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ItemAdenosinergic regulation of binge-like ethanol drinking and associated locomotor effects in male C57BL/6J mice(Elsevier, 2015-08) Fritz, Brandon M.; Boehm II, Stephen L.; Department of Psychology, School of ScienceWe recently observed that the addition of caffeine (a nonselective adenosine receptor antagonist) to a 20% ethanol solution significantly altered the intoxication profile of male C57BL/6J (B6) mice induced by voluntary binge-like consumption in the 'Drinking-in-the-Dark' (DID) paradigm. In the current study, the roles of A1 and A2A adenosine receptor subtypes, specifically, in binge-like ethanol consumption and associated locomotor effects were explored. Adult male B6 mice (PND 60-70) were allowed to consume 20% ethanol (v/v) or 2% sucrose (w/v) for 6days via DID. On day 7, mice received a systemic administration (i.p.) of the A1 antagonist DPCPX (1, 3, 6mg/kg), the A2A antagonist MSX-3 (1, 2, 4mg/kg), or vehicle immediately prior to fluid access in DID. Antagonism of the A1 receptor via DPCPX was found to dose-dependently decrease binge-like ethanol intake and associated blood ethanol concentrations (p's<0.05), although no effect was observed on sucrose intake. Antagonism of A2A had no effect on ethanol or sucrose consumption, however, MSX-3 elicited robust locomotor stimulation in mice consuming either solution (p's<0.05). Together, these findings suggest unique roles for the A1 and A2A adenosine receptor subtypes in binge-like ethanol intake and its associated locomotor effects. ItemAlcohol exposure disrupts mu opioid receptor-mediated long-term depression at insular cortex inputs to dorsolateral striatum(Nature Publishing group, 2018-04-03) Muñoz, Braulio; Fritz, Brandon M.; Yin, Fuqin; Atwood, Brady K.; Psychiatry, School of MedicineDrugs of abuse, including alcohol, ablate the expression of specific forms of long-term synaptic depression (LTD) at glutamatergic synapses in dorsal striatum (DS), a brain region involved in goal-directed and habitual behaviors. This loss of LTD is associated with altered DS-dependent behavior. Given the role of the µ-opioid receptor (MOR) in behavioral responding for alcohol, we explored the impact of alcohol on various forms of MOR-mediated synaptic depression that we find are differentially expressed at specific DS synapses. Corticostriatal MOR-mediated LTD (mOP-LTD) in the dorsolateral striatum occurs exclusively at inputs from anterior insular cortex and is selectively disrupted by in vivo alcohol exposure. Alcohol has no effect on corticostriatal mOP-LTD in dorsomedial striatum, thalamostriatal MOR-mediated short-term depression, or mOP-LTD of cholinergic interneuron-driven glutamate release. Disrupted mOP-LTD at anterior insular cortex–dorsolateral striatum synapses may therefore be a key mechanism of alcohol-induced neuroadaptations involved in the development of alcohol use disorders., µ-opioid receptors (MOR) are known to modulate the reward effects of drugs of abuse, and MOR activation induces long-term depression (LTD) at striatal synapses. Here the authors show that alcohol exposure disrupts MOR-induced LTD only at specific cortical inputs to the striatum. ItemConcomitant Caffeine Increases Binge Consumption of Ethanol in Adolescent and Adult Mice, But Produces Additive Motor Stimulation Only in Adolescent Animals(Wiley, 2016-06) Fritz, Brandon M.; Quoilin, Caroline; Kasten, Chelsea R.; Smoke, Michael; Boehm, Stephen L., II; Psychology, School of ScienceBACKGROUND: Binge co-consumption of highly caffeinated energy drinks with alcohol (ethanol [EtOH]) has become a common practice among adolescents/young adults and has been associated with an increased incidence of hazardous behaviors. Animal models are critical in advancing our understanding the neurobehavioral consequences of this form of binge drinking. Surprisingly, virtually no work has explored caffeine and EtOH co-consumption or its long-term consequences in adolescent animals. The primary objective of the current study was to extend a previously established mouse model of voluntary binge caffeine and EtOH co-consumption to explore adolescent consumption and responses compared to adults. METHODS: Adolescent and adult male C57BL/6J mice had daily limited access to caffeine (0.03% w/v), EtOH (20% v/v), a combined EtOH/caffeine solution, or water for 14 days via