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

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repeated cocaine exposure alters the membrane properties and ion channel function of mPFC pyramidal neurons in drug-withdrawn rats, leading to an increased firing in response to excitatory stimuli.

Fos regulates neuronal activity in the nucleus accumbens.

Repeated exposure to drugs of abuse induces a variety of persistent changes in the brain and the dopamine D1 receptor plays a major role in the process. To understand intracellular mechanisms contributing to cocaine-induced neuroadaptations, we previously examined the role of the immediate early gene Fos using a mouse in which Fos is disrupted primarily in D1 receptor-expressing neurons in the brain. We found that both dendritic remodeling of medium spiny neurons and behavioral sensitization induced by repeated exposure to cocaine are attenuated in the mutant mice.

Repeated cocaine administration increases voltage-sensitive calcium currents in response to membrane depolarization in medial prefrontal cortex pyramidal neurons.

The medial prefrontal cortex (mPFC) plays a critical role in cocaine addiction. However, evidence to elucidate how the mPFC is functionally involved in cocaine addiction remains incomplete. Recent studies have revealed that repeated cocaine administration induces various neuroadaptations in pyramidal mPFC neurons, including a reduction in voltage-gated K+ currents (VGKCs) and a possible increase in voltage-sensitive Ca2+ currents (I(Ca)).

Cocaine-induced plasticity of intrinsic membrane properties in prefrontal cortex pyramidal neurons: adaptations in potassium currents.

Drug-induced adaptations in the prefrontal cortex (PFC) contribute to several core aspects of addictive behaviors, but the underlying neuronal processes remain essentially unknown. Here, we demonstrate that repeated in vivo exposure to cocaine persistently reduces the voltage-gated K+ current (VGKC) in PFC pyramidal neurons, resulting in enhanced membrane excitability. Analysis of dopamine D1-class receptor (D1R)-mediated modulation of VGKC indicates that, despite the absence of direct D1R stimulation, downstream D1 signaling (the cAMP/protein kinase A pathway) is increased during withdrawal from chronic cocaine treatment and plays a central role in the drug-induced membrane plasticity in PFC.

Repeated cocaine administration increases membrane excitability of pyramidal neurons in the rat medial prefrontal cortex.

Although the medial prefrontal cortex (mPFC) plays a critical role in cocaine addiction, the effects of chronic cocaine on mPFC neurons remain poorly understood. Here, we performed visualized current-clamp recordings to determine the effects of repeated cocaine administration on the membrane excitability of mPFC pyramidal neurons in rat brain slices. Following repeated cocaine administration (15 mg/kg/day i.