Exposure to the Abused Inhalant Toluene Alters Medial Prefrontal Cortex Physiology

Inhalants, including toluene, target the addiction neurocircuitry and are often one of the first drugs of abuse tried by adolescents. The medial prefrontal cortex (mPFC) is involved in regulating goal-directed/reward-motivated behaviors and different mPFC sub-regions have been proposed to promote (prelimbic, PRL) or inhibit (infralimbic, IL) these behaviors. While this dichotomy has been studied in the context of other drugs of abuse, it is not known whether toluene exposure differentially affects neurons within PRL and IL regions. To address this question, we used whole-cell electrophysiology and determined the intrinsic excitability of PRL and IL pyramidal neurons in adolescent rats 24 h following a brief exposure to air or toluene vapor (10 500 p.p.m.). Prior to exposure, fluorescent retrobeads were injected into the NAc core (NAcc) or shell (NAcs) sub-regions to identify projection-specific mPFC neurons. In toluene treated adolescent rats, layer 5/6 NAcc projecting PRL (PRL5/6) neurons fired fewer action potentials and this was associated with increased rheobase, increased spike duration, and reductions in membrane resistance and amplitude of the I_h current. No changes in excitability were observed in layer 2/3 NAcc projecting PRL (PRL2/3) neurons. In contrast to PRL neurons, layer 5 IL (IL5) and layer 2/3 (IL2/3) NAcc projecting neurons showed enhanced firing in toluene-exposed animals and in IL5 neurons, this was associated with a reduction in rheobase and AHP. For NAcs projecting neurons, toluene exposure significantly decreased firing of IL5 neurons and this was accompanied by an increased rheobase, increased spike duration, and reduced I_h amplitude. The intrinsic excitability of PRL5, PRL2/3, and IL2/3 neurons projecting to the NAcs was not affected by exposure to toluene. The changes in excitability observed 24 h after toluene exposure were not observed when recordings were performed 7 days after the exposure. Finally, there were no changes in intrinsic excitability of any region in rats exposed to toluene as adults. These findings demonstrate that specific projections of the reward circuitry are uniquely susceptible to the effects of toluene during adolescence supporting the idea that adolescence is a critical period of the development that is vulnerable to drugs of abuse.