Sucrose fading was used to initiate self-administration of ethanol on an FR4 schedule in male Fischer 344 rats. Rats showed low response rates for ethanol alone. After administration of liquid diet containing ethanol, ethanol intake increased over levels prior to administration of the liquid diet. In situ hybridization compared mRNA for the inducible or constitutive 70 kD heat shock proteins in ethanol and nonethanol rats. Both inducible and constitutive mRNAs were found in nonethanol and ethanol tissues. In peripheral organs, radiolableling was higher in ethanol tissue. In brain regions, nonethanol tissues showed higher radiolabeling.

CNPQ / A exposição aguda, sub-crônica ou crônica ao etanol está envolvida com diversos problemas que afetam o cérebro e o sistema nervoso central, provocando déficits de aprendizagem e memória de curto ou longo prazo. Compostos bioativos como carotenoides, são novas opções terapêuticas capazes de reduzir os déficits de memória e atuar na redução do risco de doenças e manutenção da saúde. Neste sentido, a luteína, um carotenoide que contribui contra o estresse oxidativo, pode atuar como uma droga capaz de modificar ou atenuar os danos neuronais e os déficits de memória induzidos por etanol. Assim, no presente estudo foi avaliado o efeito da luteína sobre os déficits de memória induzidos por etanol em ratos na tarefa de reconhecimento de objetos. Os resultados encontrados demonstraram que a administração de luteína (100 mg/kg) melhorou a memória dos ratos na tarefa de reconhecimento de objetos [F(3,34) = 7,13; p < 0,05], enquanto as doses de 15 ou 50 mg/kg não apresentaram efeito; a administração sub-crônica de etanol (3 g/kg) causou déficit de memória em ratos na tarefa de reconhecimento de objetos [F(3,37) = 3.06; p < 0.05]; e a de luteína (50 mg/kg) preveniu o déficit de memória induzido pelo etanol [F(3,39) = 7.64; p < 0.05]. Além disso, a administração de luteína, etanol e a combinação luteína e etanol não alteraram os parâmetros de estresse oxidativo avaliados no córtex e hipocampo. Sugerindo que a prevenção do déficit de memória induzido por etanol não envolve estresse oxidativo no córtex e hipocampo. Assim, baseado nos resultados obtidos, a luteína pode ser considerada uma alternativa no tratamento dos déficits de memória induzidos por etanol, entretanto, mais estudos são necessários para avaliar o mecanismo envolvido neste efeito. / The acute exposure, sub-acute or chronic is involved with various problems affecting the brain and central nervous system, resulting in learning deficits and short or longterm memory. Bioactive compounds such as carotenoids, are new therapeutic options able to reduce memory deficits and act in reducing the risk of diseases and health maintenance. In this sense, lutein, a carotenoid that contributes against oxidative stress, can act as a drug able to modify or reduce neuronal damage and memory deficits induced by ethanol. Thus, this study evaluated the effect of lutein on memory deficits in rats induced by ethanol in the object recognition task. The results showed that lutein administration (100 mg/kg) improved the memory of rats in the recognition task objects [F(3,34) = 7.13; p < 0.05], while doses of 15 or 50 mg / kg showed no effect; the sub-chronic administration of ethanol (3 g/kg) caused memory deficit in rats recognition task objects [F(3,37) = 3.06; p < 0.05]; and lutein (50 mg/kg) prevents the memory deficit induced by ethanol [F(3,39) = 7.64; p < 0.05]. Furthermore, lutein administration, ethanol and combination lutein and ethanol did not change the parameters of oxidative stress evaluated in the cortex and hippocampus. This suggests that the prevention of memory deficits induced by ethanol does not involve oxidative stress in the cortex and hippocampus. Thus, based on the results obtained, lutein may be considered an alternative in the treatment of memory deficits induced by ethanol, however, more studies are needed to evaluate the mechanism involved in this effect.

