Hampered LTD formation and thin spine loss in the Nucleus Accumbens of ethanol dependent rats

Alcoholism involves long-term cognitive deficits, including memory impairment, resulting in substantial cost to society. Neuronal refinement and stabilization are hypothesized to confer resilience to poor decision-making and addictive-like behaviors, such as excessive ethanol drinking and dependence. Accordingly, structural abnormalities are likely to contribute to synaptic dysfunctions that occur from suddenly ceasing the use of alcohol after chronic ingestion. Here we show that ethanol dependent rats display a loss of dendritic spines in medium spiny neurons of the Nacc shell, accompanied by a reduction of TH-immunostaining and PSD-95 positive elements. Further analysis indicates that ‘long thin’, but not ‘mushroom’, spines are selectively affected. In addition, patch-clamp experiments from Nacc slices reveal that LTD formation is hampered with parallel changes in field potential recordings and reductions in NMDA-mediated synaptic currents. These changes are restricted to the withdrawal phase of ethanol dependence suggesting their relevance in the genesis of signs and/or symptoms affecting ethanol withdrawal, and thus the whole addicting cycle. Overall these results highlight the key role of dynamic alterations in dendritic spines and their presynaptic afferents on the evolution of alcohol dependence. Furthermore, they suggest that the selective loss of ‘long thin’ spines together with a reduced NMDAr function may affect learning. Disruption of this LTD could contribute to the rigid emotional and motivational state observed in alcohol dependence.