Browsing by Subject "Reward"

Now showing 1 - 10 of 21
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    Aggression Results in the Phosphorylation of ERK1/2 in the Nucleus Accumbens and the Dephosphorylation of mTOR in the Medial Prefrontal Cortex in Female Syrian Hamsters
    (MDPI, 2023-01-10) Borland, Johnathan M.; Dempsey, Desarae A.; Peyla, Anna C.; Hall, Megan A. L.; Kohut-Jackson, Abigail L.; Mermelstein, Paul G.; Meisel, Robert L.; Neurology, School of Medicine
    Like many social behaviors, aggression can be rewarding, leading to behavioral plasticity. One outcome of reward-induced aggression is the long-term increase in the speed in which future aggression-based encounters is initiated. This form of aggression impacts dendritic structure and excitatory synaptic neurotransmission in the nucleus accumbens, a brain region well known to regulate motivated behaviors. Yet, little is known about the intracellular signaling mechanisms that drive these structural/functional changes and long-term changes in aggressive behavior. This study set out to further elucidate the intracellular signaling mechanisms regulating the plasticity in neurophysiology and behavior that underlie the rewarding consequences of aggressive interactions. Female Syrian hamsters experienced zero, two or five aggressive interactions and the phosphorylation of proteins in reward-associated regions was analyzed. We report that aggressive interactions result in a transient increase in the phosphorylation of extracellular-signal related kinase 1/2 (ERK1/2) in the nucleus accumbens. We also report that aggressive interactions result in a transient decrease in the phosphorylation of mammalian target of rapamycin (mTOR) in the medial prefrontal cortex, a major input structure to the nucleus accumbens. Thus, this study identifies ERK1/2 and mTOR as potential signaling pathways for regulating the long-term rewarding consequences of aggressive interactions. Furthermore, the recruitment profile of the ERK1/2 and the mTOR pathways are distinct in different brain regions.
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    The apéritif effect: Alcohol's effects on the brain's response to food aromas in women
    (Wiley Blackwell (John Wiley & Sons), 2015-07) Eiler, William J. A.; Džemidžić, Mario; Case, K. Rose; Soeurt, Christina M.; Armstrong, Cheryl L. H.; Mattes, Richard D.; O'Connor, Sean J.; Harezlak, Jaroslaw; Acton, Anthony J.; Considine, Robert V.; Kareken, David A.; Department of Neurology, IU School of Medicine
    OBJECTIVE: Consuming alcohol prior to a meal (an apéritif) increases food consumption. This greater food consumption may result from increased activity in brain regions that mediate reward and regulate feeding behavior. Using functional magnetic resonance imaging, we evaluated the blood oxygenation level dependent (BOLD) response to the food aromas of either roast beef or Italian meat sauce following pharmacokinetically controlled intravenous infusion of alcohol. METHODS: BOLD activation to food aromas in non-obese women (n = 35) was evaluated once during intravenous infusion of 6% v/v EtOH, clamped at a steady-state breath alcohol concentration of 50 mg%, and once during infusion of saline using matching pump rates. Ad libitum intake of roast beef with noodles or Italian meat sauce with pasta following imaging was recorded. RESULTS: BOLD activation to food relative to non-food odors in the hypothalamic area was increased during alcohol pre-load when compared to saline. Food consumption was significantly greater, and levels of ghrelin were reduced, following alcohol. CONCLUSIONS: An alcohol pre-load increased food consumption and potentiated differences between food and non-food BOLD responses in the region of the hypothalamus. The hypothalamus may mediate the interplay of alcohol and responses to food cues, thus playing a role in the apéritif phenomenon.
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    Brain Responses to Sugar: Implications for Alcohol Use Disorder and Obesity
    (2024-05) Alessi, Jonathan P.; Yoder, Karmen K.; Kareken, David A.; Džemidžić, Mario; Considine, Robert V.; Harezlak, Jaroslaw
    Obesity and alcohol use may together account for 640,000 adult deaths each year in the United States. In both cases, overconsumption drives untoward effects. Alcohol use and obesity also both relate to sweet liking, as sugar consumption is consistently linked to weight gain and intense sweet liking has been linked to an inherited risk for alcohol use disorder (AUD). However, the neural underpinnings of these associations are largely unknown. Thus, we used sugar-sweetened water administration during functional magnetic resonance imaging (fMRI) to probe these relationships in two studies. In the first, we tested the relationship between a known AUD risk factor, subjective response to alcohol, and the brain response to both sucrose and monetary reward in 140 young adults. We found a significant positive correlation between the enjoyable component of subjective responses to a standardized intravenous alcohol exposure and activation to high-concentration sucrose (but not monetary reward) in the right dorsal anterior insula and the supplementary motor area, supporting a role for these regions in AUD risk. In the second study, we investigated the neural mechanisms of sweet liking decreases following bariatric surgery, the most effective obesity treatment. Here, we evaluated the change in brain activation to sucrose in 24 women before (BMI 47.0 + 6.9 kg/m2) and 21 women after (BMI 37.6 + 6.5 kg/m2) bariatric surgery and compared the pre- and post-surgical activation patterns to those of 21 normal to overweight (BMI 23.5 + 2.5 kg/m2) control participants. Brain activation did not differ between controls and surgery participants at either time point. However, activation to sucrose in reward, but not sensory, regions decreased significantly after surgery, consistent with reduced drive to consume sweet foods. Together, these studies highlight the utility of quantifying brain responses to sweet taste as a method to understand the mechanisms underlying overconsumptive behavior.
