IU Indianapolis ScholarWorks :: Browsing by Author "Logrip, Marian L."

Browsing by Author "Logrip, Marian L."

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Blockade of Striatal Dopamine D1 Receptors Reduces Quinine-Resistant Alcohol Intake
(2019-05) Houck, Christa A.; Grahame, Nicholas J.; Boehm, Stephen L.; Logrip, Marian L.; Hopf, F. Woodward
Drinking despite aversive consequences, or compulsive drinking, is a criterion of alcohol use disorder and can be modeled in rodents by adding bitter quinine into alcohol. Previous studies have shown the development of quinine-resistant ethanol (EtOH) drinking following a drinking history, but used animals that achieved relatively low blood alcohol levels. Selectively bred crossed High Alcohol Preferring (cHAP) mice average over 250 mg/dl during a two-bottle choice procedure. Compulsive drinking is hypothesized to be D1-receptor mediated via the dorsolateral striatum (DLS). We hypothesized that 2 weeks of free-choice EtOH would lead to quinine resistance and intra-DLS infusion of a D1-antagonist, SCH23390, would attenuate quinine-resistant alcohol drinking with no effect on non-conflicted EtOH drinking. Infusion of SCH23390 into the DMS would not affect quinine-resistant drinking. cHAP mice had guide cannulae placed in the DLS or DMS and had either two weeks (2W) of EtOH and water two-bottle choice or were EtOH naïve (0W). Mice were infused with either SCH23390 or saline immediately prior to one 10% EtOH and water test day and SCH23390 did not disturb alcohol drinking. The following day, we adulterated the EtOH with 0.32-g/L quinine (0.89 mM), and mice received the same microinjection. For animals cannulated in the DLS, 2W history group infused with saline drank more quinine-adulterated EtOH than the 0W saline mice. While SCH23390 infused 0W animals looked no different from saline treated mice, it attenuated quinine + EtOH intake in the 2W animals to the level of 0W animals. Interestingly, DMS-cannulated mice demonstrated similar behavior, with SCH23390 reducing EtOH + quinine consumption, while leaving EtOH consumption undisturbed. Quinine resistance following 2 weeks of free-choice EtOH consumption is attenuated by acute administration of a D1-antagonist in the DLS, suggesting that an alcohol history induces compulsivity and that dopamine contributes to this behavior. This is unique to compulsive drinking, as non-conflicted EtOH drinking was unaffected.
Cell-Specific Spinophilin Function Underlying Striatal Motor Adaptations Associated with Amphetamine-Induced Behavioral Sensitization
(2022-07) Watkins, Darryl Shumon; Yamamoto, Bryan K.; Atwood, Brady K.; Baucum, Anthony J. II; Hudmon, Andy; Logrip, Marian L.
Striatal-mediated pathological disease-states such as Obsessive-Compulsive Disorder (OCD), Parkinson’s Disease (PD), and psychostimulant drug addiction/abuse are coupled with distinct motor movement abnormalities. In addition, these disorders are associated with perturbed synaptic transmission. Proper synaptic transmission is critical for maintaining neuronal communication. Furthermore, in many striatal-dependent disease-states, the principle striatal neurons, medium spiny neurons (MSNs), exhibit differential perturbations in downstream signaling. Signal transduction pathways that are localized to the glutamatergic post-synaptic density (PSD) of GABAergic MSNs regulate protein phosphorylation in a tightly controlled manner. Alterations in the control of this phosphorylation in striatal MSNs are observed in myriad striatal pathological diseasestates and can give rise to perturbations in synaptic transmission. While serine/threonine kinases obtain substrate specificity, in part, by phosphorylating specific consensus sites, serine/threonine phosphatases such as protein phosphatase 1 (PP1) are much more promiscuous. To obtain substrate selectivity, PP1 associates with targeting proteins. The major targeting protein for PP1 in the PSD of striatal dendritic spines is spinophilin. Spinophilin not only binds PP1, but also concurrently interacts with myriad synaptic proteins. Interestingly, dopamine depletion, an animal model of PD, modulates spinophilin protein-protein interactions in the striatum. However, spinophilin function on basal striatal-mediated motor behaviors such as the rotarod or under hyperdopaminergic states such as those observed following psychostimulant-induced behavioral sensitization are less well characterized. To elucidate spinophilin function more specifically, we have generated multiple transgenic animals that allow for cell type-specific loss of spinophilin as well as cell-specific interrogation of spinophilin protein interactions. Here, I report the functional role of spinophilin in regulating striatal mediated motor behaviors and functional changes associated with amphetamine-induced locomotor sensitization. In addition, we define changes in spinophilin protein-protein interactions that may mediate these behavioral changes. Furthermore, global loss of spinophilin abrogates amphetamine-induced sensitization and plays a critical role in striatal motor learning and performance. The data suggest that the striatal spinophilin protein interactome is upregulated in MSNs following psychostimulant administration. In addition, loss of spinophilin changes protein expression in myriad psychostimulant-mediated striatal adaptations. Taken together the data suggests that spinophilin’s protein-protein interactions in the striatum are obligate for appropriate striatal mediated motor function.
Chronic Stress and Sex as Mediators of the Basolateral-Centromedial Amygdala Circuit and its Response to Acute Ethanol
(2020-05) Gainey, Sean; Logrip, Marian L.; Lapish, Christopher C.; Baucum II, Anthony J.
Anxiety disorders are the most common class of mental disorders in the United States, and they both promote and exacerbate disorders of substance abuse. Mounting evidence of sex differences in the relationship between anxiety disorders and alcoholism supports the potential existence of an anxiety-dependent vulnerability to alcohol abuse in women compared with men. One potential point of overlap in the physiological systems involved in anxiety response and reward processing is the amygdala. Here, a model of chronic stress in rodents was employed to probe changes in the electrophysiological and biochemical properties of the amygdala at a post-stress baseline and during a post-stress first exposure to alcohol. Electrophysiological data revealed that neurons in the centromedial amygdala were more responsive to stimulation in the basolateral amygdala in females compared with males, but a history of chronic stress altered the female response to match that of males with or without a history of chronic stress. Protein analysis of postsynaptic glutamatergic receptor expression and phosphorylation in the amygdala did not indicate any differences based on sex or exposure to stress or alcohol. These data demonstrate a sex difference in stress-induced alterations in amygdala circuitry and indicate a potential role for this circuitry in the comorbidity of anxiety disorders and alcoholism.
Exploring the Effects of a Corticotropin Releasing Factor (CRF) Receptor Antagonist on Habit Expression
(2020-12) Haines, Kari; Czachowski, Cristine L.; Grahame, Nicholas J.; Logrip, Marian L.
Some individuals with alcohol use disorder (AUD) continue to drink because they have developed a habit in which they are not considering the consequences of their actions. Habitual actions persist despite changes in reward and are often studied using devaluation procedures. Stress hormones, such as corticotropin releasing factor (CRF), have been linked to AUD when examining binge-like drinking and withdrawal in rodents. Stress has been examined in the switch from goal-directed to habitual behavior, and CRF has often mimicked the effects of stress exposure. This study looked at the possible direct effects of CRF on habit expression in rats using an operant paradigm. Finding possible novel mechanisms of habit could create an avenue for future novel treatment options. Female and male Long Evans rats were trained on a variable interval schedule using sucrose as a reward. Rats then underwent devaluation procedures including both sensory-specific satiety and conditioned taste aversion (CTA) to test for habitual behaviors. Prior to an extinction session post-CTA, animals were treated with either 20 mg/kg R121919, a CRF1 receptor antagonist, or vehicle. A second extinction session was conducted where animals received the alternative treatment. Lever presses were recorded as a measure of goal-directed or habitual behavior. Sensory-specific satiety devaluation tests revealed that animals were not sensitive to devaluation. This was further supported by both post-CTA extinction sessions. R121919 had no effect on lever pressing in either devalued or valued groups. Further research is needed to explore how a CRF receptor antagonist may affect habit formation or the transition from goal-directed to habit behaviors. Future studies should also examine any possible interaction effects CRF may have with alcohol or stress on habitual behaviors.
