Inhibition of nitric oxide sinthase prevents behavioural sensitization and associated alteration in neuronal excitability i the rat mPFC after repeated cocaine administration.

PEREZ MF; L. GABACH,; L.M. CANCELA; S. SAMMUT; X.-T. HU; RAMIREZ O.; WEST A

Washintong DC

Congreso; Neuroscience Meeting,; 2008

Neuroscience society

The medial prefrontal cortex (mPFC), a forebrain region that regulates cognitive function and reward-motivated behaviors, has been implicated in the neuropathological mechanisms that underlie 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. Similar dysregulation has also been found in cocaine-withdrawn rats when they are challenged by additional cocaine stimulus. Additionally, we have demonstrated that repeated cocaine exposure alters the membrane properties and ion channel function of mPFC pyramidal neurons in drug-withdrawn rats, leading to increased firing of these cells in response to excitatory stimuli. Recent studies suggest that nitric oxide (NO), a diffusible neuromodulator that modulates excitability of neurons in several brain structures, may play a role in initiating and maintaining behavioral effects of psychostimulants. Pharmacological or genetic disruption of neuronal NO synthase (NOS) activity attenuates the development of sensitization of psychostimulants. Moreover, acute cocaine administration increases in vivo NO release in mPFC in a manner which is attenuated by neuronal NOS inhibition. However, the role of NO in the mechanisms by which cocaine affects membrane excitability is not well studied. In this study, combined behavioral and electrophysiological experiments were performed to determine (1) whether behavioral sensitization induced by repeated cocaine exposure is associated with enhanced activity of mPFC pyramidal neurons in cocaine-withdrawn rats, and (2) whether inhibition of NOS prevents or reduces the changes induced by repeated cocaine exposure and withdrawal. 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%) solution), cocaine (15 mg/kg, i.p.), or cocaine and the selective neuronal NOS inhibitor 7-NI (50 mg/kg, i.p.). We found that cocaine sensitization increased the membrane excitability of pyramidal cells as evidenced by increases in the number of evoked spikes and reductions in inward and outward rectification. Interestingly, co-administration of 7-NI prevented the changes in membrane excitability observed in mPFC pyramidal neurons after short-term withdrawal from cocaine. These findings indicate that NO plays a very important role in chronic cocaine-induced dysregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal.