us to formulate an interactive reward region (IRR) characterization problem for the scenario that the UAV and the jammer compete with each other to maximize their respective rewards via power and mobility control. Then, we propose a transmit and jamming power optimization algorithm to characterize the IRR with power control, by leveraging successive convex approximation technique, where two transmit power design schemes are given in closed-form expressions from a game-theoretic perspective. Furthermore, the IRR with joint power and mobility control is characterized based on alternating optimization, in which both the UAV and jammer can simultaneously adjust their power and trajectories. Finally, extensive simulation results reveal that joint transmit power and trajectory optimization can enlarge the IRR, and increasing the UAV mobility and flight time length improves the UAV reward.

Binge-Eating Precursors in Children and Adolescents: Neurodevelopment, and the Potential Contribution of Ultra-Processed Foods.

Binge-eating disorder (BED) is a highly prevalent disorder. Subthreshold BED conditions (sBED) are even more frequent in youth, but their significance regarding BED etiology and long-term prognosis is unclear. A better understanding of brain findings associated with BED and sBED, in the context of critical periods for neurodevelopment, is relevant to answer such questions. The present narrative review starts from the knowledge of the development of emotional self-regulation in youth, and the brain circuits supporting emotion-regulation and eating behaviour. Next, neuroimaging studies with sBED and BED samples will be reviewed, and their brain-circuitry overlap will be examined. Deficits in inhibition control systems are observed to precede, and hyperactivity of reward regions to characterize, sBED, with overlapping findings in BED. The imbalance between reward/inhibition systems, and the implication of interoception/homeostatic processing brain systems should be further examined. Recent knowledge of the potential impact that the high consumption of ultra-processed foods in paediatric samples may have on these sBED/BED-associated brain systems is then discussed. There is a need to identify, early on, those sBED individuals at risk of developing BED at neurodevelopmental stages when there is a great possibility of prevention. However, more neuroimaging studies with sBED/BED pediatric samples are needed.

The body mass index is associated with increased temporal variability of functional connectivity in brain reward system.

The reward system has been proven to be contributed to the vulnerability of obesity. Previous fMRI studies have shown abnormal functional connectivity of the reward system in obesity. However, most studies were based on static index such as resting-state functional connectivity (FC), ignoring the dynamic changes over time. To investigate the dynamic neural correlates of obesity susceptibility, we used a large, demographically well-characterized sample from the Human Connectome Project (HCP) to determine the relationship of body mass index (BMI) with the temporal variability of FC from integrated multilevel perspectives, i.e., regional and within- and between-network levels. Linear regression analysis was used to investigate the association between BMI and temporal variability of FC, adjusting for covariates of no interest. We found that BMI was positively associated with regional FC variability in reward regions, such as the ventral orbitofrontal cortex and visual regions. At the intra-network level, BMI was positively related to the variability of FC within the limbic network (LN) and default mode network (DMN). At the inter-network level, variability of connectivity of LN with DMN, frontoparietal, sensorimotor, and ventral attention networks showed positive correlations with BMI. These findings provided novel evidence for abnormal dynamic functional interaction between the reward network and the rest of the brain in obesity, suggesting a more unstable state and over-frequent interaction of the reward network and other attention and cognitive networks. These findings, thus, provide novel insight into obesity interventions that need to decrease the dynamic interaction between reward networks and other brain networks through behavioral treatment and neural modulation.

Relation of Overweight/Obesity to Reward Region Response to Food Reward and the Moderating Effects of Parental History of Eating Pathology in Adolescent Females.

To test whether overweight/obesity is associated with an elevated reward region response to milkshake cues and a low reward region response to milkshake receipt. To test whether the risk for eating pathology moderates the effects of weight status on the neural response to milkshake cues and milkshake receipt. The current study used functional magnetic resonance imaging (fMRI) to examine the neuronal responses of female adolescents (n = 80; M age = 14.6 ± 0.9; M BMI = 21.9 ± 3.6; 41% with a biological parental history of eating pathology) during a food receipt paradigm. Females with overweight/obesity showed a greater ventromedial prefrontal cortex (vmPFC), and ventral anterior cingulate (ACC) response to milkshake cues and a greater ventral striatum, subgenual ACC, and dorsomedial prefrontal cortex response to milkshake receipt than those with a healthy weight. Females with overweight/obesity plus a parental history of eating pathology showed a greater vmPFC/medial orbitofrontal cortex response to milkshake cues than those without a parental history of eating pathology and those with a healthy weight. Females with overweight/obesity and without a parental history of eating pathology showed a greater thalamus and striatum response to milkshake receipt. Overweight/obesity is associated with an elevated reward region response to palatable food cues and food receipt. A risk for eating pathology enhances the reward region response to food cues in those with excess weight.

