Browsing by Author "Czachowski, Cristine L."
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Item A critical review of front-loading: A maladaptive drinking pattern driven by alcohol's rewarding effects(Wiley, 2022) Ardinger, Cherish E.; Lapish, Christopher C.; Czachowski, Cristine L.; Grahame, Nicholas J.; Psychology, School of ScienceFront‐loading is a drinking pattern in which alcohol intake is skewed toward the onset of reward access. This phenomenon has been reported across several different alcohol self‐administration protocols in a wide variety of species, including humans. The hypothesis of the current review is that front‐loading emerges in response to the rewarding effects of alcohol and can be used to measure the motivation to consume alcohol. Alternative or additional hypotheses that we consider and contrast with the main hypothesis are that: (1) front‐loading is directed at overcoming behavioral and/or metabolic tolerance and (2) front‐loading is driven by negative reinforcement. Evidence for each of these explanations is reviewed. We also consider how front‐loading has been evaluated statistically in previous research and make recommendations for defining this intake pattern in future studies. Because front‐loading may predict long‐term maladaptive alcohol drinking patterns leading to the development of alcohol use disorder (AUD), several future directions are proposed to elucidate the relationship between front‐loading and AUD.Item Achieving pharmacologically relevant IV alcohol self-administration in the rat(2012-09-27) Windisch, Kyle Allyson; Czachowski, Cristine L.; Grahame, Nicholas J.; Kosobud, Ann E. K.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.Item Assessing initial/early aversion-resistant drinking across male and female alcohol-preferring and non-preferring rats(Wiley, 2025) Haines, Kari M.; Smith, Nicholle E; Czachowski, Cristine L.; Psychology, School of ScienceBackground: One trait of alcohol use disorder (AUD) is continuing to drink despite negative consequences. The current study investigated initial/early aversion-resistant drinking (ARD) across selectively bred alcohol-preferring lines to assess aversion resistance with minimal ethanol history and subsequent ethanol-seeking and drinking profiles. Additionally, ARD was assessed in alcohol-preferring and non-preferring rats using a sucrose reinforcer to determine if ARD may be a genetic risk factor for AUD. Methods: Male and female alcohol-preferring rats were given four concentrations of quinine (0.03, 0.10, 0.30, and 1.00 g/L-in random order) in an ethanol solution in the homecage for 30 min daily across 12 days. Seeking and drinking were then assessed in the operant chambers. Additional groups of alcohol-preferring and non-preferring rats were given access to the same concentrations of quinine-adulterated sucrose using the same daily, random-order presentation. Results: In ethanol, all preferring lines performed similarly, showing resistance to quinine at the lowest concentration. In the homecage, high-alcohol-drinking (HAD)1 rats drank high levels of ethanol similar to alcohol-preferring (P) rats, whereas in an operant task were more similar to the HAD2 rats. In sucrose, P and HAD2 rats were shown to be aversion resistant at low concentrations of quinine compared to baseline. Overall, the non-preferring lines all demonstrated sensitivity to quinine-adulterated sucrose. Conclusions: This study demonstrates alcohol-preferring lines show similar ARD when ethanol is the reinforcer. Regarding motivated responding, P rats show high-seeking and drinking behaviors as previously observed. In the homecage, HAD1 rats drink similarly to P rats indicating that different conditions (i.e., free vs. operant access) influence drinking behaviors between these lines. Importantly, in a sucrose reinforcer, alcohol-preferring rats are more aversion-resistant than non-preferring lines, while non-preferring lines show high sensitivity to aversion, suggesting an overall tendency to demonstrate a low level of compulsive behavior.Item Differential COMT expression and behavioral effects of COMT inhibition in male and female Wistar and alcohol preferring rats(Elsevier, 2017) McCane, Aqilah M.; DeLory, Michael J.; Timm, Maureen M.; Janetsian-Fritz, Sarine S.; Lapish, Christopher C.; Czachowski, Cristine L.; Department of Psychology, School of SciencePolymorphisms of the catechol-O-methyl transferase (COMT) gene have been associated with alcoholism, suggesting that alterations in the metabolism of catecholamines may be a critical component of the neuropathology of alcoholism. In the current experiments, the COMT inhibitor tolcapone was utilized in an operant behavioral model of reinforcer-seeking and drinking to determine if this compound was capable of remediating the excessive seeking and drinking phenotype of the alcohol-preferring P rat. Tolcapone was administered to male and female alcohol-reinforced P and Wistar rats. Additionally, tolcapone was administered to male sucrose-reinforced P and Wistar rats to determine if its effects also extended to a natural reinforcer. Animals were trained to make an operant response that resulted in 20 min uninterrupted access to the reinforcer