Abstract
Chronic alcohol exposure causes marked changes in reinforcement mechanisms and motivational state that are thought to contribute to the development of cravings and relapse during protracted withdrawal. The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system. Although the NAcc plays an important role in mediating alcohol-seeking behaviors, little is known about the molecular mechanisms underlying alcohol-induced neuroadaptive changes in NAcc function. The aim of this study was to investigate the effects of chronic intermittent ethanol (CIE) treatment, a rat model of alcohol withdrawal and dependence, on intrinsic electrical membrane properties and glutamatergic synaptic transmission of medium spiny neurons (MSNs) in the NAcc core during protracted withdrawal. We show that CIE treatment followed by prolonged withdrawal increased the inward rectification of MSNs observed at hyperpolarized potentials. In addition, MSNs from CIE-treated animals displayed a lower input resistance, faster action potentials (APs), and larger fast afterhyperpolarizations (fAHPs) than MSNs from vehicle-treated animals, all suggestive of increases in K+-channel conductances. Significant increases in the Cs+-sensitive inwardly rectifying K+-current accounted for the increased input resistance, while increases in the A-type K+-current accounted for the faster APs and increased fAHPs in MSNs from CIE rats. We also show that the amplitude and the conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated mEPSCs were enhanced in CIE-treated animals due to an increase in a small fraction of functional postsynaptic GluA2-lacking AMPARs. These long-lasting modifications of excitability and excitatory synaptic receptor function of MSNs in the NAcc core could play a critical role in the neuroadaptive changes underlying alcohol withdrawal and dependence.
Highlights
Alcohol is lawfully consumed in our society for recreational purposes
The inactivation properties of A-type and delayed rectifier K+ currents were not altered by chronic intermittent ethanol (CIE) treatment. These results suggest that CIE treatment increases the amplitude of the A-type K+ current generated at depolarizing membrane potentials, thereby contributing to faster Action potential (AP) repolarization and increased amplitude of fast afterhyperpolarizations (fAHPs) observed in current-clamp recordings of medium spiny neuron (MSN) from CIE rats
In the presence of IEM-1460, the mean AMPA miniature excitatory postsynaptic current (mEPSC) amplitude of MSNs from CIE rats was similar to the mean AMPA mEPSC amplitude from chronic intermittent vehicle (CIV) rats (Figure 8D). These results suggest that CIE treatment-induced a significant increase in the proportion of functional synaptic GluA2-lacking amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in MSNs of the nucleus accumbens (NAcc) core
Summary
Alcohol (ethanol, EtOH) is lawfully consumed in our society for recreational purposes. An important factor contributing to alcoholrelated disease is the addictive property of alcohol. Chronic alcohol exposure causes profound long-lasting neuroadaptations in brain reward systems that produce a negative affect state contributing to an increased susceptibility to relapse during protracted withdrawal (Koob et al, 2004; Koob, 2008; Koob and Le Moal, 2008). Relapse is a critical problem in treating alcoholism and the three federally approved medications for the treatment of alcohol use disorders – acamprosate, disulfiram, and naltrexone (Ross and Peselow, 2009) have shown limited efficacy in terms of craving, relapse, and abstinence rates reduction (Hughes and Cook, 1997; Mann et al, 2004; Snyder and Bowers, 2008), suggesting that these treatments may not be targeting the neuroadaptive changes that underlie the negative emotional alcohol-dependent state
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