Inhibition of neuronal nitric oxide synthase prevented alterations in medial prefrontal cortex excitability associated to repeated cocaine administration.

F. J. NASIF; X-T HU; O. A. RAMIREZ; M. F. PEREZ.

PSYCHOPHARMACOLOGY

SPRINGER

Lugar: Berlin; Año: 2011 vol. 218 p. 323 - 330

0033-3158

Rationale: the medial prefrontal cortex (mPFC), a forebrain region that regulates cognitive function and reward-motivated behaviors, has been implicated in the neuropathological mechanisms of drug addiction and withdrawal. In cocaine-abstinent human addicts, neuronal activity of the mPFC is increased in response to cocaine re-exposure or drug-associated cues. Additionally, repeated cocaine exposure alters the membrane properties and ion channel function of mPFC pyramidal neurons in drug-withdrawn rats, leading to an increased firing in response to excitatory stimuli.,Nitric oxide (NO), a diffusible neuromodulator of neuronal excitability, may play a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 initiating and maintaining behavioral effects of psychostimulants. However, the role of NO in the mechanisms by which cocaine affects membrane excitability is not well studied. Objectives: in this study we attempted to determine whether inhibition of neuronal nitric oxide synthase (nNOS) altered the changes induced by repeated cocaine exposure and withdrawal. Methods: visualized whole-cell current-clamp recordings in brain slices containing the mPFC of rats administered (once per day for 5 days) either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the NOS inhibitor 7-NI (50 mg/kg, i.p.). Results: we found that NOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. current-clamp recordings in brain slices containing the mPFC of rats administered (once per day for 5 days) either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the NOS inhibitor 7-NI (50 mg/kg, i.p.). Results: we found that NOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. attempted to determine whether inhibition of neuronal nitric oxide synthase (nNOS) altered the changes induced by repeated cocaine exposure and withdrawal. Methods: visualized whole-cell current-clamp recordings in brain slices containing the mPFC of rats administered (once per day for 5 days) either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the NOS inhibitor 7-NI (50 mg/kg, i.p.). Results: we found that NOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. current-clamp recordings in brain slices containing the mPFC of rats administered (once per day for 5 days) either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the NOS inhibitor 7-NI (50 mg/kg, i.p.). Results: we found that NOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. and reward-motivated behaviors, has been implicated in the neuropathological mechanisms of drug addiction and withdrawal. In cocaine-abstinent human addicts, neuronal activity of the mPFC is increased in response to cocaine re-exposure or drug-associated cues. Additionally, repeated cocaine exposure alters the membrane properties and ion 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 initiating and maintaining behavioral effects of psychostimulants. However, the role of NO in the mechanisms by which cocaine affects membrane excitability is not well studied. Objectives: in this study we attempted to determine whether inhibition of neuronal nitric oxide synthase (nNOS) altered the changes induced by repeated cocaine exposure and withdrawal. Methods: visualized whole-cell current-clamp recordings in brain slices containing the mPFC of rats administered (once per day for 5 days) either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the NOS inhibitor 7-NI (50 mg/kg, i.p.). Results: we found that NOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. current-clamp recordings in brain slices containing the mPFC of rats administered (once per day for 5 days) either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the NOS inhibitor 7-NI (50 mg/kg, i.p.). Results: we found that NOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. attempted to determine whether inhibition of neuronal nitric oxide synthase (nNOS) altered the changes induced by repeated cocaine exposure and withdrawal. Methods: visualized whole-cell current-clamp recordings in brain slices containing the mPFC of rats administered (once per day for 5 days) either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the NOS inhibitor 7-NI (50 mg/kg, i.p.). Results: we found that NOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. current-clamp recordings in brain slices containing the mPFC of rats administered (once per day for 5 days) either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the NOS inhibitor 7-NI (50 mg/kg, i.p.). Results: we found that NOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. : the medial prefrontal cortex (mPFC), a forebrain region that regulates cognitive function and reward-motivated behaviors, has been implicated in the neuropathological mechanisms of drug addiction and withdrawal. In cocaine-abstinent human addicts, neuronal activity of the mPFC is increased in response to cocaine re-exposure or drug-associated cues. Additionally, repeated cocaine exposure alters the membrane properties and ion 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 initiating and maintaining behavioral effects of psychostimulants. However, the role of NO in the mechanisms by which cocaine affects membrane excitability is not well studied. Objectives: in this study we attempted to determine whether inhibition of neuronal nitric oxide synthase (nNOS) altered the changes induced by repeated cocaine exposure and withdrawal. Methods: visualized whole-cell current-clamp recordings in brain slices containing the mPFC of rats administered (once per day for 5 days) either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the NOS inhibitor 7-NI (50 mg/kg, i.p.). Results: we found that NOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. current-clamp recordings in brain slices containing the mPFC of rats administered (once per day for 5 days) either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the NOS inhibitor 7-NI (50 mg/kg, i.p.). Results: we found that NOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. attempted to determine whether inhibition of neuronal nitric oxide synthase (nNOS) altered the changes induced by repeated cocaine exposure and withdrawal. Methods: visualized whole-cell current-clamp recordings in brain slices containing the mPFC of rats administered (once per day for 5 days) either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the NOS inhibitor 7-NI (50 mg/kg, i.p.). Results: we found that NOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. current-clamp recordings in brain slices containing the mPFC of rats administered (once per day for 5 days) either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the NOS inhibitor 7-NI (50 mg/kg, i.p.). Results: we found that NOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. Objectives: in this study we attempted to determine whether inhibition of neuronal nitric oxide synthase (nNOS) altered the changes induced by repeated cocaine exposure and withdrawal. Methods: visualized whole-cell current-clamp recordings in brain slices containing the mPFC of rats administered (once per day for 5 days) either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the NOS inhibitor 7-NI (50 mg/kg, i.p.). Results: we found that NOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. current-clamp recordings in brain slices containing the mPFC of rats administered (once per day for 5 days) either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the NOS inhibitor 7-NI (50 mg/kg, i.p.). Results: we found that NOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. Methods: visualized whole-cell current-clamp recordings in brain slices containing the mPFC of rats administered (once per day for 5 days) either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the NOS inhibitor 7-NI (50 mg/kg, i.p.). Results: we found that NOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. Results: we found that NOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal. Conclusions: these findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal.