Ryan R. Metzger

Differential effects of psychostimulants and related agents on dopaminergic and serotonergic transporter function.

High-dose administrations of amphetamine, methamphetamine, cathinone, methcathinone or methylenedioxymethamphetamine rapidly decrease dopamine and serotonin transporter function in vivo, as assessed in striatal synaptosomes obtained from drug-treated rats. In contrast, high-dose injections of fenfluramine, cocaine or methylphenidate had little or no effect on the activity of these transporters. Interestingly, the capacity of these agents to directly alter dopamine and serotonin uptake, as assessed in vitro by direct application to rat striatal synaptosomes, did not predict their potential to modulate transporter activity following in vivo administration. These findings demonstrate heretofore-unreported differences in the effects of these agents on monoamine transporter function, and a distinction between drug effects after direct application in vitro vs. administration in vivo.

Oxygen radicals diminish dopamine transporter function in rat striatum

Incubation of striatal synaptosomes with the oxygen radical generating enzyme, xanthine oxidase, decreased [3H]dopamine uptake: an effect attributable to a decreased Vmax. Concurrent incubation with the superoxide radical scavenger, superoxide dismutase, abolished the xanthine oxidase-induced decrease. These results indicate that, like methamphetamine administration in vivo, reactive oxygen species diminish dopamine transporter function in vitro. The significance of these findings to mechanisms responsible for effects of methamphetamine is discussed.

Methamphetamine treatment rapidly inhibits serotonin, but not glutamate, transporters in rat brain

Previous studies have demonstrated that multiple methamphetamine (METH) administrations rapidly and reversibly decrease dopamine transporter activity assessed in striatal synaptosomes. A role for reactive oxygen species was suggested by findings that: (1) METH treatment increases the formation of oxygen radicals in vivo; and (2) oxygen radicals, generated by the enzyme xanthine oxidase, attenuate dopamine uptake in vitro. To test the selectivity of transporter responses, the present study examined effects of METH and xanthine oxidase on [3H]serotonin ([3H]5HT) and [3H]glutamate transport into striatal synaptosomes. Multiple doses of METH, or incubation with xanthine oxidase, rapidly attenuated [3H]5HT transport; an effect attributable to a decrease in Vmax. The METH-induced decrease in transport activity completely recovered by 24 h, but was decreased again 1 week later. In contrast, [3H]glutamate transport was essentially unchanged after METH treatment or incubation with xanthine oxidase. These findings indicate that: (1) METH causes a rapid and reversible decrease in 5HT transporter activity; and (2) glutamate transporters are less susceptible than 5HT transporters to effects of reactive species or METH treatment.

Clinical clearance of the cervical spine in blunt trauma patients younger than 3 years: A multi-center study of the american association for the surgery of trauma

BACKGROUND Cervical spine clearance in the very young child is challenging. Radiographic imaging to diagnose cervical spine injuries (CSI) even in the absence of clinical findings is common, raising concerns about radiation exposure and imaging-related complications. We examined whether simple clinical criteria can be used to safely rule out CSI in patients younger than 3 years. METHODS The trauma registries from 22 level I or II trauma centers were reviewed for the 10-year period (January 1995 to January 2005). Blunt trauma patients younger than 3 years were identified. The measured outcome was CSI. Independent predictors of CSI were identified by univariate and multivariate analysis. A weighted score was calculated by assigning 1, 2, or 3 points to each independent predictor according to its magnitude of effect. The score was established on two thirds of the population and validated using the remaining one third. RESULTS Of 12,537 patients younger than 3 years, CSI was identified in 83 patients (0.66%), eight had spinal cord injury. Four independent predictors of CSI were identified: Glasgow Coma Score <14, GCSEYE = 1, motor vehicle crash, and age 2 years or older. A score of <2 had a negative predictive value of 99.93% in ruling out CSI. A total of 8,707 patients (69.5% of all patients) had a score of <2 and were eligible for cervical spine clearance without imaging. There were no missed CSI in this study. CONCLUSIONS CSI in patients younger than 3 years is uncommon. Four simple clinical predictors can be used in conjunction to the physical examination to substantially reduce the use of radiographic imaging in this patient population.

