Hampered long-term depression and thin spine loss in the nucleus accumbens of ethanol-dependent rats

Abstract

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 nucleus accumbens (Nacc) shell, accompanied by a reduction of tyrosine hydroxylase immunostaining and postsynaptic density 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 long-term depression (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 addictive cycle. Overall, these results highlight the key role of dynamic alterations in dendritic spines and their presynaptic afferents in the evolution of alcohol dependence. Furthermore, they suggest that the selective loss of long thin spines together with a reduced NMDA receptor function may affect learning. Disruption of this LTD could contribute to the rigid emotional and motivational state observed in alcohol dependence.A lcohol addiction is a major public health problem in the Western world. In the United States alone, about 15% of adults have an alcohol-related disorder at some point in their life, and alcohol abuse costs the economy over $220 billion per y in medical care and productivity loss (1). A general consensus has emerged on drug addiction as a substance-induced, aberrant form of neural plasticity (2, 3). The nucleus accumbens (Nacc) plays a central role in the neural circuits that are responsible for goal-directed behaviors (4, 5) and in addictive states. Its activity is heavily modulated by glutamate-(GLU) and dopamine-(DA) containing projections that originate in cortical and limbic regions and converge on a common postsynaptic target: the medium spiny neuron (MSN). Furthermore, DA modulates GLU inputs to Nacc neurons (6, 7), both by directly influencing synaptic transmission and by modulating voltage-dependent conductances (8). Accordingly, interactions between DA and GLU are involved in druginduced locomotor stimulation and addiction (9, 10) and may represent useful potential therapeutic targets (11,12). In the distal portion of the dendrites of MSNs a significant subpopulation of spines shows a particular synaptic architecture, called the "striatal microcircuit" or "synaptic triad" (13, 14), which is characterized by a double, discrete, and reciprocal interaction between DA and GLU aff...

Convergent evidence from alcohol-dependent humans and rats for a hyperdopaminergic state in protracted abstinence

“…Together with a meta-analysis of rodent studies, our data provide convergent evidence that a hyperdopaminergic state occurs during protracted abstinence. According to the literature and the time-course studies we present here, we propose that dynamical changes take place in the mesolimbic DA system during withdrawal and protracted abstinence, resulting in a hypodopaminergic state that characterizes acute withdrawal (19,35) and a hyperdopaminergic state that characterizes protracted abstinence (Fig. 2).…”

“…Experimental support for this view comes from animal work (35) and human PET studies that found reduced availability of striatal D2-like receptors compared with controls (10)(11)(12)(13)(14)(15)(16). Because these PET studies do not provide a coherent picture (20)(21)(22), we used saturated receptor autoradiography techniques to measure the number of DA receptor and DAT-binding sites in postmortem brain tissues of alcoholics and controls.…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Reduction of this form of LTD was shown after repeated noncontingent cocaine injections (Thomas et al, 2001), cocaine self-administration Moussawi et al, 2009;Kasanetz et al, 2010), ethanol consumption (Jeanes et al, 2011(Jeanes et al, , 2014Spiga et al, 2014), and heroin self-administration . Interestingly, the reduction in LTD is long-lasting in the NAcore and is also observed after 21 days of abstinence from cocaine 838 self-administration .…”

“…For example, withdrawal from nicotine self-administration shows a similar potentiation (Gipson et al, 2013b), whereas the results are mixed for studies examining the NAc after withdrawal from heroin exposure Shen et al, 2011;Wu et al, 2012). Chronic ethanol induces an increase in mEPSC frequency with no change in amplitude; however, mEPSC frequency is decreased and mEPSC amplitude is increased after withdrawal, indicating that two opposing mechanisms are activated (Spiga et al, 2014). Regardless of the specific change and the specific model used, these data support the perspective that the enduring symptoms of drug addiction may be encoded by synaptic changes in the NAc.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…For example, withdrawal from long-term ethanol exposure decreases spine density in the amydgala, concomitant with increased anxiety and decreased BDNF-Arc signaling (Pandey et al, 2008). In the NAc, both chronic alcohol drinking and alcohol withdrawal decreased spine density, accompanied by reduction in NMDAR-mediated synaptic Drug-Induced Neuroplasticity currents and hampered LTD Spiga et al, 2014). On the other hand, prolonged intermittent alcohol drinking in cynomolgus monkeys increased the density of dendritic spines and glutamatergic transmission in the putamen, but not in the caudate nucleus (Cuzon Carlson et al, 2011).…”