Paediatric obesity and metabolic syndrome associations with cognition and the brain in youth: Current evidence and future directions.

Obesity and components of the metabolic syndrome (MetS) are associated with differences in brain structure and function and in general and food-related cognition in adults. Here, we review evidence for similar phenomena in children and adolescents, with a focus on the implications of extant research for possible underlying mechanisms and potential interventions for obesity and MetS in youth. Current evidence is limited by a relative reliance on small cross-sectional studies. However, we find that youth with obesity and MetS or MetS components show differences in brain structure, including alterations in grey matter volume and cortical thickness across brain regions subserving reward, cognitive control and other functions, as well as in white matter integrity and volume. Children with obesity and MetS components also show some evidence for hyperresponsivity of food reward regions and hyporesponsivity of cognitive control circuits during food-related tasks, altered brain responses to food tastes, and altered resting-state connectivity including between cognitive control and reward processing networks. Potential mechanisms for these findings include neuroinflammation, impaired vascular reactivity, and effects of diet and obesity on myelination and dopamine function. Future observational research using longitudinal measures, improved sampling strategies and study designs, and rigorous statistical methods, promises to further illuminate dynamic relationships and causal mechanisms. Intervention studies targeted at modifiable biological and behavioural factors associated with paediatric obesity and MetS can further inform mechanisms, as well as test whether brain and behaviour can be altered for beneficial outcomes.

Histamine Regulates Accumbens Microcircuits: An Arousing Finding for Addiction Research

The concept of “reward” is evolutionarily central as it is critical to reinforce behaviors that improve the chances of survival and reproduction and avoid behaviors that reduce fitness. Feelings of reward drive organisms to engage in behaviors like the consumption of calorie-dense foods or the pursuit of sexual reproduction, and some of the most crucial brain circuitry driving this reward is relatively well understood. One key reward region is the nucleus accumbens (NAc), which integrates information delivered by glutamatergic inputs from the hippocampus (providing information on previous experiences and context), the prefrontal cortex (conveying the organism’s current plan and goals), and the amygdala (affording emotional salience and relevance). The integration of all this information in the NAc is controlled by neuromodulatory neurotransmitters, the most well-studied being dopamine delivered by projections from the ventral tegmental area. Dopamine drives increased function of D1-type NAc medium spiny neurons (MSNs) comprising the direct pathway and reinforcing behavior, while the same dopamine drives down activity of D2-type NAc MSNs comprising the indirect pathway that prevent reinforcement. In more recent years, the understanding of other neuromodulatory signals and their effects on NAc function and outputs has emerged as a key goal, and histamine actions in the NAc is primary among these signals. SEE CORRESPONDING ARTICLE ON PAGE 1041 SEE CORRESPONDING ARTICLE ON PAGE 1041 Accumbal Histamine Signaling Engages Discrete Interneuron MicrocircuitsBiological PsychiatryVol. 93Issue 11PreviewCentral histamine (HA) signaling modulates diverse cortical and subcortical circuits throughout the brain, including the nucleus accumbens (NAc). The NAc, a key striatal subregion directing reward-related behavior, expresses diverse HA receptor subtypes that elicit cellular and synaptic plasticity. However, the neuromodulatory capacity of HA within interneuron microcircuits in the NAc remains unknown. Full-Text PDF

Transgenerational effects of opioids on cardiovascular outcomes of the rat offspring

