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.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(+)-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(+) channel blocker Ba(2+) depolarized the resting membrane potential (RMP) and enhanced membrane potential response to injection of hyperpolarizing current pulses. However, the effects of Ba(2+) on RMP and hyperpolarized membrane potentials were significantly attenuated in cocaine-withdrawn neurons compared with saline-pretreated cells.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(+) 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.
Nasif
Fernando J
FJ
Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, Chicago Medical School, 3333 Green Bay Road, North Chicago, Illinois 60064, USA.
Sidiropoulou
Kyriaki
K
Hu
Xiu-Ti
XT
White
Francis J
FJ
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001464:Barium / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D005071:Evoked Potentials / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology; D017966:Pyramidal Cells / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D024642:Potassium Channels, Voltage-Gated; D001464:Barium; D003042:Cocaine