Browsing by Subject "methamphetamine"

Now showing 1 - 7 of 7
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    Core Body Temperature Regulation and Locomotor Activity
    (Office of the Vice Chancellor for Research, 2014-04-11) Yoo, Yeonjoo; Kelley, Maire; Zaretsky, Dmitry; Molkov, Yaroslav
    Methamphetamine (Meth) enhances locomotor activity, and is known to cause life-threatening hyperthermia. There has been much debate about whether the locomotion plays a major role in hyperthermia caused by Meth or other stimulants. The existing model of the neural circuitry putatively involved in this phenomenon [1] accurately reproduces the temperature response to the different doses of Meth. We compared locomotor activity observed in the same experiments with activation patterns of neuronal populations as predicted by the model. We found that time-courses of locomotor activity closely resembles the activity of one particular node in the model putatively representing the medullary level. However, the data on locomotion did not match the model in the initial phase of the response within 1 hour after the injection. Therefore, we hypothesized that there were some changes in thermogenesis and heat exchange mechanisms that largely control temperature response during the first hour and make the influence of locomotion relatively small. The objective of the study was to measure the temperature dynamics in rats running on a treadmill at different speeds and to construct a mathematical model explaining the mechanism of their core body temperature response to such an intervention that takes into account potential changes in heat exchange, sensory input and feedback control mechanisms. In the experiments for every speed of 0, 6, 12, and 18 m/min we had 4 rats running for 15 min. For each speed we averaged the temperature over 4 rats to get the average temperature response curve. First, we found that the temperature response curves for different treadmill speeds were not different statistically. Second, every response curve starts with a short but profound (~0.25 deg C in the first 5 min) drop in the body temperature followed by virtually linear rise of the temperature which significantly (by ~1 deg C) overshoots the baseline temperature. To explain these findings we set up a model in a form of a system of two differential equations that described the change in the body temperature and the change in the body heat production under the hypothesis that there are contributions of varying heat exchange, sensory input and feedback mechanisms in thermogenesis. All parameters in the system were subject to fitting experimental time series of temperature response of rats to 4 consistent speeds of 0, 6, 12, and 18 m/min on treadmills. We found, that a sudden drop of the body temperature below the baseline in the first five minutes after rats were removed from their cages and placed on a treadmill was a result of the increased heat dissipation caused by changes in the body position and movement of rats. The following fast recovery of the body temperatures to the normal level was provided by the feedback mechanisms activated by the temperature drop and changed sensory input. Meth continues to stimulate thermogenesis even after the baseline temperature is achieved from feedback mechanisms. Estimated contribution of the locomotion was negligible as compared to the latter and hence played a relatively small role in the temperature change. We predict that varying locomotion might manifest itself in temperature dynamics after much longer (~1 hour) exposure to running. The suggested system, which considers major factors defining body temperature response, can help to uncover the mechanisms of hyperthermia elicited by Meth, but also can be used to understand the thermoregulatory mechanisms which underlie the responses to simultaneous changes in environmental and physical conditions.
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    HIV and drug abuse mediate astrocyte senescence in a β‐catenin‐dependent manner leading to neuronal toxicity
    (Wiley, 2017-10) Yu, Chunjiang; Narasipura, Srinivas D.; Richards, Maureen H.; Hu, Xiu‐Ti; Yamamoto, Bryan; Al‐Harthi, Lena; Pharmacology and Toxicology, School of Medicine
    Emerging evidence suggests that cell senescence plays an important role in aging‐associated diseases including neurodegenerative diseases. HIV leads to a spectrum of neurologic diseases collectively termed HIV‐associated neurocognitive disorders (HAND). Drug abuse, particularly methamphetamine (meth), is a frequently abused psychostimulant among HIV+ individuals and its abuse exacerbates HAND. The mechanism by which HIV and meth lead to brain cell dysregulation is not entirely clear. In this study, we evaluated the impact of HIV and meth on astrocyte senescence using in vitro and several animal models. Astrocytes constitute up to 50% of brain cells and play a pivotal role in marinating brain homeostasis. We show here that HIV and meth induce significant senescence of primary human fetal astrocytes, as evaluated by induction of senescence markers (β‐galactosidase and p16INK 4A), senescence‐associated morphologic changes, and cell cycle arrest. HIV‐ and meth‐mediated astrocyte senescence was also demonstrated in three small animal models (humanized mouse model of HIV/NSG‐huPBMCs, HIV‐transgenic rats, and in a meth administration rat model). Senescent astrocytes in turn mediated neuronal toxicity. Further, we show that β‐catenin, a pro‐survival/proliferation transcriptional co‐activator, is downregulated by HIV and meth in human astrocytes and this downregulation promotes astrocyte senescence while induction of β‐catenin blocks HIV‐ and meth‐mediated astrocyte senescence. These studies, for the first time, demonstrate that HIV and meth induce astrocyte senescence and implicate the β‐catenin pathway as potential therapeutic target to overcome astrocyte senescence.