Opioid use disorder (OUD) is one of the greatest public health threats in the US. In 2020, more than 69,000 Americans died of a drug overdose involving opioids. Starting in 2014, an alarming third wave is on the rise now caused by synthetic opioids, specifically illicit fentanyl (FEN). OUD among pregnant women is an understudied area related to the opioid epidemic, showing a 5-fold increase incidence of neonatal opioid withdrawal syndrome (NOWS). Currently, the only two FDA-approved medications indicated for medication assisted treatment (MAT) during pregnancy are methadone and buprenorphine. While some general guidelines have been established to place pregnant woman on MAT, the misuse of fentanyl has challenged the current pharmacotherapies, urging for the characterization of pre-clinical models.The aim of this study was to investigate the trasngenerational effects of opioids on the cardiovascular system. We subjected female rats to opioids exposure during pregnancy. We investigated: 1) In the newborns, the morphometrics and withdrawal symptoms; 2) In the adult offspring, the locomotor sensitization 3) The short and long-term plasma endogenous opioids peptides status, and 4) the transcriptomics of brain areas involved in the neural interface between motivation and action.We found that female and male neonates from opioids-treated dams are smaller through the lifespan compared to VEH-exposed counterparts (n=6, p<0.05). Also, adult offspring exposed to MOR in utero displayed sympathetic activation and increased cardiometabolic risk factors along with increased locomotor sensitization to MOR (n=4, p<0.05). In addition, we performed RNAseq analysis of the perivascular nucleolus of the hypothalamus in MOR-exposed offspring, showing increased FOSb expression (n=3 per group). ΔFosB, encoded by the fosB gene, is induced in the brain's reward regions by chronic exposure drugs of abuse and mediates sensitized responses to drug exposure.We also found that rat neonates exposed to opiods showed behavioral NOWS-like symptoms. Importantly, we found that the prenatal exposure to opioids induces a long-term dysregulation of the endogenous opioids peptides (EOP) pro-enkephalin and pro-dynorphin.Both endogenous and exogenous opioids can bind to opioid receptors, which are G-protein coupled receptors (GPCRs) that can dimerize and affect the function of other GPCRs with important neurobehavioral functions.This study provides insights regarding how opioids could affect the programming of the mechanisms regulating blood pressure control later in life. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Correction to Chantland et al. (2022).

Reports an error in "Control preference persists with age" by Eric C. M. Chantland, Kainan S. Wang, Mauricio R. Delgado and Susan M. Ravizza (Psychology and Aging, 2022[Nov], Vol 37[7], 843-847). In the original article, the odds ratio and probability were misreported in the second and third sentences of the first paragraph of the Results section. The correct information is provided in this erratum. The online version of the article has been corrected. (The following abstract of the original article appeared in record 2023-04889-001). The opportunity to exert control in one's environment is desirable, and individuals are willing to seek out control, even at a financial cost. Additionally, control-related activation of reward regions in the brain and the positive affect associated with the opportunity to exert control suggest that control is rewarding. The present study explores whether there are age-related differences in the preference for control. Older and younger adults chose whether to maintain control and play a guessing game themselves or to cede this control to the computer. Maintaining and ceding control were associated with different amounts of monetary reward that could be banked upon a successful guess. This required participants to weigh the value associated with control compared to monetary rewards. We found that older adults preferred control and traded monetary reward for control, similar to younger adults. The results suggest that the preference for exerting control may be preserved across age. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Blunted neural reward response to alcohol and greater alcohol motivation in binge drinkers in a randomized clinical experiment.

Alcohol stimulates cerebral blood flow (CBF) in brain reward regions. However, neural processes that support sustained alcohol motivation after the first drink are not well understood. Using a novel placebo-controlled, randomized, crossover experiment, 27 individuals who binge drink (BD; 15 M, 12 F) and 25 social drinkers (SD; 15 M, 10 F) underwent a behavioral test of self-motivated alcohol consumption using an Alcohol Taste Test (ATT) involving alcoholic and nonalcoholic beer on separate days. The test was followed immediately by perfusion functional magnetic resonance imaging (fMRI). On both days, participants then engaged in a post-scan ATT with placebo beer to assess sustained alcohol self-motivation without active alcohol effects. Linear mixed effects models were used to examine the effects of drinking group on the placebo-controlled effect of initial alcohol motivation on brain perfusion (whole brain corrected p < 0.001, cluster corrected p < 0.025) and on the relationship between placebo-controlled brain perfusion and sustained alcohol motivation. Initial alcohol self-motivation in the alcohol relative to placebo session led to markedly decreased activation in the medial orbitofrontal cortex (OFC) and the ventral striatum in BD relative to SD, indicative of neural reward tolerance. The BD group also showed an enhanced neural response in behavioral intention regions of the supplementary motor area (SMA) and inferior frontal gyrus (IFG) regions. Moreover, there was greater sustained alcohol motivation in BD than SD in the post-scan ATT in the alcohol relative to placebo session. Correspondingly, only in BD and only in the alcohol session, lower alcohol-induced OFC response correlated with concurrent sensitized SMA response, and each predicted the subsequent sustained higher alcohol motivation in the post-scan ATT. Alcohol-related OFC tolerance may play an important role in sustained alcohol motivation. Furthermore, both specific alcohol-related neural reward tolerance and premotor sensitization responses may contribute to escalating alcohol motivation to drive excessive alcohol intake, even in individuals without alcohol use disorder.

