Browsing by Subject "Amphetamine"

Now showing 1 - 8 of 8
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    Acute drug effects on habitual and non-habitual responding in crossed high alcohol preferring mice
    (Springer Nature, 2018-07) Houck, Christa A.; Grahame, Nicholas J.; Psychology, School of Science
    RATIONALE: Drug reward plays a central role in acquiring drug-seeking behavior. However, subjects may continue using drugs despite negative consequences because self-administration becomes habitual, and divorced from outcome values. Although a history of drug and alcohol use expedite habit acquisition, and in spite of the fact that self-administration leads to intoxication, the acute effects of drugs on habitual responding are not well understood. OBJECTIVES: We sought to observe how acute ethanol and amphetamine affect the balance between habitual and goal-directed behavior, as measured by a fluid-reinforced operant conditioning task. METHODS: Selectively bred crossed high-alcohol-preferring (cHAP) mice were trained on an operant conditioning task reinforced on a variable interval schedule with 1% banana solution, which was subsequently devalued via LiCl pairing in half the animals. Ethanol (1.0 g/kg), amphetamine (2.0 mg/kg), or saline was administered prior to a post-devaluation test. RESULTS: Overall, mice showed habitual behavior, but when divided into high- or low-responding groups based on training response rates, saline-treated, low-responding animals devalued, while saline-treated high-responding animals did not. Furthermore, amphetamine elicited devaluation even in high-responding animals, while ethanol prevented devaluation even in low-responding animals. CONCLUSIONS: These data show that ethanol shifts animals toward behaving habitually. This may illuminate why alcohol-intoxicated individuals display impaired judgment about the relative merits of drinking, and potentially serve as a mechanism by which intoxicated subjects resume previously devalued behaviors, such as comorbid drug use. These findings also show that high variable interval response rates facilitate a shift from goal-directed to habitual behavior.
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    Amphetamine enhances endurance by increasing heat dissipation
    (APS, 2016-09-01) Morozova, Ekaterina; Yoo, Yeonjoo; Behrouzvaziri, Abolhassan; Zaretskaia, Maria; Rusyniak, Daniel; Zaretsky, Dmitry; Molkov, Yaroslav; Department of Mathematical Sciences, School of Science
    Athletes use amphetamines to improve their performance through largely unknown mechanisms. Considering that body temperature is one of the major determinants of exhaustion during exercise, we investigated the influence of amphetamine on the thermoregulation. To explore this, we measured core body temperature and oxygen consumption of control and amphetamine‐trea ted rats running on a treadmill with an incrementally increasing load (both speed and incline). Experimental results showed that rats treated with amphetamine (2 mg/kg) were able to run significantly longer than control rats. Due to a progressively increasing workload, which was matched by oxygen consumption, the control group exhibited a steady increase in the body temperature. The administration of amphetamine slowed down the temperature rise (thus decreasing core body temperature) in the beginning of the run without affecting oxygen consumption. In contrast, a lower dose of amphetamine (1 mg/kg) had no effect on measured parameters. Using a mathematical model describing temperature dynamics in two compartments (the core and the muscles), we were able to infer what physiological parameters were affected by amphetamine. Modeling revealed that amphetamine administration increases heat dissipation in the core. Furthermore, the model predicted that the muscle temperature at the end of the run in the amphetamine‐treated group was significantly higher than in the control group. Therefore, we conclude that amphetamine may mask or delay fatigue by slowing down exercise‐induced core body temperature growth by increasing heat dissipation. However, this affects the integrity of thermoregulatory system and may result in potentially dangerous overheating of the muscles.
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    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.
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    Combined and sequential effects of alcohol and methamphetamine in animal models
    (Elsevier, 2021) Stafford, Alexandra M.; Yamamoto, Bryan K.; Phillips, Tamara J.; Pharmacology and Toxicology, School of Medicine
    Comorbid drug use, often alcohol with other drugs, poses significant health and societal concerns. Methamphetamine is among the illicit drugs most often co-used with alcohol. The current review examines the animal literature for impacts of comorbid alcohol and methamphetamine exposure. We found evidence for additive or synergistic effects of combined or sequential exposure on behavior and physiology. Dopaminergic, serotonergic, and glutamatergic systems are all impacted by combined exposure to alcohol and methamphetamine and cyclooxygenase-2 activity plays an important role in their combined neurotoxic effects. Adverse consequences of comorbid exposure include altered brain development with prenatal exposure, impaired learning and memory, motor deficits, gastrotoxicity, hepatotoxicity, and augmented intake under some conditions. Given high susceptibility to drug experimentation in adolescence, studies of co-exposure during the adolescent period and of how adolescent exposure to one drug impacts later use or sensitivity to the other drug should be a priority. Further, to gain traction on prevention and treatment, additional research to identify motivational and neurobiological drivers and consequences of comorbid use is needed.