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    Co-administration of ethanol and nicotine: the enduring alterations in the rewarding properties of nicotine and glutamate activity within the mesocorticolimbic system of female alcohol-preferring (P) rats
    (Springer-Verlag, 2015-12) Deehan, Gerald A.; Hauser, Sheketha R.; Waeiss, R. Aaron; Knight, Christopher P.; Toalston, Jamie E.; Truitt, William A.; McBride, William J.; Rodd, Zachary A.; Department of Psychiatry, IU School of Medicine
    RATIONALE: The co-abuse of ethanol (EtOH) and nicotine (NIC) increases the likelihood that an individual will relapse to drug use while attempting to maintain abstinence. There is limited research examining the consequences of long-term EtOH and NIC co-abuse. OBJECTIVES: The current experiments determined the enduring effects of chronic EtOH, NIC, or EtOH + NIC intake on the reinforcing properties of NIC and glutamate (GLU) activity within the mesocorticolimbic (MCL) system. METHODS: Alcohol-preferring (P) rats self-administered EtOH, Sacc + NIC, or EtOH + NIC combined for 10 weeks. The reinforcing properties of 0.1-3.0 μM NIC within the nucleus accumbens shell (AcbSh) were assessed following a 2-3-week drug-free period using intracranial self-administration (ICSA) procedures. The effects of EtOH, Sacc, Sacc + NIC, or EtOH + NIC intake on extracellular levels and clearance of glutamate (GLU) in the medial prefrontal cortex (mPFC) were also determined. RESULTS: Binge intake of EtOH (96-100 mg%) and NIC (21-27 mg/mL) were attained. All groups of P rats self-infused 3.0 μM NIC directly into the AcbSh, whereas only animals in the EtOH + NIC co-abuse group self-infused the 0.3 and 1.0 μM NIC concentrations. Additionally, self-administration of EtOH + NIC, but not EtOH, Sacc or Sacc + NIC, resulted in enduring increases in basal extracellular GLU levels in the mPFC. CONCLUSIONS: Overall, the co-abuse of EtOH + NIC produced enduring neuronal alterations within the MCL which enhanced the rewarding properties of NIC in the AcbSh and elevated extracellular GLU levels within the mPFC.
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    Compulsive alcohol drinking in rodents is associated with altered representations of behavioral control and seeking in dorsal medial prefrontal cortex
    (Springer, 2022-07-09) Timme, Nicholas M.; Ma, Baofeng; Linsenbardt, David; Cornwell , Ethan; Galbari, Taylor; Lapish, Christopher C.; Psychology, School of Science
    A key feature of compulsive alcohol drinking is continuing to drink despite negative consequences. To examine the changes in neural activity that underlie this behavior, compulsive alcohol drinking was assessed in a validated rodent model of heritable risk for excessive drinking (alcohol preferring (P) rats). Neural activity was measured in dorsal medial prefrontal cortex (dmPFC—a brain region involved in maladaptive decision-making) and assessed via change point analyses and novel principal component analyses. Neural population representations of specific decision-making variables were measured to determine how they were altered in animals that drink alcohol compulsively. Compulsive animals showed weakened representations of behavioral control signals, but strengthened representations of alcohol seeking-related signals. Finally, chemogenetic-based excitation of dmPFC prevented escalation of compulsive alcohol drinking. Collectively, these data indicate that compulsive alcohol drinking in rats is associated with alterations in dmPFC neural activity that underlie diminished behavioral control and enhanced seeking.
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    Conditioned Inhibition of Fear and Reward in Male and Female Rats
    (Elsevier, 2024) Krueger, Jamie N.; Patel, Nupur N.; Shim, Kevin; Ng, Ka; Sangha, Susan; Psychiatry, School of Medicine
    Stimuli in our environment are not always associated with an outcome. Some of these stimuli, depending on how they are presented, may gain inhibitory value or simply be ignored. If experienced in the presence of other cues predictive of appetitive or aversive outcomes, they typically gain inhibitory value and become predictive cues indicating the absence of appetitive or aversive outcomes. In this case, these cues are referred to as conditioned inhibitors. Here, male and female Long Evans rats underwent cue discrimination training where a reward cue was paired with sucrose, a fear cue with footshock, and an inhibitor cue resulted in neither sucrose or footshock. During a subsequent summation test for conditioned inhibition of fear and reward, the inhibitor cue was presented concurrently with the reward and fear cues without any outcome, intermixed with trials of reinforced reward and fear trials. Males showed significant conditioned inhibition of freezing, while females did not, which was not dependent on estrous. Both males and females showed significant conditioned inhibition of reward. During a retardation of fear acquisition test, the inhibitor was paired with footshock and both males and females showed delayed acquisition of fear. During a retardation of reward acquisition test, the inhibitor was paired with sucrose, and females showed delayed acquisition of reward, while males did not. In summary, males and females showed significant reward-fear-inhibitor cue discrimination, conditioned inhibition of reward, and retardation of fear acquisition. The main sex difference, which was not estrous-dependent, was the lack of conditioned inhibition of freezing in females. These data imply that while the inhibitor cue gained some inhibitory value in the females, the strength of this inhibitory value may not have been great enough to effectively downregulate freezing elicited by the fear cue.
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    Correction: High-intensity sweet taste as a predictor of subjective alcohol responses to the ascending limb of an intravenous alcohol prime: an fMRI study
    (Springer Nature, 2024) Alessi, Jonathan; Dzemidzic, Mario; Benson, Katherine; Chittum, George; Kosobud, Ann; Harezlak, Jaroslaw; Plawecki, Martin H.; O’Connor, Sean J.; Kareken, David A.; Neurology, School of Medicine
    Correction to: Neuropsychopharmacology 10.1038/s41386-023-01684-3, published online 07 August 2023 The publication date for reference 21 was corrected from 2016 to 1977. The correct reference should read “Radloff LS. The CES-D Scale. Appl Psychol Meas. 1977;1:385–401”. The original article has been corrected.
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    Determination of the Rewarding Capacity of Edible and Injected Delta-9-Tetrahydrocannabinol in Adolescent and Adult Mice
    (2020-05) Smoker, Michael P.; Lapish, Christopher C.; Boehm II, Stephen L.; Goodlett, Charles R.; Mackie, Kenneth P.
    Cannabis (and its main psychoactive component, THC) is one of the most widely-used drugs in the world, and recent expansion of its legal status has made it available in a variety of formulations and at a potency unrivaled in history. While its medicinal properties are gaining scientific support, so too is its potential to lead to abuse and dependence. Both initiation of cannabis use and frequent cannabis use are most prevalent in adolescence, and compared to adults, cannabis use by adolescents is associated with a greater likelihood of developing cannabis dependence and cannabis use disorder. Given the ethical limitations surrounding research that provides cannabis to non-users or non-adults, animal models of drug use can be valuable tools for the study of causes and consequences related to drug use, as well as allowing for investigating brain mechanisms underlying these factors. However, only recently have models in which animals reliably use cannabis (THC) at levels above its respective vehicle and at levels which produce consistent behavioral and physiological effects become available, and in no case has age-related differences in this use been examined. Thus, one goal of the current study was to directly compare the self-administration of edible THC (a route of administration used by humans and a formulation increasing in popularity) between adolescent and adult mice. Adolescents also appear to be differentially sensitive to various effects of several classes of drugs, and they have been shown to be less sensitive to the aversive effects of cannabis, thereby putting them at greater risk for elevated and continued use. Evidence also suggests that, in addition to the risk associated with adolescent cannabis use, having initial positive subjective experiences resulting from its use is a strong predictor of subsequent cannabis dependence. Thus, the second goal of the current study was to use the place conditioning paradigm to examine the reward- (or aversion-) inducing properties of THC in adolescent and adult C57BL/6J mice, using both the traditional experimenter-administered THC (via injection) as well as edible THC self-administration. Prior to initiating these THC studies, sensitivity of the place conditioning procedure to age-related differences in drug-induced reward was validated using cocaine, yielding locomotor stimulation in both ages and a decreased sensitivity to cocaine’s rewarding properties in adolescent mice. When provided limited access to edible THC dough in doses ranging from 0.0 to 6.0 mg/kg, mice showed a dose-dependent reduction in consumption across access sessions, and this reduction was more rapid in adult mice at the highest doses, suggesting that adolescent mice might have been less sensitive to its aversive properties. These same mice, as well as a separate group of mice receiving injection (also 0.0 to 6.0 mg/kg THC), were given place conditioning sessions, alternating between THC dough and control dough or THC injection and vehicle injection, for 6 days per week and were tested once per week across a total of 3 weeks. Mice conditioned using edible THC showed a neutral response (neither reward nor aversion) at all doses. However, mice conditioned using injected THC showed a conditioned place aversion to the highest dose, which was more pronounced in adult mice. Interestingly, in mice self-administering edible THC, the dose of THC consumed was related to the outcome of place conditioning, such that a conditioned place preference was observed for adult mice which shifted their consumption of 3.0 mg/kg edible THC downward relative to those mice with full consumption of 3.0 mg/kg, and for adolescent mice which had the highest degree of consumption of 6.0 mg/kg edible THC relative to those mice with the lowest consumption of 6.0 mg/kg. Furthermore, initial place preference outcomes at the individual level at test 1 predicted subsequent doses of edible THC consumed, suggesting mice adjust their self-administration of edible THC based on the subjective experience it produces. Besides its impact in place conditioning, THC also had differential effects on body weight and locomotor activity based on age and route of administration. Collectively, this project demonstrates that adolescent mice are less sensitive to the hedonic properties of both cocaine and THC, and that differences in edible THC self-administration between ages, and between individuals within an age, are likely related the subjective experience of its rewarding and aversive properties.
