Indiana University-Purdue University Indianapolis (IUPUI) / Background: Group II metabotropic glutamate receptors (mGluR2/3) are predominately presynaptically located Gi/o coupled receptors that are highly expressed in the cortex, nucleus accumbens, amygdala, and hippocampus. Previous studies suggest that group II mGluRs are involved in regulating ethanol (EtOH) consumption and seeking following extinction (Backstrom and Hyytia, 2005; Kufahl, et al., 2011). The sipper tube model, which allows for procedural separation of seeking and consumption, was used to further clarify the role of mGluR2/3 in EtOH-seeking and consumption. The non-selective group II mGluR agonist LY379268 (LY37) and selective mGluR2 positive allosteric modulator (PAM) BINA were used to determine the relative contribution of mGlu2 and mGlu3 receptors on EtOH seeking and consumption. Following characterization of the agonist and PAM on EtOH reinforcement, a microinjection study was performed examining the effect of blockade of nucleus accumbens core mGluR2/3 on systemic agonist induced suppression of EtOH-seeking. Methods: For the systemic agonist/PAM experiments, separate groups of male Wistar rats [n=8-9 group; LY37 (0-2.0 mg/kg) and BINA (0-20 mg/kg)] were trained to complete a response requirement (RR) of 10 lever presses that resulted in access to 10% EtOH or 2% sucrose (in separate groups) for a 20-minute drinking period. For consummatory testing, animals received weekly drug injections with a RR1. The RR was then increased over sessions to a RR20. For appetitive testing, animals received weekly drug injections followed by a non-reinforced extinction session. To determine effects of blockade of NAc core mGluR2/3 receptors on agonist-induced suppression of EtOH-seeking, a separate group of male Wistar rats (n=15) was trained to complete a RR10 for access to 10% EtOH. Animals were surgically implanted with bilateral guide cannulae terminating 1mm above the NAc core. Following recovery, animals received four sets of microinjections in a balanced design (systemic vehicle + core vehicle, systemic LY37 + core vehicle, systemic LY37 + core LY34, and systemic vehicle + core LY34). A final non-balanced microinjection of LY37 was then performed. Results and Conclusions: Systemic administration of the mGluR2/3 agonist LY37 significantly reduced EtOH- and sucrose- seeking with no systematic effect on locomotion. Systemic administration of the selective mGluR2 PAM BINA had no significant effect on either seeking or consumption. These findings suggest that modulation of glutamatergic neurotransmission by a systemic mGluR2/3 agonist, but not allosteric modulation of mGluR2, significantly reduces reinforcer seeking. Intra- accumbens core administration of LY37 significantly reduced EtOH-seeking, suggesting a role of NAc core mGluR2/3 modulation in EtOH-seeking during maintenance drinking. Systemic administration of LY37 was also found to significantly reduce sucrose consumption and body weight 24-hours following systemic administration, meriting further examination of the role of mGluR2/3 receptors on feeding behavior.

Indiana University-Purdue University Indianapolis (IUPUI) / Harmful alcohol use is a global concern, which has made research in this area a prime public health interest. Previous research has identified alcohol-related attentional biases (Cox et al., 2002, 2007; Marissen et al., 2006; Streeter et al., 2008) and impulsivity (see Acton, 2003; Dick et al., 2010; Mulder, 2002) as two important predictors that affect alcohol use, seeking, and relapse (Cox et al., 2002; Robbins & Ehrman, 2004). Recent review of the literature has also revealed that there is a significant relationship between these two constructs (Coskunpinar & Cyders, 2013). The current study used college undergraduate social drinkers (at least 3 drinks per week) (n = 42, mean age = 23.27 (SD = 5.21), female: 69.2%) to examine the relationship between specific trait impulsivity facets and alcohol-related attentional biases and to examine how this relationship is affected by measurement type (eye movement, reaction time measures), attentional bias constructs (initial orientation, delayed disengagement), and environmental cues (specifically mood and alcohol olfactory cues). Participants had alcohol-related attentional bias as measured by reaction time (areas of interest: p < .05) and eye-movement data (areas of interest: p < .05), which was not affected by mood, odor, or urgency.

