Sarcosine attenuates toluene-induced motor incoordination, memory impairment, and hypothermia but not brain stimulation reward enhancement in mice

Abstract

Toluene, a widely used and commonly abused organic solvent, produces various behavioral disturbances, including motor incoordination and cognitive impairment. Toluene alters the function of a large number of receptors and ion channels. Blockade of N-methyl-d-aspartate (NMDA) receptors has been suggested to play a critical role in toluene-induced behavioral manifestations. The present study determined the effects of various toluene doses on motor coordination, recognition memory, body temperature, and intracranial self-stimulation (ICSS) thresholds in mice. Additionally, the effects of sarcosine on the behavioral and physiological effects induced by toluene were evaluated. Sarcosine may reverse toluene-induced behavioral manifestations by acting as an NMDA receptor co-agonist and inhibiting the effects of the type I glycine transporter (GlyT1). Mice were treated with toluene alone or combined with sarcosine pretreatment and assessed for rotarod performance, object recognition memory, rectal temperature, and ICSS thresholds. Toluene dose-dependently induced motor incoordination, recognition memory impairment, and hypothermia and lowered ICSS thresholds. Sarcosine pretreatment reversed toluene-induced changes in rotarod performance, novel object recognition, and rectal temperature but not ICSS thresholds. These findings suggest that the sarcosine-induced potentiation of NMDA receptors may reverse motor incoordination, memory impairment, and hypothermia but not the enhancement of brain stimulation reward function associated with toluene exposure. Sarcosine may be a promising compound to prevent acute toluene intoxications by occupational or intentional exposure.

N,N-dimethylglycine differentially modulates psychotomimetic and antidepressant-like effects of ketamine in mice

“…The psychotomimetic behaviors induced by ketamine in animals have been well documented, including motor incoordination, PPI deficits, hyperlocomotion and novel object recognition impairment (Becker et al, 2003;Chan et al, 2008;Chan et al, 2012b), which are mainly caused by NMDAR blockade because similar behavioral responses are also elicited by noncompetitive NMDAR antagonists, such Fig. 3.…”

“…It is of note that the potency of DMG might be higher than sarcosine as DMG is effective at lower doses (10-100 mg) in antipsychotic and antidepressant effects compared to sarcosine (100-600 mg) (Chan et al, 2012b;Huang et al, 2013;Yang et al, 2010). However, the effects of sarcosine and DMG were tested in rats and mice, respectively.…”

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…Other drugs acting at GABA receptors have a more varied profile of effects. For example, ethanol typically produces a modest but significant facilitation of ICSS, as do some abused solvents like toluene (Kornetsky et al, 1988;Bespalov et al, 1999;Bespalov et al, 2003;Chan et al, 2012;Fish ICSS in Abuse Potential Testing et al, 2010;Tracy et al, 2014) (Fig. 13D).…”

“…Ligands that bind directly to the glutamate or glycine sites do not facilitate ICSS and may depress ICSS at high doses. For example, ICSS was not affected or was depressed by the competitive glutamate-site antagonists midafotel and LY23959 [(2)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid] (Bespalov et al, 2006;Kenny et al, 2009) as well as by an agonist (sarcosine), partial agonist (D-cycloserine), and antagonist [L701324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(1H)-quinolinone] of the glycine binding site (Herberg and Rose, 1990;Bespalov et al, 2006;Chan et al, 2012). Studies with systemically administered glutamate site agonists have not been published, but administration of N-methyl-D,L-aspartate directly into the ventral tegmental area also failed to alter ICSS (Willick and Kokkinidis, 1995).…”

Review of Toluene Actions: Clinical Evidence, Animal Studies, and Molecular Targets

“…Inhaled toluene acts as a robust discriminative stimulus [27, 28] and also produces CNS depressant-like [29–31] amphetamine-like [32] and PCP-like discriminative effects [33]. Similar to other CNS depressant drugs, toluene has anxiolytic-like properties [34–36], anticonvulsant effects [37–41] and impairs locomotor coordination [42, 43]. It also exerts antidepressant-like actions [44] and a biphasic locomotor response; i.e., increased and decreased activity at low and high concentrations, respectively [45–48].…”