solutions. Tolcapone had no effect in female rats on either seeking or consumption of ethanol. However, reductions of both reinforcer seeking and consumption were observed in male P rats, but only of seeking in Wistars. In separate experiments, using reinforcer naïve male and female animals, COMT expression was assessed via Western Blot analysis. Sex differences in COMT expression were also observed, where male P rats exhibited a marked reduction in protein expression relative to females in the PFC. Sex differences were not observed for Wistars or in the striatum and hippocampus. These data complement our previous findings in which tolcapone reduced cue-evoked responses in P rats and further suggest clinical utility of COMT inhibitors in the treatment of addiction disorders, specifically in male high drinkers.Item Differential effects of quinine adulteration of alcohol on seeking and drinking(Elsevier, 2021) McCane, Aqilah M.; Auterson, Curtis D.; DeLory, Michael J.; Lapish, Christopher C.; Czachowski, Cristine L.; Psychology, School of ScienceAlcohol dependence is characterized by compulsive alcohol use. Alcohol-paired stimuli can drive compulsive alcohol use, induce craving, and lead to relapse. Alcohol dependence is highly heritable and individuals with a family history are at elevated risk to develop an alcohol use disorder. Understanding the association between genetic vulnerability to alcohol dependence and neural alterations which promote an addiction phenotype are critical to the prevention and treatment of alcohol dependence. Here we use selectively bred alcohol-preferring P rats and their progenitor strain, Wistar rats, to investigate the relationship between genetic liability and alcohol-seeking and drinking behaviors in a discriminative stimuli paradigm. To further investigate strain differences in motivated responding, alcohol was adulterated with quinine and intake and responding were assessed. While both strains learn to discriminate between stimuli which predict alcohol availability, P rats learn faster and consume more alcohol. Quinine adulteration reduced ethanol intake in both strains with no effect on ethanol seeking measures. These data suggest genetic vulnerability to alcohol dependence is associated with increased motivated behaviors and highlight the utility of P rats in teasing apart the neural mechanisms associated with this phenotype. Additionally, these data suggest a dissociation between the neural systems which engage ethanol drinking versus compulsive ethanol seeking.Item The Effects of Long-Term Varenicline Administration on Ethanol and Sucrose Seeking and Self-Administration in Male P Rats(Wiley, 2018) Czachowski, Cristine L.; Froehlich, Janice C.; DeLory, Michael; Psychology, School of ScienceBackground Varenicline, a partial agonist at α4β2 and full agonist at α7 nicotinic cholinergic receptors, is FDA-approved for treatment of smoking cessation and has been found to reduce alcohol craving in clinical populations. In rodents, varenicline decreases free-choice ethanol (EtOH) intake with somewhat mixed findings in operant paradigms that utilize a combined appetitive/consummatory response. Methods The present experiment utilized an operant paradigm that procedurally separates appetitive from consummatory responding and a “reward-blocking” approach (i.e., rats were able to consume EtOH during treatment) to better understand the efficacy of varenicline as a treatment for EtOH self-administration and subsequent EtOH seeking. Separate groups of EtOH- and sucrose-reinforced alcohol-preferring, male P rats experienced alternating cycles of vehicle (2-week cycles) and varenicline (0.3, 1.0, and 2.0 mg/kg self-administered in a gelatin preparation) treatment (3-week cycles) prior to daily sessions where a single lever press resulted in 20 minutes of reinforcer access. At the end of each cycle, a single extinction session assessed the seeking response in the absence of drug pretreatment. Results Varenicline dose dependently decreased EtOH intake. Sucrose intake was largely unaffected, with no overall treatment effects and only sporadic days where the medium and high dose differed from vehicle. Neither sucrose nor EtOH seeking was significantly decreased by varenicline, and there were no treatment effects on either lick or lever-press latency. Overall effect sizes were much greater for both drinking and seeking in the EtOH group as compared to the sucrose group. Conclusions Varenicline effectively attenuates EtOH self-administration during treatment, but the experience with EtOH consumption while varenicline is “on board” is not sufficient to alter subsequent EtOH seeking. The overall pattern of findings indicates that varenicline blocks the rewarding properties of EtOH while not substituting for EtOH, that the nonspecific effects on an alternate reinforcer are negligible, and that blood levels of varenicline need to be maintained in order for treatment to remain effective.Item Effects of omega-3 fatty acids on rodent models of bipolar disorder and alcoholism(2010-07-20T15:16:10Z) Case, Natalie J.; Oxford, Gerry S.; Niculescu, Alexander B.; Czachowski, Cristine L.Our laboratory has previously identified the clock gene D-box Binding Protein (DBP) as a