Inhibition of neuronal nitric oxide synthase prevents alterations in medial prefrontal cortex excitability induced by repeated cocaine administration.
BACKGROUND
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repeated cocaine exposure alters the membrane properties and ion channel function of mPFC pyramidal neurons in drug-withdrawn rats, leading to an increased firing in response to excitatory stimuli.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 clarified.


OBJECTIVE
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) with either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the nNOS inhibitor 7-NI (50 mg/kg, i.p.) were employed.


RESULTS
We found that nNOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by an 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.
Departamento de Farmacología, Facultad de Ciencias Químicas, UNC, IFEC, CONICET, Haya de la Torre y Medina Allende s/n, 5000 Córdoba, Argentina.
Fernando J
FJ
Nasif
Xiu-Ti
XT
Hu
Oscar A
OA
Ramirez
Mariela F
MF
Perez
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology
D004791:Enzyme Inhibitors; D007191:Indazoles; D052248:Nitric Oxide Synthase Type I; D003042:Cocaine; C080122:7-nitroindazole