Humans’ social relationships determine to a large degree their trajectories in life. Despite strong evidence for the impact of interpersonal relations on wellbeing, the causal links between the two are not yet fully understood. This dissertation offers a new perspective on the mechanisms through which social ties influence negative (excessive drinking) and positive (participation in recreational activities) health behaviors. In three studies employing a unique combination of social network, fMRI, and experience-sampling methods, we propose that health decisions are the result of complex computations involving prior social experiences, perceived social norms, social comparison processes, and current feelings of connections. Each chapter of this dissertation discusses one of these three studies. Chapter 1 provides evidence that past social experiences shape valuations of new information by showing that pairs of students that drink often together tend to have more similar neural responses to novel alcohol cues in regions associated with affective self-generated thought. In addition, this Chapter suggests that researchers must consider the intricate interplay between individuals’ personal goals and their communities’ norms to understand the influence of social environments on neural representations. The degree to which students aligned their neural response patterns to alcohol with those of their peers depended on interactions between their individual motives for drinking and their group’s approval of this behavior. Chapter 2 presents novel findings that people spontaneously represent social information from multiple networks (e.g., popularity and leadership) at a neural level in social cognition (right TPJ, dmPFC) and valuation (vmPFC) regions. Importantly, individuals who display higher neural sensitivity to status differences are also more likely to align their drinking behavior with their group norms in daily life. Together, our results provide insight into the neural mechanisms through which social comparison processes shape conformity and suggest social cognition and valuation regions as important hubs orchestrating this process. While Chapter 1 and Chapter 2 focus on the influence of social ties on drinking, Chapter 3 discusses the protective role of close relations during difficult times. We provide evidence that close college friendships, even if afar, helped young adults cope with the stress of the COVID-19 pandemic. Follow-up between- and within-individual analyses reveal that this buffering effect could be explained by differences in the quality of online interactions (e.g., via phone, text messaging), instances of personal disclosure, and participation in enjoyable activities. All in all, this dissertation advances our understanding of why measures of social wellbeing are the best predictor of health trajectories in life, by highlighting the important role social ties play in shaping valuation of new information, guiding behavior to meet social goals, and protecting against stress by allowing people to engage in recreational activities.

Department of Psychology / PhD (Psychology)

Indiana University-Purdue University Indianapolis (IUPUI) / Prior research indicated a high prevalence of problematic drinking among college students, suggesting a need for more effective screening approaches and treatments. The tendency to act rashly in face of strong emotions (e.g. positive and negative urgency), alcohol cravings, and cue reactivity all have been associated with problematic alcohol use. However, no studies have examined the interactive effects of alcohol cravings, urgency, and cue reactivity. I hypothesized that alcohol cravings will be associated with greater problematic drinking among individuals with higher levels of (1) urgency, (2) cue reactivity, and (3) cue reactivity and urgency. Data were collected from a sample (final n = 240) of college students through a survey, which consisted of measures of urgency, problematic drinking, and alcohol cravings. On the survey, participants were also exposed to alcohol and non-alcohol pictures, after which they assessed their level of cue reactivity. Results were examined using multiple regression and simple slope analyses. Results provided partial support for our hypotheses. Alcohol cravings were associated with greater problematic drinking at lower levels of negative urgency (b = 7.36, p< 0.001). Furthermore, alcohol cravings were most strongly associated with problematic drinking at high levels of cue reactivity and low levels of negative urgency (b = 8.69, p<0.001), and at low levels of cue reactivity and high levels of positive urgency (b = 6.56, p<0.001). These findings emphasize the importance of considering urgency and cue reactivity in understanding how alcohol cravings create risk for problematic drinking.

Indiana University-Purdue University Indianapolis (IUPUI) / Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is found in heavy alcohol users. Negative urgency is a personality trait reflecting the tendency to act rashly in response to negative emotional states, and is associated with problematic alcohol consumption. The current study examined the relationship between negative urgency and HPA axis functioning following (1) negative mood induction and (2) intravenous alcohol administration among heavy social drinkers (proposed n = 40). I hypothesized the following: (1) Negative mood induction would result in an increase of cortisol release as compared to neutral mood induction; (1a) Negative urgency would be related to increased cortisol release in response to negative mood induction; (1b) Negative urgency would partially mediate the relationship between mood induction and cortisol release; (2) Acute IV alcohol administration would result in increased cortisol levels in the neutral mood condition, but decreased cortisol levels in the negative mood condition; and (2a) Negative urgency would be related to the suppression of cortisol release in the negative mood condition in response to acute IV alcohol administration. Repeated measures analyses of variance, the PROCESS macro, and paired samples t-tests were used to examine study hypotheses. Hypotheses were largely unsupported. Writing mood induction procedures reduced salivary cortisol levels in negative mood (t(35)= 2.49, p= 0.02) and there was a trend decrease in neutral mood (t(35)= 1.87, p= 0.07). Alcohol administration also reduced salivary cortisol levels in both negative mood (t(35)= 3.99, p< 0.01) and neutral mood (t(35)= 2.60, p= 0.01). However, salivary cortisol changes were no different than typical circadian patterns in response to mood induction (t(231)= 0.37, p=0.71) or in response to acute alcohol administration (t(231)= 0.44, p= 0.64). Negative urgency had a trend main effect on salivary cortisol level in response to acute IV alcohol administration, such that those higher in negative urgency were more similar to typical circadian patterns (F(19,28)= 1.59, p=0.13). This could serve as preliminary support for a psychological mechanism for the alcohol sensitivity hypothesis. Overall these findings suggest the current study failed to sufficiently manipulate salivary cortisol levels. Future studies should consider methodological techniques when exploring these relationships, including IV compared to oral alcohol administration, mood compared to stress manipulations, and cortisol compared to other HPA axis biomarkers.