candidate gene for bipolar disorder and alcoholism using a Convergent Functional Genomics (CFG) approach. In subsequent work, we established mice with a homozygous deletion of DBP as a stress-reactive genetic animal model of bipolar disorder and co-morbid alcoholism. In the present study, we found that the omega-3 fatty acid, DHA, may have mood stabilizing capabilities in stressed DBP knockout mice, and reduces alcohol consumption in these mice as well as in the alcohol preferring (P) rats. Given their potential health benefits and their relative lack of negative side-effects, omega-3 fatty acids may become an important supplement for bipolar patients and co-morbid alcoholics, a potential that warrants continued research.Item Effects of Prazosin Treatment on Ethanol- and Sucrose-Seeking and Intake in P Rats(2012-09-20) Verplaetse, Terril Lee; Czachowski, Cristine L.; Grahame, Nicholas J.; Neal-Beliveau, Bethany S.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.Item Evaluating sex and line differences in successive negative contrast and ethanol consumption using alcohol preferring and high alcohol drinking rats(Wiley, 2025) Smith, Nicholle E.; Czachowski, Cristine L.; Psychology, School of ScienceBackground: The loss of a job or relationship are a couple of examples of unexpected reward loss. Life events, such as these can induce negative emotional reactions (e.g., anxiety and stress), which have been associated with increased alcohol consumption and in turn, an increased risk of developing an alcohol use disorder (AUD). The present study analyzed consummatory successive negative contrast (SNC) for the first time in alcohol preferring (P) and high alcohol drinking (HAD) rats that have been selectively bred to consume high amounts of ethanol. Following reward loss, animals were given free access to ethanol to determine whether consumption would increase as a possible indication of any negative emotional reaction. Methods: Male and female P and HAD rats were split into shifted and unshifted groups receiving either 32% or 4% sucrose for 5 min across 10 preshift days. Subsequently, all animals received 4% sucrose for four postshift days, across which, animals were given access to 20% ethanol for 30 min after access to 4% sucrose. Results: Male and female P rats demonstrated a longer contrast effect than HAD rats, indicated by a longer recovery time following the downshift in reward. Conversely, HAD males did not demonstrate a contrast effect following this downshift in reward unlike their female counterparts. Surprisingly, P rats who experienced a loss of reward consumed significantly less ethanol than animals who did not. Lastly, individual measure of contrast size, or shift ratio, was significantly associated with greater ethanol consumption in HAD males only, who did not display a contrast effect. Conclusions: These data indicate different reactivity to SNC between these two lines and sexes, suggesting different genetic and sex-related mechanisms underlying sensitivity to an unexpected loss of reward and ethanol consumption following this loss.Item Excessive Ethanol-Seeking as Related to Impulsive Behavior as Measured by Delay Discounting(Office of the Vice Chancellor for Research, 2013-04-05) Havard, Katharine A.; Beckwith, S. Wesley; Czachowski, Cristine L.The discounting of delayed rewards, a specific type of impulsive behavior, has been associated with alcohol use disorders. However, the way in which this characteristic is related to the genetic and behavioral paths which lead to high-drinking is a newly emerging area of alcohol research. Rodents selectively bred for extreme high vs. low alcohol preference have shown parallel patterns of delay discounting. This study investigated whether or not delayed discounting is preferentially related to ethanol-seeking vs. consumption. Alcohol preferring rats (P; n=5), High Alcohol Drinking rats (HAD2; n=15), and Long Evans rats (LE; n=11) were used and have previously been identified as high seeking/high drinking, moderate seeking/high drinking, and moderate seeking/moderate drinking, respectively. Six levels of delay (0, 2, 4, 8, 12 and 16 seconds) were assessed using a sucrose reinforcer. The average indifference points for each delay were then fitted to hyperbolic equations to yield a single parameter (k). An ANOVA for those values, along with post hoc testing, revealed Ps to have larger k values than both HAD2s and LEs. However, the HAD2s and LEs were not different from each other. A mixed ANOVA for indifference points showed a main effect of Delay (p<.01), Group (p<.01), and no group/delay interaction (p=.08). The main effect of group revealed the same pattern of findings for the indifference points as for the k values. Both the higher k values and the lower indifference points of the Ps indicate their steeper discounting in comparison to both HAD2s and LE. These results suggest that this measure of impulsivity could be associated with the quantity of ethanol-seeking, and not just with the inclination to consume ethanol. These results extend previous findings, and as all animals were ethanol naïve, these results support the idea that increased impulsivity is a characteristic that precedes addictive disorders.