Repeated Cocaine Administration Increases Membrane Excitability of Pyramidal Neurons in the Rat Medial Prefrontal Cortex

Abstract

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.p. for 5 days) with a 3-day withdrawal, alterations in membrane properties, including increased input resistance, reduced intensity of intracellular injected currents required for generation of Na ϩ -dependent spikes (rheobase), and an increased number of spikes evoked by depolarizing current pulses were observed in mPFC neurons. The current-voltage relationship was also altered in cocaine-pretreated neurons showing reduced outward rectification during membrane depolarization and decreased inward rectification during membrane hyperpolarization. Application of the K ϩ channel blocker Ba 2ϩ depolarized the resting membrane potential (RMP) and enhanced membrane potential response to injection of hyperpolarizing current pulses. However, the effects of Ba 2ϩ on RMP and hyperpolarized membrane potentials were significantly attenuated in cocaine-withdrawn neurons compared with saline-pretreated cells. These findings indicate that repeated cocaine administration increased the excitability of mPFC neurons after a short-term withdrawal, possibly via reducing the activity of the potassium inward rectifiers (K ir ) and voltage-gated K ϩ currents. Similar changes were also observed in cocaine-pretreated mPFC neurons after a long-term (2-3 weeks) withdrawal, revealing a persistent increase in excitability. These alterations in mPFC neuronal excitability may contribute to the development of behavioral sensitization and withdrawal effects following chronic cocaine exposure.

Progression of Cellular Adaptations in Medial Prefrontal and Orbitofrontal Cortex in Response to Repeated Amphetamine

“…Our findings are consistent with previous electrophysiological studies reporting inhibition of mPFC activity by amphetamine under anesthesia (Mora et al, 1976) and alteration in membrane excitability and evoked firing rate in vitro (Peterson et al, 2000;Dong et al, 2005;Nasif et al, 2005). Our observation of the rapid onset of plasticity at the level of PFC neuronal ensembles suggests that other measures of psychostimulant-induced plasticity with delayed onset (Wolf, 1998;Porrino and Lyons, 2000;Nestler, 2004;Robinson and Kolb, 2004) may be secondary to changes in cortical firing.…”

Dopamine D2 Receptor Modulation of K+ Channel Activity Regulates Excitability of Nucleus Accumbens Neurons at Different Membrane Potentials

“…Blockade of these outflowing K ϩ currents leads to depolarization from RMP (Nasif et al 2005). Because these K ϩ channels belong to the superfamily of the inward rectifier and activity of inwardly rectifying K ϩ channels is reduced with D 2 R stimulation (see above), we also studied whether the RMP of NAc neurons was modulated by D 2 Rs.…”

“…These K ϩ channels are highly expressed in the NAc (Karschin et al 1996;Talley et al 2001). Blockade of this K ϩ efflux depolarizes RMP in neurons (Nasif et al 2005). Our findings not only show a D 2 R-modulated membrane depolarization from RMP, but also unmask its mechanism in which activation of PI-PLC was responsible for this D 2 R action on decreasing "leak" K ϩ currents.…”

“…This brain region is involved in control of cognitive tasks (Kalivas et al 2005;Nicola et al 2000;Pennartz et al 1994). Activity of NAc neurons is regulated by both DA D 1 -and D 2 -class receptors (D 1 Rs and D 2 Rs, respectively) (Hu and White 1997;Hu et al 2005;White and Wang 1986).…”

Long-Term Neuroadaptations Produced by Withdrawal from Repeated Cocaine Treatment: Role of Dopaminergic Receptors in Modulating Cortical Excitability

“…Arguing against this possibility, recent studies in dissociated PFC pyramidal cells after withdrawal from cocaine demonstrate increased excitability as a result of a decreased voltage-gated and inwardly rectifying I k and enhanced L-type I Ca2ϩ (Dong et al, 2005;Nasif et al, 2005a). Moreover, Nasif et al (2005b) showed that repeated cocaine administration increased the membrane excitability of PFC neurons in slices. The apparent contradictory findings on excitability between recordings in vitro and in vivo suggest that cocaine-induced neuroadaptations in the circuit in which the PFC pyramidal cells are embedded are critically affecting excitability.…”