Phenotype-dependent inhibition of glutamatergic transmission on nucleus accumbens medium spiny neurons by the abused inhalant toluene

Abstract

Abused inhalants are voluntary inhaled at high concentrations to produce intoxicating effects.Results from animal studies show that the abused inhalant toluene triggers behaviors, such as selfadministration and conditioned place preference that are commonly associated with addictive drugs. Little is known however about how toluene affects neurons within the nucleus accumbens (NAc), a brain region within the basal ganglia that mediates goal-directed behaviors and is implicated in the development and maintenance of addictive behaviors. Here, we report that toluene inhibits a component of the after-hyperpolarization potential (AHP), and dose-dependently inhibits NMDA-mediated currents in rat NAc medium spiny neurons (MSN). Moreover, using the multivariate statistical technique, partial least squares discriminative analysis (PLS-DA) to analyze electrophysiological measures from rat NAc MSNs, we show that toluene induces a persistent depression of AMPA-mediated currents in one subtype of NAc medium spiny neurons, and that the electrophysiological features of MSN neurons predicts their sensitivity to toluene. The CB1 receptor antagonist AM281 blocked the toluene-induced long-term depression of AMPA currents, indicating that this process is dependent on endocannabinoid signaling. The neuronal identity of recorded cells was examined using dual histochemistry and shows that toluene-sensitive NAc neurons are dopamine D2 MSNs that express preproenkephalin mRNA. Overall, the results from these studies indicate that physiological characteristics obtained from NAc MSNs during wholecell patch clamp recordings reliably predict neuronal phenotype, and that the abused inhalant toluene differentially depresses excitatory neurotransmission in NAc neuronal subtypes.

A brief exposure to toluene vapor alters the intrinsic excitability of D2 medium spiny neurons in the rat ventral striatum

“…Using D2-Cre reporter rats, this effect was found to be restricted to NAc shell D2+ MSNs and was accompanied by changes in electrophysiological parameters recorded from these neurons. These findings are consistent with and add to findings from previous studies reporting selective effects of toluene on neurons within the addiction neurocircuitry that vary based on brain region, neuronal cell-type and projection target (Beckley et al, 2016;Wayman and Woodward, 2018b). The mechanism underlying the selective effect of toluene on D2+ MSN intrinsic excitability observed in this study is currently unknown.…”

“…et al 10.3389/fnins.2023.1235866 Frontiers in Neuroscience 07 frontiersin.org synaptic signaling was observed in glutamatergic pyramidal neurons in the mPFC and basolateral amygdala following bath application of toluene (Beckley and Woodward, 2011;Woodward, 2023). D2 MSNs in the NAc have been shown to undergo eCB-mediated LTD (Grueter et al, 2010) as well as depolarization-induced suppression of excitation (DSE) that also involves endocannabinoid signaling (Kreitzer and Regehr, 2001;Beckley et al, 2016). Whether in vivo exposure to toluene vapor induces LTD or DSE in NAc D2 MSNs is not known but these events could trigger compensatory changes that underlie the increase in intrinsic excitability of D2 NAc shell MSNs observed during injections of low to moderate amounts of current.…”

Self-Administration of Toluene Vapor in Rats

“…This could reflect changes in neural signaling induced by repeated toluene exposures that outlast the brief period of active vapor inhalation. Although not tested in the present study, we have previously shown that acute exposure of brain slices to toluene induces a long-lasting, endocannabinoid-dependent reduction in AMPA-mediated synaptic glutamatergic signaling in the medial prefrontal cortex ( Beckley and Woodward, 2011 ) and nucleus accumbens ( Beckley et al, 2016 ). Future studies could investigate whether manipulating endocannabinoid signaling alters the pattern of toluene self-administration.…”

Descripción anátomo-funcional de un suicidio por consumo adictivo de inhalables, estudio de caso post-mortem

“…Los inhalables de tipo solventes de pegamento tienen una rápida absorción por parte del organismo, y actúan en los órganos más ricos en lípidos, como es la estructura cerebral (Müller & Kornhuber, 2017;Tormoehlen et al, 2014). Así que una exposición crónica de altos niveles de pureza de la sustancia durante largos periodos de tiempo y un volumen demasiado elevado de pegamento en el torrente sanguíneo pueden originar desmotivación, una persistencia mnésica de experiencias desagradables y alteraciones cognitivas, que son el resultado de cambios dopaminérgicos en el sistema mesolímbico y núcleo accumbens; algo muy similar a lo que sucede en la abstinencia (Beckley et al, 2015;Cruz, 2011;Howard et al, 2010;Tormoehlen et al, 2014;Wayman & Woodward, 2018).…”

“…Una diversidad de trabajos de investigación realizados a partir del modelo animal refieren que el abuso de inhalables puede provocar alteraciones en la vía de distribución dopaminérgica y regiones asociadas, como es el caso del área tegmental ventral y del núcleo accumbens (Beckley et al, 2015;Bowen, Batis, Paez-Martínez, & Cruz, 2006;Cruz, 2011;Howard et al, 2010;Tormoehlen, Tekulve, & Nañagas, 2014;Wayman & Woodward, 2018). Inclusive, las proyecciones que se producen desde la misma región tegmental ventral hacia el núcleo accumbens a través de la vía de recompensa cerebral meso-accumbens parten del sistema mesolímbico (Figura 1) y se han considerado como las responsables de la conducta adictiva (Bowen et al, 2006;Cairney, Maruff, Burns, & Currie, 2002;Da Silva, 2018).…”