the binge-like drinking paradigm, drinking-in-the-dark (DID). Home cage locomotor activity was measured during DID in a subset of mice. Following DID, all mice rested for 18 days so that adolescents reached adulthood, whereupon all mice underwent 7 days of continuous access 2-bottle choice drinking for 10% (v/v) EtOH or water. RESULTS: Co-consumption with caffeine significantly increased EtOH intake and resultant blood ethanol concentrations in both adolescent and adult mice. In addition, adolescent mice exhibited a uniquely robust locomotor stimulant response to caffeine and EtOH co-consumption. Later EtOH intake and preference was not influenced, however, by prior fluid consumption history via DID. CONCLUSIONS: Together with findings from the human literature, our results suggest that caffeine co-consumption may positively influence binge alcohol consumption in adolescents/young adults. Importantly, this age group may be particularly sensitive to the additive stimulant effects of caffeinated alcohol consumption, an effect which may be related to the high incidence of associated negative outcomes in this population. These observations are particularly concerning considering the heightened plasticity of the adolescent brain. ItemThe Effect of Alcohol Consumption History on Sensitivity and Acute Functional Tolerance to the Ataxic Effects of Alcohol in C57BL/6J Mice(Office of the Vice Chancellor for Research, 2014-04-11) Fetzer, William R.; Fritz, Brandon M.; Boehm, Stephen L., IIBinge alcohol drinking may increase the rate of development of acute functional tolerance (AFT; within session tolerance) and decrease initial sensitivity to alcohol, which in turn may increase the binge drinking behavior. The focus of this study is to determine the effects of the alcohol pre-exposure on two major responses to alcohol, sensitivity and tolerance. Sixty male C57BL/6J mice in the range of 60 to 80 days old were placed in one of the five groups varying their duration of the alcohol pre-exposure. Mice were tested for ataxic sensitivity and tolerance following 0, 1, 4, 8, or 15 days of binge alcohol consumption. The pre-exposure was conducted in the limited access drinking paradigm over the course of the dark cycle for fifteen consecutive days. The static dowel task, which requires mice to balance on an elevated wooden dowel, was utilized to determine the sensitivity, recovery length, and AFT capacity to alcohol-induced ataxia. AFT was quantified by comparing the blood alcohol concentration (BAC) at loss of balance to the BAC at recovery. Although it appeared that 4 and 15 days of repeated binge alcohol drinking reduced sensitivity to alcohol, there were no main effect of the group (p > 0.05). Analysis of the recovery of balance was significant (p < 0.05), with post-hoc tests indicating that mice with 4, 8, and 15 days of repeated binge alcohol drinking recovering the ability to balance on the static dowel earlier than the 0 group. However, the analysis of AFT was not significant, indicating that prior binge alcohol drinking, regardless of duration, did not alter development of within session tolerance. Future studies evaluating AFT using these physiological markers are needed to validate the contradictory findings and advance the scientific knowledge of the relationship between binge drinking and AFT. ItemThe effect of prior alcohol consumption on the ataxic response to alcohol in high-alcohol preferring mice(Elsevier, 2014-12) Fritz, Brandon M.; Boehm, Stephen L.; Department of Psychiatry, IU School of MedicineWe have previously shown that ethanol-naïve high-alcohol preferring (HAP) mice, genetically predisposed to consume large quantities of alcohol, exhibited heightened sensitivity and more rapid acute functional tolerance (AFT) to alcohol-induced ataxia compared to low-alcohol preferring mice. The goal of the present study was to evaluate the effect of prior alcohol self-administration on these responses in HAP mice. Naïve male and female adult HAP mice from the second replicate of selection (HAP2) underwent 18 days of 24-h, 2-bottle choice drinking for 10% ethanol vs. water, or water only. After 18 days of fluid access, mice were tested for ataxic sensitivity and rapid AFT following a 1.75 g/kg injection of ethanol on a static dowel apparatus in Experiment 1. In Experiment 2, a separate group of mice was tested for more protracted AFT