Genetic and Pharmacologic Manipulation of TLR4 Has Minimal Impact on Ethanol Consumption in Rodents
(Society for Neuroscience, 2017-02-01) Harris, R. Adron; Bajo, Michal; Bell, Richard L.; Blednov, Yuri A.; Varodayan, Florence P.; Truitt, Jay M.; de Guglielmo, Giordano; Lasek, Amy W.; Logrip, Marian L.; Vendruscolo, Leandro F.; Roberts, Amanda J.; Roberts, Edward; George, Olivier; Mayfield, Jody; Billiar, Timothy R.; Hackam, David J.; Mayfield, R. Dayne; Koob, George F.; Roberto, Marisa; Homanics, Gregg E.; Psychiatry, School of Medicine
Toll-like receptor 4 (TLR4) is a critical component of innate immune signaling and has been implicated in alcohol responses in preclinical and clinical models. Members of the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune) consortium tested the hypothesis that TLR4 mediates excessive ethanol drinking using the following models: (1) Tlr4 knock-out (KO) rats, (2) selective knockdown of Tlr4 mRNA in mouse nucleus accumbens (NAc), and (3) injection of the TLR4 antagonist (+)-naloxone in mice. Lipopolysaccharide (LPS) decreased food/water intake and body weight in ethanol-naive and ethanol-trained wild-type (WT), but not Tlr4 KO rats. There were no consistent genotypic differences in two-bottle choice chronic ethanol intake or operant self-administration in rats before or after dependence. In mice, (+)-naloxone did not decrease drinking-in-the-dark and only modestly inhibited dependence-driven consumption at the highest dose. Tlr4 knockdown in mouse NAc did not decrease drinking in the two-bottle choice continuous or intermittent access tests. However, the latency to ethanol-induced loss of righting reflex increased and the duration decreased in KO versus WT rats. In rat central amygdala neurons, deletion of Tlr4 altered GABAA receptor function, but not GABA release. Although there were no genotype differences in acute ethanol effects before or after chronic intermittent ethanol exposure, genotype differences were observed after LPS exposure. Using different species and sexes, different methods to inhibit TLR4 signaling, and different ethanol consumption tests, our comprehensive studies indicate that TLR4 may play a role in ethanol-induced sedation and GABAA receptor function, but does not regulate excessive drinking directly and would not be an effective therapeutic target., SIGNIFICANCE STATEMENT Toll-like receptor 4 (TLR4) is a key mediator of innate immune signaling and has been implicated in alcohol responses in animal models and human alcoholics. Members of the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune) consortium participated in the first comprehensive study across multiple laboratories to test the hypothesis that TLR4 regulates excessive alcohol consumption in different species and different models of chronic, dependence-driven, and binge-like drinking. Although TLR4 was not a critical determinant of excessive drinking, it was important in the acute sedative effects of alcohol. Current research efforts are directed at determining which neuroimmune pathways mediate excessive alcohol drinking and these findings will help to prioritize relevant pathways and potential therapeutic targets.
Molecular tools to elucidate factors regulating alcohol use
(Elsevier, 2018) Logrip, Marian L.; Psychology, School of Science
Alcohol use disorders (AUD) are pervasive societal problems, marked by high levels of alcohol intake and recidivism. Despite these common disease traits, individuals diagnosed with AUD display a range of disordered drinking and alcohol-related behaviors. The diversity in disease presentation, as well as the established polygenic nature of the disorder and complex neurocircuitry, speak to the variety in neurochemical changes resulting from alcohol intake that may differentially regulate alcohol-related behaviors. Investigations into the molecular adaptations responsible for maladaptive alcohol-related behavioral outcomes require an ever-evolving set of molecular tools to elucidate with increasing precision how alcohol alters behavior through neurochemical changes. This review highlights recent advances in molecular methodology, addressing how incorporation of these cutting-edge techniques not only may enhance current knowledge of the molecular bases of AUD, but also may facilitate identification of improved treatment targets that may be therapeutic in specific subpopulations of AUD individuals.
Sex differences in responses of the basolateral-central amygdala circuit to alcohol, corticosterone and their interaction
(Elsevier, 2017-03-01) Logrip, Marian L.; Oleata, Christopher; Roberto, Marisa; Psychology, School of Science
Alcohol use disorders are chronically relapsing conditions that pose significant health challenges for our society. Stress is a prevalent trigger of relapse, particularly for women, yet the mechanisms by which alcohol and stress interact, and how this differs between males and females, remain poorly understood. The glutamatergic circuit connecting the basolateral (BLA) and central (CeA) nuclei of the amygdala is a likely locus for such adaptations, yet the impact of alcohol, corticosterone and their interaction on this circuit has been understudied. In particular, no studies have addressed sex differences in these effects or potential differential responses between the lateral and medial subdivisions of the central nucleus. Thus, we assessed the effects of alcohol and corticosterone treatments on BLA-evoked compound glutamatergic responses in medial and lateral CeA neurons from male and female rats. We observed minimal differences between medial and lateral CeA responses to alcohol and corticosterone in male rats, which were primarily sensitive to alcohol-induced inhibition of glutamatergic postsynaptic potentials. Unlike male neurons, cells from female rats displayed reduced sensitivity to alcohol’s inhibitory effects. In addition, female neurons diverged in their sensitivity to corticosterone, with lateral CeA neuronal responses significantly blunted following corticosterone treatment and medial CeA neurons largely unchanged by corticosterone or subsequent co-application of alchol. Together these data highlight striking differences in how male and female amygdala respond to alcohol and the stress hormone corticosterone, factors which may impact differential susceptibility of the sexes to alcohol- and stress-related disorders.
