Phenotype-dependent inhibition of glutamatergic transmission onnucleus accumbens medium spiny neurons by the abused inhalanttoluene

摘要

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 self-administration 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 ofrecorded cells was examined using dual histochemistry and shows thattoluene-sensitive NAc neurons are dopamine D2 MSNs that expresspreproenkephalin mRNA. Overall, the results from thesestudies indicate that physiological characteristics obtained from NAc MSNsduring whole-cell patch clamp recordings reliably predict neuronal phenotype,and that the abused inhalant toluene differentially depresses excitatoryneurotransmission in NAc neuronal subtypes.