development using a dual-injection approach where a second, larger (2.0 g/kg) injection of ethanol was given following the initial recovery of performance on the task. HAP2 mice that had prior access to alcohol exhibited a blunted ataxic response to the acute alcohol challenge, but this pre-exposure did not alter rapid within-session AFT capacity in Experiment 1 or more protracted AFT capacity in Experiment 2. These findings suggest that the typically observed increase in alcohol consumption in these mice may be influenced by ataxic functional tolerance development, but is not mediated by a greater capacity for ethanol exposure to positively influence within-session ataxic tolerance. ItemThe effect of voluntary binge caffeine and ethanol co-exposure on neurobehavioral sensitivity to cocaine in male C57BL/6J mice(2016-05) Fritz, Brandon M.; Boehm, Stephen L., II; Czachowski, Cristine Lynn; Kinzig, Kimberly; Engleman, Eric A.; Grahame, Nicholas J.Recently, the co-consumption of highly caffeinated energy drinks and alcohol has become a public health concern. Consumption of these beverages has been linked to a wide variety negative consequences including alcohol poisoning, driving under the influence, physical harm, and sexual violence. The more protracted consequences of caffeinated alcohol consumption have received very little attention, however. Some evidence suggests that individuals that frequently consume energy drinks mixed with alcohol are more likely to develop an alcohol use disorder. Interestingly, both caffeine and alcohol use alone have been linked to polydrug abuse. It is therefore of interest whether combined caffeine and alcohol consumption may pose an additive risk for substance abuse. Given that both compounds can positively influence dopamine signaling in mesolimbocortical reward circuitry via different mechanisms, this is an important question to address. Psychostimulants, such as cocaine, are of particular interest considering the significant involvement of dopamine in their effects. The current project explored this possibility employing an established mouse model of binge caffeine and alcohol co-consumption. Male C57BL/6J mice underwent 14 days of daily, 2hr limited access to water, alcohol, caffeine, or combined caffeine and alcohol. Water was freely available after these sessions. In Experiment 1, mice underwent an 11-day locomotor sensitization protocol for cocaine initiating on day 15. Locomotor sensitization has been associated with a greater propensity to self-administer psychostimulants in rodents. Mice were subjected to injections of cocaine (5 or 10 mg/kg; i.p.) or saline every other day, with 15 minute activity monitoring until day 25. In Experiment 2, a separate group of mice underwent an identical drinking procedure. A conditioned place preference (CPP) protocol commenced on day 15. CPP assesses the conditioned rewarding effects of cues associated with drugs of abuse. On day 15, mice received saline injections and were immediately placed onto a neutral floor texture (paper) in the place conditioning box for 15 minutes in order to habituate the animals to the apparatus and injection procedure. Starting on day 16, mice received daily alternating systemic injections of cocaine (1 or 5 mg/kg; i.p.) and saline or saline throughout (naïve controls) and were placed onto one of two particular tactile floor cues: a metal floor with holes punched out or a grid floor made of metal rods. Mice were exposed to the other injection/floor pairing on the alternate days. Mice were placed into these activity monitors for 15 minute conditioning sessions. These sessions alternated drug and vehicle over the course of 8 days so that a total of 4 drug and 4 saline injections were given. The first place preference test occurred on day 24 wherein all mice were injected with saline and offered access to both floor textures. On day 25, mice were returned to the conditioning protocol for another 8 days and a second CPP test on day 33. The results of Experiment 1 suggested that prior caffeine consumption, irrespective of the presence of ethanol, enhanced the initial psychomotor stimulating effect of 10 mg/kg cocaine. However, prior fluid consumption history did not influence the capacity to develop locomotor sensitization. The results of Experiment 2 indicate that prior caffeine and/or ethanol consumption had no influence on the