Associations between resting-state neural connectivity and positive affect in social anxiety disorder.

Social anxiety disorder (SAD) has been characterized by deficits in social motivation and lack of reactivity to pleasurable stimuli (i.e., positive affect; [PA]). Recent neuroimaging work has shifted toward examining positively valenced motivational systems in SAD focused on reward responses. However, little is known about the associations of reward connectivity and PA in individuals with SAD. As such, the purpose of the current study was to determine whether connectivity among key units of reward neurocircuitry meaningfully relate to PA and whether these key units are more heterogeneous in SAD as compared to controls. Thirty-one participants who met diagnostic criteria for SAD and 33 control participants were included (Mage = 24.8, SD = 6.9; 55% cisgender man). Seed-based timeseries correlations were conducted in NiTime to extract region of interest (ROI) coupling correlation strength values. ANOVAs were carried out to assess whether individuals with SAD differed in ROI-to-ROI connectivity strength as compared to controls. Correlations and variance analyses were also conducted to examine the relationship between ROI-to-ROI connectivity strength and PA, as well as heterogeneity in connectivity strength and PA expression. Weaker connectivity between the left and right orbital frontal cortex was observed when comparing the SAD to the control group. Within the SAD group, PA was associated with several reward-related ROI couplings; however, these links were not observed among controls. Results further demonstrated that individuals with SAD had significantly more variability in reward connectivity strength as compared to controls. Overall, these results provide emergent evidence for the association between reward regions and PA in individuals with SAD. Additionally, these findings show that individuals with SAD demonstrate greater heterogeneity in reward connectivity.

Current and emerging medications for the management of obesity in adults.

Current and emerging medications for the management of obesity in adults.

The Neural Processes in Food Decision-making and their Effect on Daily Diet Management in Successful and Unsuccessful Restrained Eaters

This study aimed to explore the neural mechanisms underlying food decision making in unsuccessful restrained eaters (US-REs) and successful restrained eaters (S-REs). During a functional magnetic resonance imaging scan, participants were required to choose between pairs of high- and low-calorie foods under the following conditions: the congruent condition (choose between high- and low-calorie foods with the same level of tastiness) and incongruent condition (choose between high-calorie foods tastier than the corresponding low-calorie foods). Subsequently, the participants’ diets were monitored for one week. The behavioral results showed that US-REs (n = 28) chose more high-calorie foods than S-REs (n = 26); in contrast, S-REs spent more time in choosing for the incongruent than the congruent condition. The fMRI results found that US-REs exhibited more activity in reward regions (caudate and thalamus) than S-REs in the congruent condition. In the incongruent condition, S-REs showed stronger functional connectivity between the conflict-monitoring region (anterior cingulate cortex) and inhibitory-control regions (inferior frontal gyrus [IFG] and medial frontal gyrus) than US-REs. In both the conditions, increased activation of the insula, putamen, middle frontal gyrus, and IFG could predict increased food intake among US-REs in the following week. Furthermore, in both the conditions, increased IFG activation could predict decreased food cravings among S-REs during the following week. Our results suggest that US-REs have a strong reward response to food. Compared to US-REs, S-REs are more guided more by the goal of weight control, and exhibit strong functional connections between the conflict-monitoring and inhibitory-control regions. Therefore, eating enjoyment and weight-control goals influence restrained eating in daily life.

Differential neural reward reactivity in response to food advertising medium in children.

