Measurement of glutamate and aspartate in Planaria

Rawls, Scott M.; Gómez, Teresa; Stagliano, Gregory W.; Raffa, Robert B.

doi:10.1016/j.vascn.2005.10.004

Cited by 35 publications

(21 citation statements)

References 32 publications

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“…Planarians do synthesize glutamate and GABA and display abstinence-induced withdrawal that is highly dependent on increased glutamate transmission (Eriksson and Panula, 1994; Rawls et al, 2006, 2007). Seizure is associated with excessive glutamate transmission and failures of inhibitory control (Sheldon and Robinson, 2007; Campbell and Hablitz, 2008; Guo et al, 2010), and it is well documented that ceftriaxone displays anti-glutamate effects through enhancement of cellular glutamate uptake (Rothstein et al, 2005; Chu et al, 2007; Rawls et al, 2010a, b; Miller et al, 2008; Knackstedt et al, 2010; Sari et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

β-lactamase inhibitors display anti-seizure properties in an invertebrate assay

et al. 2010

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SummaryAntibiotics containing a β-lactam ring (e.g., ceftriaxone) display anti-glutamate effects that underlie their efficacy in animal models of CNS diseases (Rothstein et al., 2005). We hypothesized that the structurally related β-lactamase inhibitors (clavulanic acid, tazobactam)-which also contain a β-lactam ring -will mimic ceftriaxone efficacy in an invertebrate (planarian) assay designed to screen for anti-seizure activity (Rawls et al., 2009). Glutamate or cocaine administration produced planarian seizure-like activity (pSLA). Glutamate-or cocaine-induced pSLA was inhibited by ceftriaxone, clavulanic acid, or tazobactam, but not by the non-β-lactam antibiotic vancomyocin. The present findings indicate β-lactamase inhibitors display efficacy, and mimic ceftriaxone activity, in an invertebrate anti-seizure screen. These results suggest β-lactamase inhibitors particularly ones such as clavulanic acid that display enhanced brain penetrability, oral bioavailability, and negligible anti-bacterial activity might offer an attractive alternative to direct antibiotic therapy for managing CNS diseases caused by increased glutamate transmission and provide a solution to the growing concern that ceftriaxone will be of only limited utility as a CNS-active therapeutic because of its intolerable side effects. Keywords clavulanic acid; tazobactam; ceftriaxone; β-lactam antibiotic; glutamate; planaria β-lactam antibiotics enhance cellular glutamate uptake through activation of glutamate transporter subtype 1 (GLT-1), a predominantly astrocytic transporter that is responsible for about 90% of glutamate uptake in the brain and widely recognized by neuroscientists as a promising target to manage CNS diseases caused by excessive glutamate transmission. The representative β-lactam antibiotic ceftriaxone has already been successfully used as a pharmacological probe. It is active in preclinical models of CNS diseases such as amyotrophic lateral sclerosis,

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Section: Discussionmentioning

confidence: 99%

β-lactamase inhibitors display anti-seizure properties in an invertebrate assay

et al. 2010

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“…Planarians display mammalian-like behaviors during exposure to addictive substances that include enhanced motility and stereotypical activity; abstinence-related withdrawal; behavioral sensitization to cocaine; cross-sensitization to cocaine and glutamate; and conditioned place preference to methamphetamine (Kusayama and Watanabe, 2000; Raffa et al, 2008; Raffa and Valdez, 2001; Raffa and Rawls, 2008; Rawls et al, 2006, 2007, 2008, 2009; Venturini et al, 1989; Umeda et al, 2005; Palladini et al, 1996; Pagán et al, 2008, 2009; Rowlands and Pagán, 2008). Two studies demonstrated that acute nicotine exposure alters stereotypical activity and motility and produces quantifiable withdrawal effects following cessation of exposure (Buttarelli et al, 2000; Pagán et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Nicotine behavioral pharmacology: Clues from planarians