development or expression of CPP for 1 mg/kg or 5 mg/kg cocaine. Collectively, these results suggest that a history of caffeine consumption may increase the stimulant response to a moderate dose of cocaine, perhaps indicating cross-sensitization. Although the conditioned rewarding effects of cocaine were not altered by prior caffeine and/or ethanol consumption, an enhanced stimulant response may be indicative of enhanced cocaine abuse potential. This study demonstrates that moderate caffeine consumption may influence an individual’s early interactions with cocaine which may eventually influence the likelihood of later problematic use. ItemGenetic relationship between predisposition for binge alcohol consumption and blunted sensitivity to adverse effects of alcohol in mice(Wiley Blackwell (Blackwell Publishing), 2014-05) Fritz, Brandon M.; Cordero, Kristy A.; Barkley-Levenson, Amanda M.; Metten, Pamela; Crabbe, John C.; Boehm, Stephen L.; Department of Psychology, IU School of ScienceBACKGROUND: Initial sensitivity to ethanol (EtOH) and the capacity to develop acute functional tolerance (AFT) to its adverse effects may influence the amount of alcohol consumed and may also predict future alcohol use patterns. The current study assessed sensitivity and AFT to the ataxic and hypnotic effects of EtOH in the first replicate of mice (HDID-1) selectively bred for high blood EtOH concentrations (BECs) following limited access to EtOH in the Drinking in the Dark (DID) paradigm. METHODS: Naïve male and female HDID-1 and HS/Npt mice from the progenitor stock were evaluated in 3 separate experiments. In Experiments 1 and 2, EtOH-induced ataxia was assessed using the static dowel task. In Experiment 3, EtOH-induced hypnosis was assessed by using modified restraint tubes to measure the loss of righting reflex (LORR). RESULTS: HDID-1 mice exhibited reduced initial sensitivity to both EtOH-induced ataxia (p < 0.001) and hypnosis (p < 0.05) relative to HS/Npt mice. AFT was calculated by subtracting the BEC at loss of function from the BEC at recovery (Experiments 1 and 3) or by subtracting BEC at an initial recovery from the BEC at a second recovery following an additional alcohol dose (Experiment 2). The dowel test yielded no line differences in AFT, but HS/Npt mice developed slightly greater AFT to EtOH-induced LORR than HDID-1 (p < 0.05). CONCLUSIONS: These results suggest that HDID-1 mice exhibit aspects of blunted ataxic and hypnotic sensitivity to EtOH which may influence their high EtOH intake via DID, but do not display widely different development of AFT. These findings differ from previous findings with the high alcohol-preferring (HAP) selected mouse lines, suggesting that genetic predisposition for binge, versus other forms of excessive alcohol consumption, is associated with unique responses to EtOH-induced motor incoordination. ItemGenetic Selection for Alcohol Preference in Mice Alters Dorsal Striatum Neurotransmission(Wiley, 2019-11) Fritz, Brandon M.; Munoz, Braulio; Atwood, Brady K.; Pharmacology and Toxicology, School of MedicineBackground Although it is widely acknowledged that the risk of developing an alcohol use disorder (AUD) is strongly influenced by genetic factors, very little is known about how this genetic predisposition may alter neurotransmission in a way that promotes AUD susceptibility. The dorsal striatum has garnered increased attention as a brain region of interest in AUD development given its significant roles in goal‐directed and habitual behavior. Methods In the present work, dorsal striatal neurotransmission parameters were measured in preclinical mouse models of high and low AUD risk. We performed brain slice whole‐cell patch clamp electrophysiological recordings from medium spiny neurons (MSNs) in the dorsomedial (DMS) and dorsolateral (DLS) striatum of naïve adult male and female selectively bred high‐ and low‐alcohol–preferring lines of mice (HAP and LAP). Results We found that MSNs of HAP mice were significantly more excitable than those of LAP mice, specifically in the DLS. Additionally, the frequencies of spontaneous glutamate‐ and GABA‐mediated currents were both elevated in HAP mice relative to LAP mice in both dorsal striatal subregions, whereas amplitude differences were more variable between lines and subregions. AMPAR/NMDAR current ratios were significantly lower in HAP mice in both DLS and