Food cues including food advertisements (ads) activate brain regions related to motivation and reward. These responses are known to correlate with eating behaviors and future weight gain. The objective of this study was to compare brain responses to food ads by different types of ad mediums, dynamic (video) and static (images), to better understand how medium type impacts food cue response. Children aged 9-12 years old were recruited to complete a functional magnetic resonance imaging (fMRI) paradigm that included both food and non-food dynamic and static ads. Anatomical and functional images were preprocessed using the fMRIPrep pipeline. A whole-brain analysis and a targeted region-of-interest (ROI) analysis for reward regions (nucleus accumbens, orbitofrontal cortex, amygdala, insula, hypothalamus, ventral tegmental area, substantia nigra) were conducted. Individual neural responses to dynamic and static conditions were compared using a paired t-test. Linear mixed-effects models were then constructed to test the differential response by ad condition after controlling for age, sex, BMI-z, physical activity, and % of kcal consumed of a participant's estimated energy expenditure in the pre-load prior to the MRI scan. A total of 115 children (mean=10.9 years) completed the fMRI paradigm. From the ROI analyses, the right and left hemispheres of the amygdala and insula, and the right hemisphere of the ventral tegmental area and substantia nigra showed significantly higher responses for the dynamic food ad medium after controlling for covariates and a false discovery rate correction. From the whole-brain analysis, 21 clusters showed significant differential responses between food ad medium including the precuneus, middle temporal gyrus, superior temporal gyrus, and inferior frontal gyrus, and all regions remained significant after controlling for covariates. Advertising medium has unique effects on neural response to food cues. Further research is needed to understand how this differential activation by ad medium ultimately affects eating behaviors and weight outcomes.

Cell Type–Specific Whole-Genome Landscape of ΔFOSB Binding in the Nucleus Accumbens After Chronic Cocaine Exposure

BackgroundThe ability of neurons to respond to external stimuli involves adaptations of gene expression. Induction of the transcription factor ΔFOSB in the nucleus accumbens, a key brain reward region, is important for the development of drug addiction. However, a comprehensive map of ΔFOSB’s gene targets has not yet been generated. MethodsWe used CUT&RUN (cleavage under targets and release using nuclease) to map the genome-wide changes in ΔFOSB binding in the 2 main types of nucleus accumbens neurons—D1 or D2 medium spiny neurons—after chronic cocaine exposure. To annotate genomic regions of ΔFOSB binding sites, we also examined the distributions of several histone modifications. Resulting datasets were leveraged for multiple bioinformatic analyses. ResultsThe majority of ΔFOSB peaks occur outside promoter regions, including intergenic regions, and are surrounded by epigenetic marks indicative of active enhancers. BRG1, the core subunit of the SWI/SNF chromatin remodeling complex, overlaps with ΔFOSB peaks, a finding consistent with earlier studies of ΔFOSB’s interacting proteins. Chronic cocaine use induces broad changes in ΔFOSB binding in both D1 and D2 nucleus accumbens medium spiny neurons of male and female mice. In addition, in silico analyses predict that ΔFOSB cooperatively regulates gene expression with homeobox and T-box transcription factors. ConclusionsThese novel findings uncover key elements of ΔFOSB’s molecular mechanisms in transcriptional regulation at baseline and in response to chronic cocaine exposure. Further characterization of ΔFOSB’s collaborative transcriptional and chromatin partners specifically in D1 and D2 medium spiny neurons will reveal a broader picture of the function of ΔFOSB and the molecular basis of drug addiction.

Mu Opioid Receptor Activation Mediates (S)-ketamine Reinforcement in Rats: Implications for Abuse Liability

Background(S)-ketamine is an NMDA receptor antagonist, but it also binds to and activates mu opioid receptors (MORs) and kappa opioid receptors in vitro. However, the extent to which these receptors contribute to (S)-ketamine’s in vivo pharmacology is unknown. MethodsWe investigated the extent to which (S)-ketamine interacts with opioid receptors in rats by combining in vitro and in vivo pharmacological approaches, in vivo molecular and functional imaging, and behavioral procedures relevant to human abuse liability. ResultsWe found that the preferential opioid receptor antagonist naltrexone decreased (S)-ketamine self-administration and (S)-ketamine–induced activation of the nucleus accumbens, a key brain reward region. A single reinforcing dose of (S)-ketamine occupied brain MORs in vivo, and repeated doses decreased MOR density and activity and decreased heroin reinforcement without producing changes in NMDA receptor or kappa opioid receptor density. ConclusionsThese results suggest that (S)-ketamine’s abuse liability in humans is mediated in part by brain MORs.

Control preference persists with age.