Indiana University-Purdue University Indianapolis (IUPUI) / The present study sought to identify the effects of chronic lithium administration on ethanol intakes in high alcohol-preferring (HAP) mice. Lithium is a well-established treatment for bipolar disorder and has demonstrated efficacy in reducing impulsivity, an endophenotype of the disease. Impulsivity is also a prominent trait of alcoholism. HAP mice display a preference for consuming substantial amounts of ethanol and exhibit abnormally high levels of impulsivity. Previous work has determined that chronic lithium exposure in HAP mice reduces their levels of impulsivity. The present study analyzed fluctuations in established intake patterns after lithium exposure and how pre-exposure to lithium would affect ethanol intake acquisition. The results showed an increase in ethanol intake and no change in preference for ethanol over water in lithium treated mice. There was an increase in overall total fluid consumption in these mice, likely resulting from polydipsic effects. There also appeared to be a potentiated lithium toxicity effect found in those mice pre-exposed to lithium. The conclusion was that lithium therapy does not decrease ethanol consumption in HAP mice.

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.

Indiana University-Purdue University Indianapolis (IUPUI) / Alcohol related problems and abuse continue to be serious problems in the U.S. today affecting nearly 17.6 million Americans. Understanding of the specific genes and related behaviors associated with alcohol use may provide substantial preventative measures for those who are at an increased risk. Genetically selected lines such as the high-alcohol preferring (HAP) and low-alcohol preferring (LAP) mice have been created to examine which endophenotypes co-segregate with alcohol preference. One behavioral trait that has been commonly associated with alcohol related problems is impulsivity. Impulsivity is the inability to withhold a response (motor impulsivity) or to act without forethought (cognitive impulsivity). The latter comprises much of the research and literature today using delay discounting models to tease out differences in subject’s wiliness to discount larger reinforcers for smaller immediate reinforcers. This study utilized relatively two newer paradigms associated with motor impulsivity in attempt to test differences in response disinhibition between two independent replicate HAP and LAP lines. It is hypothesized that the genes responsible for alcohol preference would be genetically correlated with motor impulsivity as HAP mice would display a greater degree of response disinhibition. Two independent replicates consisting of 48 mice (24 HAP II and 24 LAP II, representing the 37th generation; 24 HAP III and 24 LAP III, representing the 13th generation) were tested in two separate identical experiments. Each experiment was comprised of three phases. Phase I utilized a fixed interval (FI) 120s procedure for 30 days. After the 30 days of FI exposure mice were immediately moved to phase II for 10 days which implored a differential reinforcement of low rate procedure (DRL) at a time interval of 20s. Phase III used the same procedures as Phase II except the DRL was increased to 32s. As hypothesized, there was a moderate genetic correlation between alcohol preference and impulsivity as the HAP II mice displayed greater response disinhibition throughout all three phases compared to the LAP II mice. No differences were observed amongst the replicate III mice in any of the three phases. The findings from this study provide additional support that a genetic correlation between alcohol preference and impulsivity exists as seen in the delay discounting literature. Though this was observed in only one of the two replicates, interpretations must be taken at caution as the replicate III mice are still in the early stages of selection. It is possible at this stage in the selection process that increases in alcohol over successive generations are associated with selecting for taste until a threshold is met where selection shifts to pharmacologic drinking relevance. Until later generations of replicate III mice are studied where pharmacologic drinking occurs, conclusions from this study provide a moderate genetic correlation between alcohol preference and impulsivity.

Indiana University-Purdue University Indianapolis (IUPUI) / Naltrexone (NTX) is clinically efficacious at attenuating alcohol intake in non-abstinent alcoholics and, to a lesser extent, craving, independent of intake. While generally regarded as a non-selective opioid antagonist, NTX has been shown to have concentration dependent selectivity with lower doses (< 1.0 mg/kg) selective for the mu receptor and doses exceeding 1.0 mg/kg capable of binding to delta and kappa receptors. Like the mu system, the delta receptor system has also been implicated in mediating the rewarding effects of EtOH. In contrast, the role of the kappa system is less clear though recent evidence suggests that kappa activation may mediate EtOH aversion. Thus, the present study sought to evaluate the effects of both mu-selective and non-selective doses of naltrexone, the selective delta antagonist naltrindole (NTI), and the selective kappa agonist U50,488H (U50) in a paradigm that procedurally separates the motivation to seek versus consume a reinforcer to assess whether these receptor-selective drugs differentially affects these behaviors in both selected (alcohol-preferring P rats) and non-selected (Long Evans) rats, and whether these effects are specific to EtOH. Rats were trained to complete a single response requirement that resulted in access to either 2% sucrose or 10% EtOH for a 20-min drinking session. In three separate experiments, rats were injected (using a balanced design) with either vehicle or 1 of 3 doses of drug: U50 (IP; 2.5, 5.0, or 10.0mg/kg), NTI (IP; 2.5, 5.0, or 10.0 mg/kg), low NTX (SC; 0.1, 0.3, or 1.0 mg/kg) or high NTX (SC; 1.0, 3.0, or 10.0 mg/kg) on both consummatory and appetitive treatment days. Following either a 20 (U50), 15 (NTI), or 30 minute (NTX) pretreatment, rats were placed into an operant chamber and intake (consummatory) or lever responses (appetitive) and response latencies were recorded. The results showed that overall: U50, NTI, and NTX attenuated intake and responding for sucrose and EtOH. Independent of reinforcer, LE rats were more sensitive to U50’s effects on intake while P rats were more sensitive to the effects on seeking. P rats reinforced with EtOH were more sensitive to NTI’s effects on intake and seeking than all other rat groups. P rats were more sensitive overall to lower doses of NTX than LE rats and lower doses of NTX were more selective in attenuating EtOH responding vs. sucrose. Higher doses of NTX suppressed intake and responding across both lines and reinforcers. These results demonstrate that craving and intake may be differentially regulated by the kappa, delta, and mu opioid receptor systems as a function of “family history” and suggest that different mechanisms of the same (opioid) system may differentially affect craving and intake.

Despite decades of research on amphetamine derivatives, a class of compounds sharing a structural foundation with amphetamine, crucial gaps remain in our understanding of these drugs in a variety of animal species and humans. This dissertation addresses three of these gaps through a multi-level approach involving studies in both humans and mice. Specifically, it focuses on investigating the lack of information regarding: 1) repeated dosing of 3,4-methylenedioxymethamphetamine in humans, 2) methamphetamine/alcohol combinations in humans and 3) methamphetamine/oxycodone combinations in mice. Study 1 involved administering three consecutive doses of 3,4 methylenedioxymethamphetamine to human volunteers at 12- and 24-hour intervals while physiological, behavioral, and subjective measures were collected. Study 2 reanalyzed Kirkpatrick and colleagues (2012a) data to evaluate repeated administrations of methamphetamine and alcohol. The reanalysis focused on quantifying the physiological and subjective effect differences between the first and second administrations, which occurred at a 12-hour interval on the same day, an aspect not previously analyzed or reported by the original authors. Study 3 utilized well-established animal models such as Conditioned Place Preference, Open Field Test, and Novel Object Recognition to evaluate the reward-like and aversive effects of methamphetamine and oxycodone combinations in mice. Study 1 was the first to quantify the effects of multiple 3,4-methylenedioxymethamphetamine doses administered over a 36-hour period of time. Initially, acute 3,4-methylenedioxymethamphetamine produced dose-dependent increases in peak heart rate, blood pressure, and more positive than negative subjective effects. However, by the third dose, many of these effects dissipated, heart rate was no longer elevated, and residual mood effects were minor. Overall, the data do not support the general perception that 3,4-methylenedioxymethamphetamine produces dangerous cardiovascular and residual mood effects in humans following repeated administration. The results of Study 2, again a first in the field, discovered that contrary to expectations, heart rate increases produced by the methamphetamine/alcohol combination were not further increased with repeated dosing, but rather attenuated. In fact, methamphetamine offset alcohol-induced intoxication, even after repeated administration. Study 3 revealed that combining methamphetamine and oxycodone in mice increased reward as measured by Conditioned Place Preference, but not more than either drug alone. However, methamphetamine lengthened the duration of Conditioned Place Preference for the lower oxycodone dose and offset the oxycodone-induced disruptions in novel object recognition performance. One crucial cross-species observation was that methamphetamine mitigated adverse effects such as alcohol-related intoxication and oxycodone cognitive disruption, even after repeated administration. While seemingly beneficial, this observation raises concerns that individuals who combine these drugs may be at risk of underestimating their overall degree of impairment, potentially leading to hazardous activities like driving while intoxicated or engaging in risky behaviors. Sharing this insight is crucial to encourage informed, responsible behavior and safeguard public safety. In conclusion, these studies have significantly enhanced our understanding of two frequently used amphetamine derivatives and their interactions with two commonly used psychoactive drugs—oxycodone and alcohol. Most importantly, we strongly advocate for robust empirical experimentation to counteract misinformation related to 3,4-methylenedioxymethamphetamine and methamphetamine. These endeavors are crucial for developing more precise assessments of the risks and benefits associated with these substances, and for improving drug policies and optimizing public health interventions.

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) / In order to elucidate the role of classical conditioning in food and alcohol co-consumption, the present study examined: (1) the effects of alcohol odor cues on alcohol and food cravings and attentional bias (bias in selective attention toward either food or alcohol pictures relative to neutral pictures); and (2) the role of alcohol odor cue elicited cravings and attentional biases on subsequent consumption. Participants (n = 77; mean age = 30.84, SD = 9.46; 51.9% female, 83.1% Caucasian) first completed the lab portion of the study. In this portion, they were exposed to alcohol and neutral odorants, after which their food and alcohol cravings and attentional bias were assessed. Participants then received an online survey the next day, on which they reported their level of food and alcohol consumption following the lab portion of the study. Using repeated measures analysis of covariance, alcohol odor cues were differentially effective in increasing food and alcohol attentional bias and cravings (Fs= 0.06 to 2.72, ps= 0.03 to 0.81). Using logistic and multiple regressions, alcohol odor cue elicited alcohol attentional bias, food attentional bias, and food cravings were associated with later alcohol consumption, but not with later food consumption or concurrent consumption (βs = -0.28 to 0.48, ps = 0.02 to 0.99; Exp(B)s = 0.95 to 1.83, ps = 0.33 to 0.91). Overall, alcohol odor cues can become conditioned stimuli that elicit conditioned food-related and alcohol-related responses, both of which persist long enough to motivate later alcohol consumption; however, these conditioned responses might not persist long enough to motivate later food or concurrent consumption. These findings serve as a first step in clarifying the role of classical conditioning in concurrent consumption. In particular, they suggest that additional empirical investigations are needed to: (1) clarify the classical conditioning mechanisms underlying concurrent consumption; and (2) examine whether interventions targeting classical conditioning mechanisms are effective for reducing alcohol use.

Indiana University-Purdue University Indianapolis (IUPUI) / Smoke-free legislation in the United States has unintentionally resulted in a decline in alcohol consumption. However, more recently electronic-cigarettes (e-cigs), which are associated with alcohol use, are reportedly being used to circumvent smoking bans. The present study surveyed community dwelling individuals in the United States reporting e-cigs may be used where they drink (N=365, mean age=33.63, SD=9.91, 53.2% female, 78.9% Caucasian) to examine how e-cig use and alcohol consumption varies by the presence of smoking prohibition where one consumes alcohol. Results indicated that smoking prohibition was associated with a greater likelihood of being an ecig user than a cigarette user (OR=3.40, p<.001) and a higher likelihood of being an e-cig user than a dual user (OR=3.37, p<.001). Smoking prohibition was not associated with AUDIT scores (B=-0.06, p=.21), total drinks (B=-.07, p=.19), or average drinks (B=-0.02, p=.76). E-cig users reported significantly fewer average drinks when smoking is prohibited as compared to allowed, t(55)=3.26, p=.002. Overall, current results suggest smoking prohibition is associated with a greater likelihood of being an e-cig user; however, smoking prohibitions are not associated with alcohol consumption and related problems in the current participants, who all reported being able to use e-cigs where they consume alcohol. Future research should address potential conceptual, methodological, and sample limitations in order to better discern this relationship, as this line of research could have important implications for e-cig policy and alcohol use treatment