DMS. Conclusions Collectively, these results suggest that genetic predisposition for high or low alcohol consumption produces significantly different basal functional states within both DLS and DMS which may be important factors in the behavioral phenotypes of HAP and LAP mice. ItemA High-fat, High-sugar ‘Western’ Diet Alters Dorsal Striatal Glutamate, Opioid, and Dopamine Transmission in Mice(Elsevier, 2018-02) Fritz, Brandon M.; Muñoz, Braulio; Yin, Fuqin; Bauchle, Casey; Atwood, Brady K.; Psychiatry, School of MedicineUnderstanding neuroadaptations involved in obesity is critical for developing new approaches to treatment. Diet-induced neuroadaptations within the dorsal striatum have the capacity to drive excessive food seeking and consumption. Five-week-old C57BL/6J mice consumed a high-fat, high-sugar ‘western diet’ (WD) or a control ‘standard diet’ (SD) for 16 weeks. Weight gain, glucose tolerance, and insulin tolerance were measured to confirm an obese-like state. Following these 16 weeks, electrophysiological recordings were made from medium spiny neurons (MSNs) in the medial (DMS) and lateral (DLS) portions of dorsal striatum to evaluate diet effects on neuronal excitability and synaptic plasticity. In addition, fast-scan cyclic voltammetry evaluated dopamine transmission in these areas. WD mice gained significantly more weight and consumed more calories than SD mice and demonstrated impaired glucose tolerance. Electrophysiology data revealed that MSNs from WD mice demonstrated increased AMPA-to-NMDA receptor current ratio and prolonged spontaneous glutamate-mediated currents, specifically in the DLS. Evoked dopamine release was also significantly greater and reuptake slower in both subregions of WD striatum. Finally, dorsal striatal MSNs from WD mice were significantly less likely to demonstrate mu-opioid receptor-mediated synaptic plasticity. Neuronal excitability and GABAergic transmission were unaffected by diet in either striatal subregion. Our results demonstrate that a high-fat, high-sugar diet alters facets of glutamate, dopamine, and opioid signaling within the dorsal striatum, with some subregion specificity. These alterations within a brain area known to play a role in food motivation/consumption and habitual behavior are highly relevant for the clinical condition of obesity and its treatment. ItemInput-selective adenosine A1 receptor-mediated synaptic depression of excitatory transmission in dorsal striatum(Springer Nature, 2021-03-18) Fritz, Brandon M.; Yin, Fuqin; Atwood, Brady K.; Pharmacology and Toxicology, School of MedicineThe medial (DMS) and lateral (DLS) dorsal striatum differentially drive goal-directed and habitual/compulsive behaviors, respectively, and are implicated in a variety of neuropsychiatric disorders. These subregions receive distinct inputs from cortical and thalamic regions which uniquely determine dorsal striatal activity and function. Adenosine A1 receptors (A1Rs) are prolific within striatum and regulate excitatory glutamate transmission. Thus, A1Rs may have regionally-specific effects on neuroadaptive processes which may ultimately influence striatally-mediated behaviors. The occurrence of A1R-driven plasticity at specific excitatory inputs to dorsal striatum is currently unknown. To better understand how A1Rs may influence these behaviors, we first sought to understand how A1Rs modulate these distinct inputs. We evaluated A1R-mediated inhibition of cortico- and thalamostriatal transmission using in vitro whole-cell, patch clamp slice electrophysiology recordings in medium spiny neurons from both the DLS and DMS of C57BL/6J mice in conjunction with optogenetic approaches. In addition, conditional A1R KO mice lacking A1Rs at specific striatal inputs to DMS and DLS were generated to directly determine the role of these presynaptic A1Rs on the measured electrophysiological responses. Activation of presynaptic A1Rs produced significant and prolonged synaptic depression (A1R-SD) of excitatory transmission in the both the DLS and DMS of male and female animals. Our findings indicate that A1R-SD at corticostriatal and thalamostriatal inputs to DLS can be additive and that A1R-SD in DMS occurs primarily at thalamostriatal inputs. These findings advance the field’s understanding of the functional roles of A1Rs in striatum and implicate their potential contribution to neuropsychiatric diseases.