Indiana University-Purdue University Indianapolis (IUPUI) / Alcohol consumption produces a complex array of effects that can be divided into two types: the explicit pharmacological effects of ethanol (which can be quite separate temporally from time of intake) and the more temporally “relevant” effects (primarily olfactory and taste) that bridge the time from intake to the onset of the pharmacological effects. Dissociating these effects is essential to untangling the neurologic underpinnings of alcohol abuse and dependence. Intravenous self-administration of ethanol allows for controlled and precise dosing, bypasses first order absorption kinetics allowing for a faster onset of pharmacologic effects, and eliminates the confounding “non-pharmacological” effects associated with oral consumption. Intravenous self-administration of ethanol has been reliably demonstrated in both mouse and human experimental models; however, consistent intravenous self-administration of pharmacologically relevant levels of ethanol remains elusive in the rat. Previous work has demonstrated reliable elevated intravenous ethanol self administration using a compound reinforcer of oral sucrose and intravenous ethanol. The present study sought to elucidate the role of each component of this reinforcer complex using a multiple schedule study design. Male P rats had free access to both food and water during all intravenous self-administration sessions and all testing was performed in conjunction with the onset of the dark cycle. Once animals achieved stable operant responding on both levers for an orally delivered 1% sucrose solution (1S) on a FR4 schedule, surgery was conducted to implant an indwelling jugular catheter. Animals were habituated to the attachment of infusion apparatus and received twice daily sessions for four days to condition each lever to its associated schedule. Animals were then trained to respond on a multiple FR4-FR4 schedule composed of alternating 2.5 minute components. During one component only oral 1S was presented, while in the second component a compound reinforcer of oral 1S + IV 20% ethanol was presented (25 mg/kg/injection). Both levers were extended into the chamber during the session, with the active lever/schedule alternating as the session progressed across components. Average ethanol intake was 0.47 ± 0.04 g/kg. A significant increase in sucrose only reinforcers and sucrose lever error responding was found suggesting that sucrose not ethanol is responsible for driving overall responding. The current findings suggest that the existing intravenous ethanol self-administration methodology remains aversive in the rat.

The purpose of this qualitative study was to understand the social, cultural, and structural factors that contribute to or inhibit alcohol use and abuse in the Army among young males, unmarried or married without a present spouse. Seventeeen single, or separated, young male soldiers stationed at Fort Bragg Army Base were interviewed to provide insight into the research questions. Soldiers were largely located through face-to-face canvassing. The interviews, which lasted from 45 to 90 minutes, took place face-to-face and were then transcribed. Interviews were analyzed using grounded theory approach by locating patterns, themes and relationships to come to generalizations. The themes that emerged from the interviews include: 1) stresses of army work/life; 2) social/entertainment use; 3) tradition/brotherhood/entitlement; 4) fear/consequences; 5) impressionable youth; 6) treatment. While the themes which emerged were reported in discrete terms, there was overlap in them. The functional aspect of alcohol use to these soldiers mixed with the impact of social interaction influencing their use served to encourage and further the use of alcohol. The drinking patterns of young male soldiers can be seen to exist on a continuum of either social integration or social stress, in line with Durkheim's conception of suicide, with the existence of being on either end of these continuums leading to excessive alcohol use. The findings confirm Durkheim's conception of social order in leading to unhealthy responses and indicate the Army needs to address the role and impact of the greater social environment in leading to alcohol misuse among young male soldiers.