Rawls

Patil

Tallarida

et al. 2011

Drug and Alcohol Dependence

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Background Nicotine is one of the world’s most addictive substances and the primary reason that humans inhale tobacco smoke. The pharmacological effects of nicotine can be investigated in planarians, aquatic flatworms that possess an integrated neural network including cephalic ganglia that some consider the earliest “brain” and spinal cord. Here, we tested the hypothesis that nicotine exposure elicits mammalian-like behaviors in planarians. Methods Planarian motility and stereotypy (C-shape hyperkinesias) were quantified following acute nicotine exposure. During repeated nicotine exposure, we investigated the presence of withdrawal, tolerance, behavioral sensitization, and environmental place conditioning. Results Acute nicotine exposure increased stereotypical activity and elicited biphasic effects on motility. A low concentration (0.01 mM) increased motility whereas higher concentrations (0.3 – 10 mM) elicited the opposite effect. Planarians exposed to nicotine (0.03 mM) for 60 min and then tested in water displayed reduced motility that was not observed during exposure to water, acute nicotine, or continuous nicotine. Nicotine-treated planarians withdrawn from the drug for 3 days before being challenged with nicotine displayed behavioral sensitization at low concentrations (0.1, 0.3 mM) but tolerance at higher concentrations (1, 3 mM). Planarians conditioned with nicotine in the ambient light (non-preferred environment) displayed a reduction in their natural preference for a dark environment. Conclusions The present results suggest nicotine elicits mammalian-like effects in planarians, including decreased motility and increased stereotypy following acute administration and abstinence-induced withdrawal, behavioral sensitization, tolerance, and place conditioning during repeated exposure.

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“…An attractive invertebrate for investigating the process of behavioral sensitization is Planaria . These flatworms possess a primitive, yet centralized, nervous system (cephalic ganglia and spinal processes); utilize mammalian-like neurotransmitter systems, including glutamate, dopamine, and serotonin; and display abstinence-related withdrawal to abused drugs that is highly dependent on increased glutamate activity (Raffa et al, 2008; Raffa and Valdez, 2001; Rawls et al, 2006, 2007, 2008; Venturini et al, 1989; Creti et al, 1992; Eriksson and Panula, 1994; Umeda et al, 2005). Most importantly, planarians display hyperactivity following acute cocaine exposure and express key substrates that mediate cocaine-induced behavioral sensitization in mammals (Palladini et al, 1996; Pagan et al, 2008; Rowlands and Pagán, 2008).…”

Section: Introductionmentioning

confidence: 99%

First evidence that drugs of abuse produce behavioral sensitization and cross sensitization in planarians

Rawls¹,

Patil²,

Yuvasheva³

et al. 2010

Behavioural Pharmacology

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Behavioral sensitization in mammals, including humans, is sensitive to factors such as administration route, testing environment, and pharmacokinetic confounds, unrelated to the drugs themselves, that are difficult to eliminate. Simpler animals less susceptible to these confounding influences may be advantageous substitutes for studying sensitization. We tested this hypothesis by determining if planarians display sensitization and cross-sensitization to cocaine and glutamate. Planarian hyperactivity was quantified as the number of C-like hyperkinesias during a 1-min drug exposure. Planarians exposed initially to cocaine (or glutamate) on day 1 were challenged with cocaine (or glutamate) after 2 or 6 days of abstinence. Acute cocaine or glutamate produced concentration-related hyperactivity. Cocaine or glutamate challenge after 2 and 6 days of abstinence enhanced the hyperactivity, indicating the substances produced planarian behavioral sensitization (pBS). Cross-sensitization experiments showed that cocaine produced greater hyperactivity in planarians previously exposed to glutamate than in glutamate-naïve planarians, and vice versa. Behavioral responses were pharmacologically selective because neither scopolamine nor caffeine produced pBS despite causing hyperactivity after initial administration, and acute GABA did not cause hyperactivity. Demonstration of pharmacologically-selective behavioral sensitization in planarians suggests these flatworms represent a sensitive in vivo model to study cocaine behavioral sensitization and to screen potential abuse-deterrent therapeutics.

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Measurement of glutamate and aspartate in Planaria

Cited by 35 publications

References 32 publications

β-lactamase inhibitors display anti-seizure properties in an invertebrate assay

β-lactamase inhibitors display anti-seizure properties in an invertebrate assay

Nicotine behavioral pharmacology: Clues from planarians

First evidence that drugs of abuse produce behavioral sensitization and cross sensitization in planarians

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