The effectiveness of videotape recorded feedback on reducing the rate of inappropriate, bizarre mannerisms n hospitalized individuals was examined using a multiple baseline design across three subjects. Results indicate that the technique was effective in reducing the rate of these behaviors in the treatment setting. Data on generalization of treatment effects were inconclusive. Theoretical explanations for the procedure's effectiveness are discussed.

Indiana University-Purdue University Indianapolis (IUPUI) / Extrasynaptic GABAA receptors, often identified as those containing both α4 and δ subunits, appear to be a target for the actions of alcohol (ethanol) at relatively low concentrations, perhaps suppressing the activity of GABAergic interneurons which regulate activity in the mesolimbocortical circuit. Pharmacological studies in rodents using the δ-subunit selective agonist Gaboxadol (THIP) have found both promotional and inhibitory effects on alcohol consumption. The goal of this project was to determine the role of extrasynaptic GABAA receptors located in the infralimbic cortex (ILC) in the binge-like alcohol intake of male C57BL/6J (B6) mice. The ILC is of interest due to its demonstrated involvement in stress reactivity and alcohol exposure has been shown to interfere with extinction learning; impairments of which may be related to inflexible behavior (i.e. problematic alcohol consumption). Adult male B6 mice were bilaterally implanted with stainless steel guide cannulae aimed at the ILC and were offered limited access to 20% ethanol or 5% sucrose for 6 days. On day 7, mice were bilaterally injected with 50 or 100 ng THIP (25 or 50 ng per side respectively) or saline vehicle into the ILC. It was found that the highest dose of THIP (100 ng/mouse) increased alcohol intake relative to vehicle controls, although control animals consumed relatively little ethanol following infusion. Furthermore, THIP had no effect on sucrose consumption (p > 0.05), suggesting that the effect of THIP was selective for ethanol consumption. Together, these findings suggest that the mice that consumed ethanol may have been particularly reactive to the microinfusion process relative to animals that consumed sucrose, perhaps because ethanol consumption was not as reinforcing as sucrose consumption. In addition, the observation that THIP effectively prevented the decrease in ethanol intake on day 7 induced by the microinjection process may be related to a role for the ILC in adaptive learning processes, which in turn, promote behavioral flexibility.

Indiana University-Purdue University Indianapolis (IUPUI) / Background: Previous studies show that prazosin, an α1-adrenergic receptor antagonist, decreases alcohol drinking in animal models of alcohol use and dependence and in alcohol-dependent men. These studies extended previous findings by using a paradigm that allows for separate assessment of prazosin on motivation to seek versus consume ethanol or sucrose in selectively bred rats given acute or chronic prazosin treatment. Methods: Alcohol-preferring P rats were trained to complete an operant response that resulted in access to either 2% (Exp. 1) or 1% (Exp.2) sucrose or 10% ethanol. In Experiment 1, a 4-week consummatory testing phase consisted of rats bar-pressing to “pay” a specified amount up front to gain access to unlimited ethanol (or sucrose) for a 20-minute period. A 4-week appetitive testing phase examined how much the rats would bar-press for ethanol in an extinction session when no reinforcer could be obtained. In Experiment 2, during testing, the response requirement was dropped to a 1 and daily session cycles of drug (3 weeks/ 14 sessions from Tues to Fri) or vehicle (2 weeks/ 9 sessions from Tues to Fri) treatment were alternated per drug dose for a total of 3 drug doses (3 cycles) per rat. After each drug cycle, a single non-reinforced extinction session was conducted with no drug ‘on board’ and no reinforcer access. On test days, rats were given IP injections of either vehicle or one of three doses of prazosin (Exp 1: 0.5, 1.0, 1.5 mg/kg; Exp 2: 0.25, 0.5, 1.0 mg/kg; balanced design; -30 min). Results: In Experiment 1, prazosin significantly decreased ethanol-seeking at all doses tested. The highest dose decreased ethanol intake and increased the latency to first lever-press and first lick. Sucrose-seeking and intake were decreased by the same doses of prazosin. In Experiment 2, prazosin significantly decreased reinforcer-seeking at the lowest and highest doses while ethanol intake was not decreased by prazosin. Conversely, sucrose-seeking was decreased at the highest dose of prazosin tested while sucrose consumption was decreased by all doses. Latency to lever-press for sucrose was increased by the lowest dose of prazosin compared to vehicle. Conclusions: These findings extend previous research and indicate that prazosin decreases motivation to seek ethanol and sucrose. The specificity of prazosin on different behaviors and over different reinforcers suggests that these findings are not due to prazosin-induced motor-impairment or malaise. These data suggest that prazosin may work by decreasing the reinforcing properties of reinforcers in general.

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.