The opportunity to exert control in one's environment is desirable, and individuals are willing to seek out control, even at a financial cost. Additionally, control-related activation of reward regions in the brain and the positive affect associated with the opportunity to exert control suggest that control is rewarding. The present study explores whether there are age-related differences in the preference for control. Older and younger adults chose whether to maintain control and play a guessing game themselves or to cede this control to the computer. Maintaining and ceding control were associated with different amounts of monetary reward that could be banked upon a successful guess. This required participants to weigh the value associated with control compared to monetary rewards. We found that older adults preferred control and traded monetary reward for control, similar to younger adults. The results suggest that the preference for exerting control may be preserved across age. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Purinergic P2X7 receptor antagonist inhibits methamphetamine-induced reward, hyperlocomotion, and cortical IL-7A levels in mice: A role for P2X7/IL-17A crosstalk in methamphetamine behaviors?

P2X7 receptors are dysregulated during psychostimulant exposure. Furthermore, P2X7 receptors enhance endogenous systems (e.g., cytokines, dopamine, and glutamate) that facilitate psychostimulant addiction. Therefore, using mouse locomotor, conditioned place preference (CPP), and intracranial self-stimulation (ICSS) assays, we tested the hypothesis that methamphetamine (METH) reward and acute locomotor activation requires P2X7 receptor activity. We also investigated effects of P2X7 blockade on METH-induced changes in cytokine levels in brain reward regions. A438079 (5, 10, 50 mg/kg), a P2X7 antagonist, did not affect spontaneous locomotor activity but reduced hyperlocomotion caused by acute METH (1 mg/kg) exposure. A438079 (10 mg/kg) also prevented expression of METH CPP without causing aversive or rewarding effects. For ICSS experiments, METH (1 mg/kg) facilitated brain reward function as interpreted from reductions in baseline threshold. In the presence of A438079 (50 mg/kg), METH-induced facilitation of ICSS was reduced. Repeated METH exposure (1 mg/kg × 7 d) caused enhancement of IL-17A levels in the prefrontal cortex (PFC) that was normalized by A438070 (10 mg/kg × 7 d). The present data suggest that P2X7 receptor activity contributes to rewarding and locomotor-stimulant effects of METH through a potential mechanism involving IL-17A, which has recently been implicated in anxiety.

Effects of a Novel Beta Lactam Compound, MC-100093, on the Expression of Glutamate Transporters/Receptors and Ethanol Drinking Behavior of Alcohol-Preferring Rats.

Chronic ethanol exposure affects the glutamatergic system in several brain reward regions including the nucleus accumbens (NAc). Our laboratory has shown that chronic exposure to ethanol reduced the expression of glutamate transporter 1 (GLT-1) and cystine/glutamate exchanger (xCT) and, as a result, increased extracellular glutamate concentrations in the NAc of alcohol-preferring (P) rats. Moreover, previous studies from our laboratory reported that chronic ethanol intake altered the expression of certain metabotropic glutamate receptors in the brain. In addition to central effects, chronic ethanol consumption induced liver injury, which is associated with steatohepatitis. In the present study, we investigated the effects of chronic ethanol consumption in the brain and liver. Male P rats had access to a free choice of ethanol and water bottles for five weeks. Chronic ethanol consumption reduced GLT-1 and xCT expression in the NAc shell but not in the NAc core. Furthermore, chronic ethanol consumption increased fat droplet content as well as peroxisome proliferator-activated receptor alpha (PPAR-α) and GLT-1 expression in the liver. Importantly, treatment with the novel beta-lactam compound, MC-100093, reduced ethanol drinking behavior and normalized the levels of GLT-1 and xCT expression in the NAc shell as well as normalized GLT-1 and PPAR-α expression in the liver. In addition, MC-100093 attenuated ethanol-induced increases in fat droplet content in the liver. These findings suggest that MC-100093 may be a potential lead compound to attenuate ethanol-induced dysfunction in the glutamatergic system and liver injury. SIGNIFICANCE STATEMENT: This study identified a novel beta-lactam, MC-100093, that has demonstrated upregulatory effects on GLT-1. MC-100093 reduced ethanol drinking behavior and normalized levels of GLT-1 and xCT expression in the NAc shell as well as normalized GLT-1 and PPAR-α expression in the liver. In addition, MC-100093 attenuated ethanol-induced increases in fat droplet content in the liver.