Sex Differences in Risk and Resilience: Stress Effects on the Neural Substrates of Emotion and Motivation
(Society for Neuroscience, 2018-10-31) Wellman, Cara L.; Bangasser, Debra A.; Bollinger, Justin L.; Coutellier, Laurence; Logrip, Marian L.; Moench, Kelly M.; Urban, Kimberly R.; Psychology, School of Science
Risk for stress-sensitive psychopathologies differs in men and women, yet little is known about sex-dependent effects of stress on cellular structure and function in corticolimbic regions implicated in these disorders. Determining how stress influences these regions in males and females will deepen our understanding of the mechanisms underlying sex-biased psychopathology. Here, we discuss sex differences in CRF regulation of arousal and cognition, glucocorticoid modulation of amygdalar physiology and alcohol consumption, the age-dependent impact of social stress on prefrontal pyramidal cell excitability, stress effects on the prefrontal parvalbumin system in relation to emotional behaviors, contributions of stress and gonadal hormones to stress effects on prefrontal glia, and alterations in corticolimbic structure and function after cessation of chronic stress. These studies demonstrate that, while sex differences in stress effects may be nuanced, nonuniform, and nonlinear, investigations of these differences are nonetheless critical for developing effective, sex-specific treatments for psychological disorders.
Sex differences in the long-term effects of past stress on alcohol self-administration, glucocorticoid sensitivity and phosphodiesterase 10A expression
(Elsevier, 2020-03-01) Logrip, Marian L.; Gainey, Sean C.; Psychology, School of Science
Stress responses differ by sex, and females are more susceptible to developing mental illnesses because of past stress, including alcohol use disorder. Investigation of neuroadaptations governing the interaction between past stress and future alcohol intake remains understudied in females. A history of footshock stress previously was shown to increase alcohol self-administration under relapse-like conditions in male rats, associated with elevated phosphodiesterase 10A (PDE10A) mRNA expression in the dorsomedial prefrontal cortex and basolateral amygdala. To identify sex differences in long-term stress effects, male and female Wistar rats were exposed to light-cued footshock stress prior to alcohol self-administration training. While past stress did not alter acquisition or extinction, reacquisition self-administration was oppositely impacted by past stress. Stress history slightly increased reacquisition self-administration in males, but reduced alcohol self-administration in females, relative to same-sex controls. Control females self-administered less alcohol following glucocorticoid receptor inhibition by mifepristone, which did not significantly alter alcohol consumption in the other groups. PDE10A expression in synaptically enriched fractions also differed by sex and stress history in a brain region-specific manner. Females expressed more synaptic PDE10A than males in basolateral amygdala and dorsolateral striatum, regardless of stress history, whereas dorsomedial prefrontal cortex PDE10A protein levels matched group differences in reacquisition drinking, but also were expressed at much lower levels than all other regions examined. Together, these data show stress history differentially impacts alcohol self-administration and PDE10A expression by sex, with control females consuming alcohol in a glucocorticoid receptor-sensitive fashion that may relate to sex differences in PDE10A expression.
Sexual dimorphism in the neural impact of stress and alcohol
(Elsevier, 2018) Logrip, Marian L.; Milivojevic, Verica; Bertholomey, Megan L.; Torregrossa, Mary M.; Psychology, School of Science
Alcohol use disorder is a widespread mental illness characterized by periods of abstinence followed by recidivism, and stress is the primary trigger of relapse. Despite the higher prevalence of alcohol use disorder in males, the relationship between stress and behavioral features of relapse, such as craving, is stronger in females. Given the greater susceptibility of females to stress-related psychiatric disorders, understanding sexual dimorphism in the relationship between stress and alcohol use is essential to identifying better treatments for both male and female alcoholics. This review addresses sex differences in the impact of stressors on alcohol drinking and seeking in rodents and humans. As these behavioral differences in alcohol use and relapse originate from sexual dimorphism in neuronal function, the impact of stressors and alcohol, and their interaction, on molecular adaptations and neural activity in males and females will also be discussed. Together the data reviewed herein, arising from a symposium entitled “Sex matters in stress-alcohol interactions” presented at the Fourth Volterra Conference on Stress and Alcohol, will highlight the importance of identifying sex differences to improve treatments for comorbid stress and alcohol use disorder in both populations.

Browsing by Author "Logrip, Marian L."

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