Phenotype-dependent inhibition of glutamatergic transmission on nucleus accumbens medium spiny neurons by the abused inhalant toluene.
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.
Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.|Center for Drug and Alcohol Programs, Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA.
Jacob T
JT
Beckley
Center for Drug and Alcohol Programs, Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA.
Patrick K
PK
Randall
Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
Rachel J
RJ
Smith
Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.|Center for Drug and Alcohol Programs, Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA.
Benjamin A
BA
Hughes
Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.|Center for Drug and Alcohol Programs, Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA.
Peter W
PW
Kalivas
Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.|Center for Drug and Alcohol Programs, Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA.
John J
JJ
Woodward
D000818:Animals; D004745:Enkephalins / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D058545:Inhalant Abuse; D036881:Long-Term Synaptic Depression / Q000187:drug effects*; D009025:Morpholines / Q000494:pharmacology; D016202:N-Methylaspartate; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010641:Phenotype; D011498:Protein Precursors / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012997:Solvents / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*; D014050:Toluene / Q000494:pharmacology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
D004745:Enkephalins; D009025:Morpholines; D011498:Protein Precursors; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D017448:Receptors, Dopamine D2; D012997:Solvents; D014050:Toluene; D018698:Glutamic Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C033660:preproenkephalin; C109925:AM 281
Abused inhalants; D2R medium spiny neurons; endocannabinoids; nucleus accumbens; toluene; whole-cell patch-clamp