Inhibition of neuronal nitric oxide synthase prevents alterations in medial prefrontal cortex excitability induced by repeated cocaine administration

FERNANDO J. NASIF; XIU-TI HU; OSCAR A RAMIREZ; MARIELA F. PÉREZ.

PSYCHOPHARMACOLOGY

SPRINGER

Año: 2011 vol. 218 p. 323 - 330

0033-3158

Rationale: The medial prefrontal cortex (mPFC), a forebrain region thatregulates cognitive function and reward-motivated behaviors, has beenimplicated in the neuropathological mechanisms of drug addiction andwithdrawal. In cocaine-abstinent human addicts, neuronal activity of the mPFCis increased in response to cocaine re-exposure or drug-associated cues.Additionally, repeated cocaine exposure alters the membrane properties andion channel function of mPFC pyramidal neurons in drug-withdrawn rats,leading to an increased firing in response to excitatory stimuli. Nitric oxide (NO),a diffusible neuromodulator of neuronal excitability, may play a role in initiatingand maintaining behavioral effects of psychostimulants. However, the role ofNO in the mechanisms by which cocaine affects membrane excitability is notwell clarified.Objectives: In this study, we attempted to determine whether inhibition ofneuronal nitric oxide synthase (nNOS) altered the changes induced by repeatedcocaine exposure and withdrawal.Methods: Visualized whole-cell current clamp recordings in brain slicescontaining the mPFC of rats administered (once per day for 5 days) with eithervehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), orcocaine and the nNOS inhibitor 7-NI (50 mg/kg, i.p.) were employed.Results: We found that nNOS inhibition prevented cocaine sensitization andthe increased membrane excitability of pyramidal cells, evidenced by anincreased number of evoked spikes and reductions in inward rectificationobserved after short-term withdrawal from cocaine.Conclusions: These findings suggest that NO plays an important role inchronic cocaine-induced deregulation of the mPFC activity that may contributeto the development of behavioral sensitization and cocaine withdrawal.