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    Differential importance of nucleus accumbens Ox1Rs and AMPARs for female and male mouse binge alcohol drinking
    (Springer Nature, 2021-01-08) Kwok, Claudina; Lei, Kelly; Pedrozo, Vincent; Anderson, Lexy; Ghotra, Shahbaj; Walsh, Margaret; Li, Laura; Yu, JiHwan; Hopf, Frederic Woodward; Psychiatry, School of Medicine
    Alcohol use disorder exhausts substantial social and economic costs, with recent dramatic increases in female problem drinking. Thus, it is critically important to understand signaling differences underlying alcohol consumption across the sexes. Orexin-1 receptors (Ox1Rs) can strongly promote motivated behavior, and we previously identified Ox1Rs within nucleus accumbens shell (shell) as crucial for driving binge intake in higher-drinking male mice. Here, shell Ox1R inhibition did not alter female mouse alcohol drinking, unlike in males. Also, lower dose systemic Ox1R inhibition reduced compulsion-like alcohol intake in both sexes, indicating that female Ox1Rs can drive some aspects of pathological consumption, and higher doses of systemic Ox1R inhibition (which might have more off-target effects) reduced binge drinking in both sexes. In contrast to shell Ox1Rs, inhibiting shell calcium-permeable AMPA receptors (CP-AMPARs) strongly reduced alcohol drinking in both sexes, which was specific to alcohol since this did not reduce saccharin intake in either sex. Our results together suggest that the shell critically regulates binge drinking in both sexes, with shell CP-AMPARs supporting intake in both sexes, while shell Ox1Rs drove drinking only in males. Our findings provide important new information about sex-specific and -general mechanisms that promote binge alcohol intake and possible targeted therapeutic interventions.
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    Distinct cortico-striatal compartments drive competition between adaptive and automatized behavior
    (Public Library of Science, 2023-03-21) Barnett, William H.; Kuznetsov, Alexey; Lapish, Christopher C.; Psychology, School of Science
    Cortical and basal ganglia circuits play a crucial role in the formation of goal-directed and habitual behaviors. In this study, we investigate the cortico-striatal circuitry involved in learning and the role of this circuitry in the emergence of inflexible behaviors such as those observed in addiction. Specifically, we develop a computational model of cortico-striatal interactions that performs concurrent goal-directed and habit learning. The model accomplishes this by distinguishing learning processes in the dorsomedial striatum (DMS) that rely on reward prediction error signals as distinct from the dorsolateral striatum (DLS) where learning is supported by salience signals. These striatal subregions each operate on unique cortical input: the DMS receives input from the prefrontal cortex (PFC) which represents outcomes, and the DLS receives input from the premotor cortex which determines action selection. Following an initial learning of a two-alternative forced choice task, we subjected the model to reversal learning, reward devaluation, and learning a punished outcome. Behavior driven by stimulus-response associations in the DLS resisted goal-directed learning of new reward feedback rules despite devaluation or punishment, indicating the expression of habit. We repeated these simulations after the impairment of executive control, which was implemented as poor outcome representation in the PFC. The degraded executive control reduced the efficacy of goal-directed learning, and stimulus-response associations in the DLS were even more resistant to the learning of new reward feedback rules. In summary, this model describes how circuits of the dorsal striatum are dynamically engaged to control behavior and how the impairment of executive control by the PFC enhances inflexible behavior.