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

• Published in: Addiction biology Vol. 21; no. 3; pp. 530 - 546
• Main Authors: Beckley, Jacob T., Randall, Patrick K., Smith, Rachel J., Hughes, Benjamin A., Kalivas, Peter W., Woodward, John J.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.05.2016; John Wiley & Sons, Inc
• Subjects: Abused inhalants; Addictive behaviors; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - metabolism; Animals; Basal ganglia; Cannabinoid CB1 receptors; D2R medium spiny neurons; Dopamine D2 receptors; Drug addiction; endocannabinoids; Enkephalins - genetics; Genotype & phenotype; Glutamatergic transmission; Glutamic Acid - metabolism; Glutamic acid receptors; Hyperpolarization; Immunohistochemistry; Inhalant Abuse; Inhalants; Long-term depression; Long-Term Synaptic Depression - drug effects; Morpholines - pharmacology; N-Methyl-D-aspartic acid; N-Methylaspartate; Neural Inhibition - drug effects; Neurons; Neurons - drug effects; Neurons - metabolism; Neurotransmission; Nucleus accumbens; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Phenotype; Place preference conditioning; Protein Precursors - genetics; Pyrazoles - pharmacology; Rats; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptors, Dopamine D2 - metabolism; RNA, Messenger - metabolism; Rodents; Self-administration; Solvents - pharmacology; Spiny neurons; Statistical analysis; Synaptic Transmission - drug effects; Toluene; Toluene - pharmacology; whole-cell patch-clamp; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; D2R medium spiny neurons; endocannabinoids; Abused inhalants; nucleus accumbens; whole-cell patch-clamp; toluene
• ISSN: 1355-6215; 1369-1600
• DOI: 10.1111/adb.12235

Abused inhalants are voluntarily 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, which are commonly associated with addictive drugs. However, little is known 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, and dose‐dependently inhibits N‐methyl‐D‐aspartate (NMDA)‐mediated currents in rat NAc medium spiny neurons (MSN). Moreover, using the multivariate statistical technique, partial least squares discriminative analysis to analyze electrophysiological measures from rat NAc MSNs, we show that toluene induces a persistent depression of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)‐mediated currents in one subtype of NAc MSNs, 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 whole‐cell patch‐clamp recordings reliably predict neuronal phenotype, and that the abused inhalant toluene differentially depresses excitatory neurotransmission in NAc neuronal subtypes. We report that toluene, a volatile solvent intentionally inhaled for its intoxicating effects, differentially alters glutamatergic synaptic transmission on medium spiny neurons (MSN) in the rat nucleus accumbens (NAc). Using partial least squares discriminative analysis to classify neurons by their electrophysiological properties, we show that toluene induces an endocannbinoid‐mediated long‐term depression of AMPA‐mediated currents in only one subtype of NAc MSN neurons. Using immunohistochemistry, we verify that these neurons are the indirect pathway dopamine D2 receptor MSNs.