Abstract
We previously showed that the time-dependent intensification (“incubation”) of cue-induced cocaine seeking after withdrawal from extended-access cocaine self-administration is accompanied by accumulation of Ca2+-permeable AMPA receptors (CP-AMPARs) in the rat nucleus accumbens (NAc). These results suggest an enduring change in Ca2+ signaling in NAc dendritic spines. The purpose of the present study was to determine if Ca2+ signaling via NMDA receptors (NMDARs) is also altered after incubation. Rats self-administered cocaine or saline for 10 days (6 h/day). After 45–47 days of withdrawal, NMDAR-mediated Ca2+ entry elicited by glutamate uncaging was monitored in individual NAc dendritic spines. NMDAR currents were simultaneously recorded using whole cell patch clamp recordings. We also measured NMDAR subunit levels in a postsynaptic density (PSD) fraction prepared from the NAc of identically treated rats. NMDAR currents did not differ between groups, but a smaller percentage of spines in the cocaine group responded to glutamate uncaging with NMDAR-mediated Ca2+ entry. No significant group differences in NMDAR subunit protein levels were found. The decrease in the proportion of spines showing NMDAR-mediated Ca2+ entry suggests that NAc neurons in the cocaine group contain more spines which lack NMDARs (non-responding spines). The fact that cocaine and saline groups did not differ in NMDAR currents or NMDAR subunit levels suggests that the number of NMDARs on responding spines is not significantly altered by cocaine exposure. These findings are discussed in light of increases in dendritic spine density in the NAc observed after withdrawal from repeated cocaine exposure.
Highlights
The idea that experience can shape or reorganize synaptic connections is a fundamental tenet of neuroscience [1]
nucleus accumbens (NAc) slices were prepared from Coc-SA and Sal-SA rats on WD45–47, and NMDA receptors (NMDARs) function in medium spiny neurons (MSN) spines was probed using 2-photon Ca2+ imaging combined with whole cell patch clamp recording and UV flash photolysis of caged glutamate
MSN in the NAc core were filled with a Ca2+ indicator via the patch pipette, caged glutamate was washed into the bath solution and UV flash photolysis was used to release glutamate into the extracellular space
Summary
The idea that experience can shape or reorganize synaptic connections is a fundamental tenet of neuroscience [1]. In the nucleus accumbens (NAc), it is well established that the density of dendritic spines on medium spiny neurons (MSN) is increased after withdrawal from either noncontingent or self-administered cocaine e.g., [4,5,6,7,8]. Cocaineinduced increases in dendritic branching and changes in spine head morphology have been observed [4,5,9,10]. Dendritic spine heads are the primary site of glutamatergic synaptic contacts in the NAc [11]. Several studies have provided clues to understanding the mechanisms involved in the development of increased spine density [6,12,13,14,15,16]. Little is known about functional aspects of the additional spines observed after cocaine exposure, including their content of glutamate receptors, recent reports suggest that at least some of these spines contribute to synaptic transmission [9,17]
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