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    “Meth Mouth”: Rampant Caries in methamphetamine abusers
    (2006-03) Edwards, Paul C.; Shaner, John W.; Kimmes, N.; Saini, Tarnjit S.
    Rampant dental caries is a characteristic finding in methamphetamine abusers. The popularity of methamphetamine, particularly among the gay community where it is linked to the spread of HIV, its ready availability, and rapid spread across the nation have placed methamphetamine use in an epidemic status in many communities unaccustomed to dealing with drug abuse. We present a case of a 25-year-old male “meth” abuser of unknown HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) status to promote recognition by the health care team of the association of rampant dental caries with methamphetamine abuse for appropriate intervention to ensure successful treatment and prevention of disease progression.
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    Meth Use in Indiana
    (Richard M. Fairbanks School of Public Health, 2010-07) Greene, Marion; Williams, Matthew; Wright, Eric
    Methamphetamine, a derivative of amphetamine, is a synthetic stimulant that affects the central nervous system. It is commonly known as meth, speed, and chalk; in its smoked form, it is often referred to as ice, crystal, crank, and glass. Due to its high potential for abuse, meth is classified as a Schedule II drug and is legally available only by prescription. Abuse of the drug is a serious problem in the United States, often resulting in devastating medical, psychological, social, and legal consequences. According to estimates from the 2008 National Survey on Drug Use and Health (NSDUH), 12.6 million Americans (or 5.0 percent) ages 12 and older have tried meth at least once in their life.
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    Neurotoxicity to dopamine neurons after the serial exposure to alcohol and methamphetamine: Protection by COX-2 antagonism
    (Elsevier, 2019) Blaker, Amanda L.; Rodriguez, Eric A.; Yamamoto, Bryan K.; Pharmacology and Toxicology, School of Medicine
    A significant co-morbidity exists between alcohol and methamphetamine (Meth) in humans but the consequences and mechanisms underlying their co-morbid effects remain to be identified. A consequence associated with the abuse of either alcohol or Meth involves inflammation but little is known about the role of inflammation in a possible neurotoxicity arising from their co-exposure. Sprague Dawley rats were allowed 28 days of intermittent, voluntary access to 10% ethanol (EtOH) followed by a neurotoxic binge administration of Meth. EtOH drinking followed by Meth increased microglial cell counts and produced morphological changes in microglia of the substantia nigra pars compacta 2 h after Meth administration that were distinct from those produced by either EtOH or Meth alone. These effects preceded the activation of cleaved caspase-3 in dopamine cell bodies, as well as decreases in tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra and dopamine transporter (DAT) immunoreactivity in the striatum measured at 7 days after Meth. Intervention with a selective COX-2 inhibitor during EtOH drinking prevented the changes in microglia, and attenuated the increase in cleaved caspase-3, and decreases in TH and DAT after Meth administration. Furthermore, motor dysfunction measured by a rotarod test was evident but only in rats that were exposed to both EtOH and Meth. The motor dysfunction was ameliorated by prior inhibition of COX-2 during EtOH drinking. The exaggerated neurochemical and behavioral deficits indicate that the comorbidity of EtOH and Meth induces a degeneration of the nigrostriatal pathway and support the role of inflammation produced by EtOH drinking that primes and mediates the neurotoxic consequences associated with the common co-morbidity of these drugs.
