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+-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 Ba2+ depolarized the resting membrane potential (RMP) and enhanced membrane potential response to injection of hyperpolarizing current pulses. However, the effects of Ba2+ on RMP and hyperpolarized membrane potentials were significantly attenuated in cocaine-withdrawn neurons compared with saline-pretreated cells.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 (Kir) 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.
Footnotes
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This study was supported by United States Public Health Service Grant DA12618, the Research Scientist Development Award DA00456, and the Onasis Benefit Foundation.
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Part of this work was presented at the Annual Meeting of the Society of Neuroscience, November 2001, San Diego, CA and November 2003, New Orleans, LA.
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doi:10.1124/jpet.104.075184.
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ABBREVIATIONS: mPFC, medial prefrontal cortex; VTA, ventral tegmental area; VGKC, voltage-gated outward potassium current; RMP, resting membrane potential; AHP, afterhyperpolarization; aCSF, artificial cerebrospinal fluid; I-V, current-voltage; SAL, saline; COC, cocaine; Kir, potassium inward rectifiers; IKir, inwardly rectifying K+ currents.
- Received July 29, 2004.
- Accepted November 30, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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