The effects of methamphetamine on serotonin transporter activity : Role of dopamine and hyperthermia

Abstract: Multiple administrations of methamphetamine (METH) rapidly decreased serotonin (5HT) transporter (SERT) function in rat striatum and hippocampus. The purpose of this study was to identify the mechanisms/ factors contributing to this METH‐induced decrease in SERT function. Multiple high‐dose METH injections rapidly decreased 5HT uptake without altering binding of the 5HT transporter ligand paroxetine. Hyperthermia contributed to this deficit in transporter function in striatum and hippocampus, as prevention of METH‐induced hyperthermia attenuated this decrease. A role for dopamine (DA) was suggested by findings that pretreatment with the tyrosine hydroxylase inhibitor α‐methyl‐p‐tyrosine, the D1 antagonist SCH‐23390, or the D2 antagonist eticlopride attenuated the METH‐induced decrease in striatal, but not hippocampal, SERT activity. These effects were independent of the ability of these DA‐antagonizing drugs to prevent METH‐induced hyperthermia. These results suggest that DA contributes to the decrease in SERT function caused by multiple METH injections in the striatum, but not hippocampus, and that hyperthermia facilitates these deficits in SERT function in both brain regions. In contrast, the response of SERT to a single administration of METH was DA and hyperthermia independent. These findings suggest that the mechanisms/ factors involved in decreasing SERT activity after a single administration of METH are distinct from that caused by multiple administrations.

A rapid and reversible change in dopamine transporters induced by methamphetamine

Because high doses of methamphetamine promote free radical formation, and striatal dopamine transporters are rapidly inactivated by oxidative events, we determined the effect of a single high dose of methamphetamine on dopamine transporter activity in striatal synaptosomes. One hour after methamphetamine administration, dopamine uptake decreased by 48%. This dramatic decline was totally reversed by 24 h after treatment. These findings suggest that methamphetamine reversibly decreases dopamine transporter activity by oxidative mechanisms.

Inhibitory effect of reserpine on dopamine transporter function.

Previous studies indicate that reserpine may disrupt dopamine transporter activity. Results presented herein reveal that it also inhibits potently synaptosomal [3H]dopamine uptake. In addition, reserpine administration to rats decreased the V(max) of synaptosomal dopamine transport, as assessed ex vivo 12 h after treatment. This decrease appeared, at least in part, dissociated from concurrent inhibition of the vesicular monoamine transporter-2 (VMAT-2). In separate experiments, synaptosomal dopamine uptake did not differ between wild-type and heterozygous VMAT-2 knockout mice, and reserpine treatment did not inhibit [3H]dopamine uptake into cells heterogously expressing the human dopamine transporter. Taken together, these data suggest that reserpine may transiently alter dopamine transporter function in a noncompetitive, indirect manner.

Neurologically intact children with an isolated skull fracture may be safely discharged after brief observation

PURPOSE The management of children presenting with an isolated skull fracture (ISF) posttrauma is highly variable. We sought to estimate the risk of neurologic deterioration in children with a Glasgow coma score (GCS) 15 and ISF to reduce unnecessary hospital admissions. METHODS A retrospective review at a level I pediatric trauma referral center was conducted for patients with ISF on head computed tomography from 2003 to 2008. Patients were excluded for injury greater than 24 hours prior, GCS less than 15, intracranial pathology, significant fracture depression, or complex fractures involving facial bones or skull base. RESULTS A total of 235 patients were identified with an ISF. The median age was 11 months, with falls accounting for 87% of the injuries. One hundred seventy-seven patients were admitted, and 58 patients were discharged from the emergency department after a period of observation (median, 3.3 hours). Median length of stay for those admitted to the hospital was 18.2 hours. One patient developed vomiting following overnight observation and a repeat computed tomography scan demonstrated a small extra-axial hematoma that required no intervention. The mean total costs for patients discharged from the emergency department were

The role of focused abdominal sonography for trauma (FAST) in pediatric trauma evaluation.

291 vs

Analgesic administration in the emergency department for children requiring hospitalization for long-bone fracture

1447 for those admitted for observation (P < .001). CONCLUSION Patients with a presenting GCS of 15 and an ISF can be safely discharged from the emergency department after a short period of observation if they are asymptomatic and have a reliable social environment. This could result in significant savings by eliminating inpatient costs.