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    Orexinergic Neurotransmission in Temperature Responses to Amphetamines
    (Office of the Vice Chancellor for Research, 2014-04-11) Behrouzvaziri, Abolhassan; Fu, Daniel; Tan, Patrick; Zaretskaia, Maria; Rusyniak, Daniel; Zaretsky, Dmitry; Molkov, Yaroslav
    Derivatives of amphetamines are widely abused all over the world. After long-term use cognitive, neurophysiological, and neuroanatomical deficits have been reported. Neurophysiological deficits are enhanced by hyperthermia, which itself is major mortality factor in drug abusers. Temperature responses to injections of methamphetamine are multiphasic and include both hypothermic and hyperthermic phases, which are highly dependent on ambient temperature and previous exposure to the drug. Also, amphetamine derivatives differentially affect various neuromediator systems, such as dopaminergic, noradrenergic and serotonergic. Temperature responses to methamphetamine (Meth) at room temperature have non-trivial dose-dependence, which is far from being understood. Intermediate doses of Meth cause less hyperthermia than both low and high doses of the drug. Also, maxima of all responses have different latency responses to low and high doses are virtually immediate, while a response to an intermediate dose appears to be delayed. In our previous modeling study we demonstrated that such dose-dependence could be explained by interaction of inhibitory and excitatory drives induced by Meth [1]. Recently, we have published data on the involvement of orexinergic neurotransmission in Meth-induced temperature responses [2] where the low dose (10 mg/kg, i.p.) of SB-334867 (SB), an antagonist of the first type of orexin receptors (ORX1), was injected 30 min prior to various doses of Meth. While this dose of antagonist clearly suppressed the response to low (1 mg/kg) and intermediate (5 mg/kg) doses of Meth, the effect was statistically significant only at the late phase (t > 60 min) of the response to intermediate dose. At the early phase (t < 60 min) any drug-related changes were marred by stress-induced temperature fluctuations resulting from two intraperitoneal injections. In a separate set of experiments a high dose of the same antagonist (30 mg/kg, i.p.) suppressed the effect of low doses of Meth even more, but in contrast, it significantly amplified the responses to the higher doses (5 and 10 mg/kg) of Meth. Understanding the mechanism that differentially affect excitatory and inhibitory components of temperature responses can have profound importance for explaining cases of life-threatening hyperthermia after Meth administration. Therefore, we performed a mathematical modeling study to provide mechanistic interpretation of SB action. Our previous model [1] was created to describe Meth-sensitive compartments and dynamics of the neural populations defining temperature responses for various doses of Meth. We hypothesized that a specific distribution of orexin receptors over the structures involved in the neural control of temperature is responsible for the complex dependence of the Meth-induced responses on the dose of orexin antagonist. To test this hypothesis we extended the model by incorporating ORX receptors that mediated Meth- and stress-dependent inputs. We showed that the low dose of antagonist almost fully suppresses the responses to both stress and intermediate doses of Meth by disruption of the corresponding inputs to the control structures. This allows hypothesizing that the excitatory component in temperature response to both stress and low dose of Meth is mediated by ORX1 receptors. Amplification of the response to the high dose of Meth at high dose of the antagonist points out to the involvement of a mechanism different from ORX1 receptor blockade. We speculate that at high doses SB becomes non-specific to ORX1 receptors and starts affecting ORX2 receptors. Further, ORX2 activation disinhibits the structure activated by high doses of Meth, which underlies the exaggerated responses to high doses of Meth at the presence of a high dose of SB. We conclude that both excitatory and inhibitory components in temperature responses to Meth administration and stress are mediated by orexinergic pathways. Non-specificity of SB at high doses to ORX1 receptors manifests itself in additional suppression of inhibition resulting in facilitation of the responses to high-doses of Meth.
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    Temporally distinct impairments in cognitive function following a sensitizing regimen of methamphetamine
    (2014-08-01) Janetsian, Sarine Sona; Lapish, Christopher; Neal-Beliveau, Bethany S.; Goodlett, Charles R.
    Methamphetamine (MA) is a widely abused psychostimulant that has been shown to evoke an array of neurobiological abnormalities and cognitive deficits in humans and in rodent models (Marshall & O'Dell, 2012). Alterations in cognitive function after repeated drug use may lead to impaired decision-making, a lack of behavioral control, and ultimately the inability to abstain from drug use. Human studies have shown that alterations in neurobiology resulting from prolonged MA use may lead to a number of cognitive deficits, including impairments in executive function, learning, memory, and impulsivity. These impairments, specifically those that engage the prefrontal cortex (PFC) or hippocampus (HC), may persist or recover based on the duration of abstinence. In rodents, repeated intermittent injections of MA yield protracted changes in neurobiology and behavior, which have been shown to effectively model a number of the biological and cognitive abnormalities observed in addiction. In order to assess the temporal evolution of impaired cognitive function throughout abstinence, sensitization was first induced in rats (7 x 5.0 mg/kg MA over 14 days). MA-treated rats initially exhibited a robust increase in locomotion that transitioned to stereotypy as the induction phase progressed. Then, the effects of MA sensitization on social interaction (SI), temporal order recognition (TOR) and novel object recognition (NOR) was assessed at one-day and 30-days post induction. No differences were observed in SI in either group or after a single injection of MA. However, an acute injection of 5.0 mg/kg of MA 30-minutes prior to testing dramatically reduced SI time. Impairments in TOR and NOR were observed in MA-treated rats after one day of abstinence, and impairments in TOR, but not NOR, were observed on day 30 of abstinence. No differences in TOR and NOR after a single injection of MA or saline were observed. These data establish that after 30 days of abstinence from a sensitizing regimen of MA, the ability to recall the temporal sequence that two stimuli were encountered was impaired and that was not attributable to impaired novelty detection. These data also suggest that at least some of the neurocognitive abnormalities caused by chronic MA administration may normalize after prolonged abstinence, since the ability to detect novelty recovered after 30 days of abstinence. These data provide compelling support that, since MA-sensitization caused temporal deficits in memory, PFC and HC function may be differentially impaired throughout the time course of abstinence.