Thesis (D. Tech.) -- Central University of Technology, Free State, 2008 / The purpose of this study was to evaluate brewing and consumption practices and to screen for micro-organisms and mycotoxins associated with traditional beer produced and consumed in the marginal urban settlements of the city of Kimberley in the Northern Cape Province of South Africa. The survey study revealed that traditional beer is no longer being brewed for traditional purposes only, as was the case in the past, but rather for commercial gain. Both brewers and consumers, however, appeared to be largely unaware of disease-causing micro-organisms present on the hands or bodies of handlers that can be transferred to the beverage during the handling process, and were seemingly not conversant with regard to the effects of hazardous ingredients sometimes incorporated during the brewing process. Unemployment and a lack of education emerged as pivotal factors related to the production of traditional beer and the ignorance of the associated safety thereof. The survey further indicated that although facilities such as the availability of potable water (taps in yards) and flushing toilets were sometimes in place, other facilities such as basins with hot running water were often not available. In commercially produced and homebrewed traditional beer the mean counts for total coliforms and Staphylococcus spp. were circa 105 cfu.ml-1 whereas the TVC (Total Viable Counts) and total fungi counts were 106 and 107 cfu.ml-1 respectively. The total coliforms and Staphylococcus spp. counts for homebrewed traditional beer were approximately one log-phase higher than the commercial version. The counts in the homebrewed beer probably originated from contamination during handling, while in the commercial product contamination originated either in the raw ingredients or during postprocessing and consumption. Apart from staphylococci, considerable numbers of total coliforms indicating faecal contamination were noted. A rapid, easy, reliable and accurate technique that could be used to quantify the level of mycotoxins (deoxynivalenol and citrinin) in the beer was developed through validation of the ELISA Ridascreen methodology. Using this method, the deoxynivalenol (DON) level in the beer samples was found to exceed the recommended levels suggested by the European Union, while citrinin levels in the samples varied between 35.6 ppb and 942.2 ppb. In the case of citrinin there were statistically significant differences between spring, summer and winter samples, confirming the seasonal impact on fungal growth and consequent mycotoxin production. An R2-value of 0.409 was noted between DON and citrinin, indicating a weak positive association. Finally, an awareness programme in the format of a poster with accompanying subscripts was developed to address issues of safety and hygiene of traditional beer in the study area. The poster utilises animatedstyle colour images of selected practices that need to be addressed, accompanied by slogans summarising the particular image in English, Afrikaans and Setswana. It is envisaged that, as part of a comprehensive awareness programme, the poster will contribute greatly to the quality, safety and promotion of traditional beer in the area.

Indiana University-Purdue University Indianapolis (IUPUI) / It has traditionally been posited that women show a "telescoped" development of alcohol use disorders (Kuhn, 2011). In particular, a number of clinical studies support striking sex differences in the progression from initial use of alcohol to dependence on the compound; with women showing a faster progression through landmark events associated with the development of alcohol addiction (Randall et al., 1999). However, recent studies have challenged this tenet (Keyes et al., 2010). The work presented herein was designed to determine whether females are indeed more vulnerable to the development of behavioral maladaptations following binge drinking and whether sex differences in GABA(A) receptor regulation might underlie this vulnerability. Using a mouse model of binge drinking this dissertation established that, compared to males, females escalate their binge drinking at a faster rate and maintain altered responsivity to the locomotor effects of alcohol after extended abstinence from binge drinking. Female mice also displayed significant increases in ethanol preference and intake in a continuous, two-bottle choice protocol following a shorter history of binge drinking than males. The final goal was to determine if binge drinking results in unique patterns of anxiety- or depressive-like symptoms in males and females and whether these behaviors would be associated with the dimorphic regulation of GABAA receptor subunits across the prefrontal cortex and hippocampus. Male binge drinkers displayed anxiety-like behavior during early withdrawal that dissipated after 2 weeks of abstinence. There were no significant changes in the expression of delta or gamma2 GABAA receptor subunit mRNA at this time point in the regions analyzed. Females also showed temporary anxiety-like behavior during early withdrawal from binge drinking. Additionally, females displayed significant depressive-like behavior after 2 weeks of abstinence from binge drinking. In particular, diestrus-phase females displayed significantly greater immobility in the forced-swim test after ethanol exposure and no longer maintained the reduced swim-time behavior associated with this phase of the cycle at baseline (when compared to the estrus-phase). qPCR analysis of hippocampal tissues from diestrus females supported a significant reduction in expression of gamma2 GABA(A) subunit mRNA after binge drinking. This effect was not noted for RNA isolated from hippocampal tissues taken during the estrus phase of bingers. These final data suggest possible interaction of estrous-cycle and binge drinking history that may result in the unique expression of deficits following binge drinking for females. Taken together, this work supports sex and estrous dependent effects of binge drinking on behavior and gene regulation.