Indiana University-Purdue University Indianapolis (IUPUI) / Assessments of delay discounting in rodent lines bidirectionally selected for home cage intake and preference of alcohol have had mixed findings. The current study sought to examine if delay discounting related differentially to alcohol seeking versus and alcohol drinking, two processes underlying alcohol intake and preference. Three strains of rats were utilized to answer this question Long Evans (LE), high alcohol drinking rats (HAD2), and alcohol preferring P rats. All strains were compared in an adjusting amount delay discounting task. Operant self-administration of alcohol was then assessed in the sipper tube model, and finally home cage drinking was assessed in a 24 hour 2 bottle choice paradigm. In the delay discounting it was found that the P rats were steeper discounters than both the LE and HAD2. In the sipper tube model, P rats displayed higher levels of seeking than both the HAD2s and the LE, but both the P rats and the HAD2s had higher intakes than the LE. During 24 hour home cage access, the P rats and the HAD2s had higher intake and preference for alcohol than the LE, but were not different from each other. These results show that increased discounting of delayed rewards tracks with appetitive processes versus consummatory factors and home cage intake of alcohol. This builds on prior findings using selected line pairs by providing an explanation for discordant results, and supports the hypotheses that increased delay discounting is an intermediate phenotype that predisposes individuals to alcohol use disorders.

Indiana University-Purdue University Indianapolis (IUPUI) / Losing a job or a significant other are examples of incentive shifts that result in negative emotional reactions. The occurrence of negative life events is associated with increased drinking, and alleviation of negative emotions has been cited as a drinking motive for individuals with problematic drinking patterns (Keyes et al., 2011; Adams et al., 2012). Further, there is evidence that certain genotypes drink alcohol in response to stressful negative life events (Blomeyer et al., 2008; Covault et al., 2007). It is possible that shared genetic factors contribute to both alcohol drinking and emotional reactivity, but there is a critical need for this relationship to be understood. The first aim of this proposal will use an incentive downshift paradigm to address whether emotional reactivity is elevated in mice predisposed to drink alcohol. The second aim of this proposal will address if reactivity to an incentive shift can result in rash action using a differential reinforcement of low rates of responding task, and whether this response is also associated with a predisposition for high drinking. The third aim of this proposal will investigate if experimenter administered ethanol reduces contrast effects, and if an incentive shift increases ethanol consumption in a high drinking line. The overall goal of this proposal is to investigate whether reactivity to incentive shift is an important mechanism underlying alcohol drinking in these mice, and the role an incentive shift may play in producing rash action and influencing ethanol consumption.

Indiana University-Purdue University Indianapolis (IUPUI) / Alcoholism inheritance rates have been estimated as high as 60% in a human population. Many significant features of alcohol dependence have been replicated in rodent animal models of alcoholism, however not in totality. These animal models include inbred preferring (iP) and nonpreferring (iNP) rat types. Congenic rats have been engineered from the iP and iNP strains whereby a P congenic rat has in its genome a well-chosen chromosomal portion taken from an NP rat (P.NP) and, reciprocally, an NP congenic rat has acquired the analogous DNA from a P rat (NP.P). In this case, a quantitative trait locus (QTL) from chromosome 4 is the donor genetic material for the congenic rats. It is of great interest to further study this chromosome 4 QTL because it has been found to control a significant portion of ethanol consumption behavior in iP and iNP rats. This study aimed to behaviorally profile the iP, iNP and reciprocal congenic rats. As a result of the behavioral profiling of these genetically related groups, some conclusions could be made regarding which behaviors appear to be controlled by the chromosome 4 donor DNA.This study primarily utilized the Multivariate Concentric Square Field apparatus (MCSF) to characterize behavioral profiles for the inbred and congenic rats. The Open field (OF) and Elevated plus maze (EPM) supported this effort. The MCSF is valuable in that it allows for the animals to interact within an environment that has ethological value. The 12 different zones that make up the field are characterized by some functional quality in terms of type and duration of behavior performed, etc. The behavioral data is aggregated and finally represented in terms of five functional categories, the elements of the behavioral profile: general activity, exploratory activity, risk assessment, risk taking, and shelter seeking. The study hypotheses were shaped by prior research suggesting that iPs should display lower general activity and risk taking strategy than iNPs in the MCSF. Inbred Ps should be more active in the OF and spend more time in the center of the EPM. Generally, it is expected that the iP QTL confer behavioral phenotypes to the iNP strain that deviate toward a "P" behavioral phenotype and reciprocally, the iNP QTL confer behavioral phenotypes to the iP strain that deviate toward an "NP" behavioral phenotype. The results showed that iP rats performed more risk assessment and risk taking behavior and less shelter seeking and anxiety-like behavior than iNP rats. It followed that P.NP congenic rats significantly downgraded their risk assessment and risk taking behavior when compared to iP rats. This decrease can be attributed to the chromosome 4 QTL donated from the iNP breed. All together this study concludes that risk assessment and risk taking behavior in the iP rats is controlled by the same DNA region that, in part, determines voluntary intake of ethanol consumption. Further fine mapping of the QTL region should help in discovering if the same DNA sequences that influence ethanol intake also significantly influence risk behavior.