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    Effect of Low Dose of Amphetamine on Thermoregulation System and Performance of Rats Running on Treadmills
    (Office of the Vice Chancellor for Research, 2015-04-17) Behrouzvaziri, Abolhassan; Molkov, Yaroslav; Morozova, Ekaterina; Yoo, Yeonjoo; Zaretskaia, Maria; Zaretsky, Dmitry
    Amphetamine has been used widely as a performance-enhancing drug among athletes. There are numerous reports showing that low dose of amphetamine increases one’s performance by suppressing sensations of fatigues. However, a little has been known about the mechanism by which such an effect of amphetamine is caused. The goal of this study was to investigate how a low dose of amphetamine changed the duration and the capacity of running in rats by studying thermoregulation system of rats running on treadmills with experimental results and a mathematical model. 12 rats were separated into two groups of 6 and rats in the experimental group were injected with 2mg/kg of amphetamine and ones in the control group were injected with saline. Then each rat in both groups ran on a treadmill at the room temperature (25°􀜥) while the speed and the incline of the treadmill were increased stepwise in every 3 minutes. The running time of individual rats were determined by their ability of keeping up with the intensity of running and the core body temperatures and the oxygen consumptions (􀜸􀜱􀬶)of rats were recorded during the experiments. Then a mathematical model was constructed to describe rates of temperature changes in the core and muscles by quantifying the heat dissipations and heat productions using 􀜸􀜱􀬶. Modeling revealed that amphetamine increases the heat dissipation in the core body, which slowed down the core temperature increase. Therefore rats injected with amphetamine were kept their core temperatures below approximately 40 °C for longer time, at which both groups were unable to run anymore. Additionally, the fact that the core temperature at the end of run was not significantly different between two groups, while muscle temperature was significantly different, suggests that the indicator of running capacity was the core temperature, rather than the muscle temperature. Finally, the level of overheating in muscles for the amphetamine group was severe enough to cause damages in muscles.
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    Independent of 5-HT1A receptors, neurons in the paraventricular hypothalamus mediate ACTH responses from MDMA
    (Elsevier, 2013-10-25) Zaretsky, Dmitry V.; Zaretskaia, Maria V.; DiMicco, Joseph A.; Durant, Pamela J.; Ross, Christian T.; Rusyniak, Daniel E.; Emergency Medicine, School of Medicine
    Acute and chronic complications from the substituted amphetamine 3,4-methylenedioxymethamphetamine (MDMA) are linked to activation of the hypothalamic-pituitary-adrenal (HPA) axis. How MDMA activates the HPA axis is not known. HPA responses to stress are known to be mediated through the paraventricular (PVH) hypothalamus and to involve serotonin-1a (5-HT1A) receptors. We sought to determine if the PVH and 5-HT1A receptors were also involved in mediating HPA responses to MDMA. Rats were pretreated with either saline or a 5-HT1A antagonist, WAY-100635 (WAY), followed by a systemic dose of MDMA (7.5mg/kg i.v.). Animals pretreated with WAY had significantly lower plasma ACTH concentrations after MDMA. To determine if neurons in the PVH were involved, and if their involvement was mediated by 5-HT1A receptors, rats implanted with guide cannulas targeting the PVH were microinjected with the GABAA receptor agonist muscimol, aCSF, or WAY followed by MDMA. Compared to aCSF, microinjections of muscimol significantly attenuated the MDMA-induced rise in plasma ACTH (126 vs. 588pg/ml, P=<0.01). WAY had no effect. Our data demonstrates that neurons in the PVH, independent of 5-HT1A receptors, mediate ACTH responses to MDMA.
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    Proteomic Analysis of the Spinophilin Interactome in Rodent Striatum Following Psychostimulant Sensitization
    (MDPI, 2018-12-17) Watkins, Darryl S.; True, Jason D.; Mosley, Amber L.; Baucum, Anthony J., II; Biochemistry and Molecular Biology, School of Medicine
    Glutamatergic projections from the cortex and dopaminergic projections from the substantia nigra or ventral tegmental area synapse on dendritic spines of specific GABAergic medium spiny neurons (MSNs) in the striatum. Direct pathway MSNs (dMSNs) are positively coupled to protein kinase A (PKA) signaling and activation of these neurons enhance specific motor programs whereas indirect pathway MSNs (iMSNs) are negatively coupled to PKA and inhibit competing motor programs. An imbalance in the activity of these two programs is observed following increased dopamine signaling associated with exposure to psychostimulant drugs of abuse. Alterations in MSN signaling are mediated by changes in MSN protein post-translational modifications, including phosphorylation. Whereas direct changes in specific kinases, such as PKA, regulate different effects observed in the two MSN populations, alterations in the specific activity of serine/threonine phosphatases, such as protein phosphatase 1 (PP1) are less well known. This lack of knowledge is due, in part, to unknown, cell-specific changes in PP1 targeting proteins. Spinophilin is the major PP1-targeting protein in striatal postsynaptic densities. Using proteomics and immunoblotting approaches along with a novel transgenic mouse expressing hemagglutainin (HA)-tagged spinophilin in dMSNs and iMSNs, we have uncovered cell-specific regulation of the spinophilin interactome following a sensitizing regimen of amphetamine. These data suggest regulation of spinophilin interactions in specific MSN cell types and may give novel insight into putative cell-specific, phosphatase-dependent signaling pathways associated with psychostimulants.