Browsing by Subject "Methamphetamine"
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Item Locomotor and discriminative stimulus effects of three benzofuran compounds in comparison to abused psychostimulants(Elsevier B.V., 2023-08-21) Hill, Rebecca D.; Shetty, Ritu A.; Sumien, Nathalie; Forster, Michael J.; Gatch, Michael B.AIMS: Benzofurans are used recreationally, due their ability to cause psychostimulant and/or entactogenic effects, but unfortunately produce substantial adverse effects, including death. Three benzofurans 5-(2-aminopropyl)-2,3-dihydrobenzofuran (5-APDB), 5-(2-aminopropyl)-2,3-dihydrobenzofuran (5-MAPB) and 6-(2-aminopropyl) benzofuran (6-APB) were tested to determine their behavioral effects in comparison with 2,3-methylenedioxymethamphetamine (MDMA), cocaine, and methamphetamine. METHODS: Locomotor activity was tested in groups of 8 male Swiss-Webster mice in an open-field task to screen for locomotor stimulant or depressant effects and to identify behaviorally active doses and times of peak effect. Discriminative stimulus effects were tested in groups of 6 male Sprague-Dawley rats trained to discriminate MDMA (1.5 mg/kg), cocaine (10 mg/kg), or methamphetamine (1 mg/kg) from saline using a FR 10 for food in a two-lever operant task. RESULTS: In the locomotor activity test, MDMA (ED(50) = 8.34 mg/kg) produced peak stimulant effects 60 to 80 min following injection. 5-MAPB (ED(50) = 0.92 mg/kg) produced modest stimulant effects 50 to 80 min after injection, whereas 6-APB (ED(50) = 1.96 mg/kg) produced a robust stimulant effect 20 to 50 min after injection. 5-APDB produced an early depressant phase (ED(50) = 3.38 mg/kg) followed by a modest stimulant phase (ED(50) = 2.57 mg/kg) 20 to 50 min after injection. In the drug discrimination tests, 5-APDB (ED(50) = 1.02 mg/kg), 5-MAPB (ED(50) = 1.00 mg/kg) and 6-APB (ED(50) = 0.32 mg/kg) fully substituted in MDMA-trained rats, whereas only 5-MAPB fully substituted for cocaine, and no compounds fully substituted for methamphetamine. CONCLUSIONS: The synthetic benzofuran compound 5-APDB and 5-MAPB produced weak locomotor effects, whereas 6-APB produced robust locomotor stimulant effects. All compounds were more potent than MDMA. All three compounds fully substituted in MDMA-trained rats suggesting similar subjective effects. Taken together, these results suggest that these benzofuran compounds may have abuse liability as substitutes for MDMA.Item METHAMPHETAMINE (METH) REGULATES ASTROCYTE EXCITATORY AMINO ACID TRANSPORTER-2 (EAAT-2) VIA ACTIVATION OF TRACE AMINE ASSOCIATED RECEPTOR (TAAR1) AND DOWNSTREAM CAMP SIGNALING(2014-03) Cisneros, Irma E.; Ghorpade, AnujaMethamphetamine (METH) abuse has prevailed as a drug epidemic within the United States and worldwide with an estimated 27.4 million users.Short-term side effect of METH abuse include a heightened libido and impaired judgment increasing the users chances of contracting Human immunodeficiency virus-1 (HIV-1). HIV-1 associated dementia (HAD), is the most severe manifestation of HIV-1-associated neurocognitive disorders and is an important neurological complication of HIV-1 infection characterized by cognitive, behavioral and motor dysfunction. Long-term METH users share characterized neurocognitive defects and disorders as HIV-1 infected individuals.Molecular outcomes of METH/HIV-1-induced neurotoxicity include Excitotoxicity, oxidative stress, glial cell activation, inflammation, and hyperthermia. Astrogliosis is a key pathological feature of METH exposure and HAD, however, the molecular mechanisms remain unclear. The current studies investigate METH-induced TAAR1 activation and will uncover molecular mechanisms associated with glutamate transporter (EAAT-2) dysregulation. Purpose (a): Glutamate is an excitatory neurotransmitter that is highly regulated in the central nervous system (CNS). High concentrations of extracellular glutamate result in excitotoxicity and can exacerbate neurodegenerative disorders, including human immunodeficiency virus-1 (HIV-1)-associated neurocognitive disorders (HAND). Additionally, drugs of abuse such as methamphetamine (METH) can increase the severity of excitotoxicity and can accelerate HAND. Excitatory amino acid transporter-2 (EAAT-2) is responsible for approximately 90% of extracellular glutamate uptake from the synapse and is primarily localized in astrocytes. Dysregulation of EAAT-2 leads to astrocytes decreased ability to clear glutamate. Methods (b): It is established that METH leads to excitotoxicity in neurons, however, in astrocytes the molecular mechanisms resulting in METH-mediated EAAT-2 dysregulation are unclear. Previously we showed that HIV-1ADA, METH and transient hyperthermia regulates localization and expression of astrocyte trace amine associated receptor 1 (TAAR1). Results (c): Our data shows METH-induced activation of astrocyte TAAR1 increases intracellular cAMP levels in astrocytes that is significantly decreased in siTAAR1-transfected astrocytes. Further, METH treatment downregulates EAAT-2 mRNA levels. We propose downstream cAMP signaling pathways of METH-induced astrocyte TAAR1 activation result in EAAT-2 dysregulation. Conclusions (d): The results of this study will uncover novel molecular mechanism of METH-induced astrocyte TAAR1 activation and the downstream effects of cAMP signaling on astrocyte EAAT-2 levels in the context of HAND.Item Neurobehavioral and biochemical consequences of chronic, low-dose methamphetamine exposure in male and female mice(2022-08) Davis, Delaney L.; Sumien, Nathalie; Huang, Ren-Qi; Gatch, Michael B.; Phillips, Nicole R.; Schreihofer, Derek A.; Ma, RongAlthough prescription psychostimulants are effective in reducing attention deficit hyperactivity disorder (ADHD) symptomology, misuse of these drugs can pose serious risks such as potential abuse, dependence, and/or neurotoxicity. Of particular concern is that young adults have the highest prevalence of prescription stimulant misuse, with almost 10% of college students admitting to using amphetamine (e.g. Adderall) or methylphenidate (e.g. Ritalin) products. Despite these drugs being widely used for therapeutic and recreational use, the long-term effects of prescription stimulants have not been systematically evaluated in controlled clinical trials. Therefore, it is critical to conduct this research because young adults may be a vulnerable, at-risk population to the potential adverse consequences of long-term amphetamine use. This dissertation research evaluates the biochemical and behavioral consequences of chronic exposure of the prototypical psychostimulant, methamphetamine (METH), in a rodent model. It is hypothesized that repeated doses of METH, within the therapeutic dosing range used in a clinical setting, will induce neurotoxicity through the interplay of biological mechanisms of oxidative stress, glutamate excitotoxicity, neuroinflammation and epigenetic alterations and increase susceptibility to addiction that will be exacerbated by aging processes. Overall, the body of results showed short-term alterations in brain biochemistry and behavioral function, that do not necessarily persist past 5 months after METH treatment. In conclusion, this dissertation highlights the importance of long-term studies in addressing prescription stimulant misuse in an adult population to better understand the safety of these widely used and prescribed psychostimulants.Item TAARgeting Astrogliosis and Mitochondrial Dysfunction during METH Exposure and HIV-relevant Neuroinflammation(2017-12-01) Borgmann, Kathleen; Ghorpade, Anuja; Wordinger, Robert J.; Berg, Rance E.As a popular psychostimulant, methamphetamine (METH) use leads to long-lasting, strong euphoric effects. METH exacerbates the severity and onset of HIV-associated neurocognitive disorders (HAND), which affect 30-70% of the 37.6 million people globally infected with HIV. Most neurodegenerative diseases share neuroinflammation as a common pathogenic mechanism. Neuroinflammation, HIV and METH dysregulate a wide range of brain functions including neuronal signaling, glial activation, viral infection, oxidative stress and excitotoxicity. Since neuroglia determine the outcome of neurological disease, we investigate the mechanisms regulating astrocyte-mediated neurotoxicity in the context of METH and HIV comorbidity. To these ends, we examined the expression, localization and function of the novel METH astrocyte receptor, trace amine associated receptor 1 (TAAR1) in an extended METH in vitro model, which mimics chronic residual METH concentrations between binges, and HIV-associated activation. In our model, TAAR1 levels and localization to the endoplasmic reticulum and plasma membranes increased with METH and HIV-induced astrogliosis. Extended physiological METH exposure led to augmented calcium flux, a mechanism known to mediate ER and mitochondrial, and oxidative stress. METH induced dysregulation of astrocyte mitochondrial morphology by elevating mitofusin expression and inhibitory phosphorylation of dynamin-related protein-1. While METH decreased oxygen consumption and ATP levels during acute exposure, chronic treatment significantly enhanced both. Together, these changes increased expression of antioxidant proteins, augmenting the astrocyte’s oxidative capacity, but also oxidative damage. METH and HIV activation impaired excitatory amino acid transporter 2 (EAAT2) expression and activity, which were recovered by inhibition of TAAR1 with EPPTB, a TAAR1 selective antagonist. Together, these data highlight several mechanisms regulating METH/HIV-induced, astroglia-mediated neurotoxicity and the potential for astrocyte targeted intervention via TAAR1 during chronic disease. We propose that equilibrium between agonism of neuronal TAAR1 and antagonism of astrocyte TAAR1 will need to be further investigated to balance the neuroprotective benefits of TAAR1 targeting drugs in the CNS during HIV and METH comorbidity.Item The ER-mitochondrial Interface in astrocytes during methamphetamine exposure and HIV-1 infection(2022-12) Proulx, Jessica M.; Borgmann, Kathleen; Park, InWoo; Cunningham, Rebecca L.; Krishnamoorthy, Raghu R.; Yang, Shaohua; Maddux, Scott D.Early during infection, human immunodeficiency virus 1 (HIV-1) invades the central nervous system (CNS) and can persist for life, despite effective antiretroviral treatment. Infection and activation of residential glial cells leads to low viral replication and chronic inflammation, which damage neurons contributing to a spectrum of HIV-associated neurocognitive disorders (HAND). Notably, substance use, including methamphetamine (METH) is disproportionately elevated among people living with HIV-1 and can increase the risk and severity of HAND. Thus, the National Institutes on Drug Abuse have declared HIV-1 and substance use comorbidity as a high research priority. Astrocytes are the most numerous glial cells and provide essential support to neurons. Chronic activation of astrocytes, such as during HAND or METH use disorders, can shift astrocytes to become neurotoxic. Delineating cellular targets to regulate astrocyte function is essential to ensure neuronal fitness during a pathological challenge. Endoplasmic reticulum (ER) and mitochondria contact sites, termed mitochondria-associated ER membranes (MAMs), are key cellular platforms in neuropathology, where calcium dysregulation, unfolded protein response (UPR) sensors, and mitochondrial dysfunction are notable MAM-mediated mechanisms underlying astrocyte dysfunction. We hypothesize that the ER-mitochondria interface may serve as a therapeutic target for astrocyte dysfunction via calcium and non-canonical UPR signaling during HIV-1 and METH pathogenesis. Primary human astrocytes were infected with a pseudotyped HIV-1 and/or exposed to low doses of METH for seven days. Following HIV-1 infection and/or chronic METH exposure, astrocytes had increased mitochondrial respiration, cytosolic calcium flux and protein expression of UPR/MAM mediators. Notably, inositol-requiring enzyme 1α (IRE1α) was prominently upregulated following both HIV-1 infection and chronic METH exposure. Further investigations revealed IRE1α modulates astrocyte mitochondrial respiration, glycolytic function, morphological activation, inflammation, and glutamate uptake. We then investigated a novel METH-binding receptor, trace amine-associated receptor 1 (TAAR1) as a potential upstream regulator to METHinduced UPR/MAM mediator expression. Indeed, selective antagonism of TAAR1 significantly suppressed UPR/MAM protein expression, including IRE1α. Altogether, our findings emphasize the importance and potential therapeutic intervention of UPR/MAM messengers, namely IRE1α and calcium, to combat astrocyte dysfunction, Moreover, TAAR1 may be an upstream target for METH-mediated astrocyte dysfunction.Item TRANSIENT METHAMPHETAMINE-ASSOCIATED HYPERTHERMIA MODULATES ASTROCYTE TRACE AMINE ASSOCIATED RECEPTOR-1 ACTIVATION AND EXACERBATES HIV-1-INDUCED NEURODEGENERATION(2013-04-12) Cisneros, IrmaPurpose: Methamphetamine (METH) is a highly abused and addictive psychostimulant. METH heightens sexual arousal and decreases inhibition increasing the probability for acquiring human immunodeficiency virus-1 (HIV-1). HIV-1 results in cognitive effects, such as HIV-associated dementia (HAD) characterized by similar neurotoxic mechanisms as METH. Astrogliosis and hyperthermia are key pathological features of METH exposure and HAD. In context of our studies, METH abuse increases brain temperature by approximately 2° C, mimicking a fever common during early HIV-1 infection. A moderate increase in brain temperature exacerbates neuroinflammatory processes synergistically effecting METH/HIV-1-associated neurodegeneration. Methods: Astrocytes sensitivity to METH led to the investigation of astrocyte TAAR1 as a receptor mechanism for METH-induced effects in astrocytes. Previously we showed localization and function of astrocyte TAAR1. Documented TAAR1 thermoregulatory responses led the expansion of our studies to investigate METH-associated hyperthermia in METH/HIV-1-induced astrocyte activation. Results: Furthermore, preliminary data suggest TAAR1 regulation in the presence of thermal stress. Elevated temperatures increased GFAP expression and cytokine secretion. We propose activation of astrocyte TAAR1 mediates METH/HIV-1-induced neurodegeneration, further modulated by METH-associated hyperthermia. Conclusions: The results will lead to understanding of the mechanisms and pathological features associated with METH and HIV-1 neurodegeneration and potential therapeutic targets in the CNS.