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...

BackgroundChronic cocaine consumption is associated with a decrease in mesolimbic dopamine transmission that maintains drug intake. transcranial magnetic stimulation (TMS) is gaining reliability, a useful therapeutic tool in drug addiction, since it can modulate cortico-limbic activity resulting in reduction of drug craving.AimsIn the present study, we investigated the therapeutic effect of bilateral TMS of prefrontal cortex (PFC) in reducing cocaine intake, in a sample of treatment-seeking patients with current cocaine use disorder (DSM-V).MethodsTen cocaine addicts (DSM-V) were randomly assigned to the active or sham stimulation protocol in a double-blind experimental design. Twelve repetitive TMS (rTMS) sessions were administered three times a week for 4 weeks at 100% of motor threshold, over bilateral PFC. Cocaine intake (ng/mg) was assessed by hair analysis at baseline (before treatment, T0), after 1 month (end of treatment, T1), 3 (T2), and 6 (T3) months later. All subjects received psychological support weekly.ResultsThe two-way ANOVA for repeated measures did not show a significant effect of the interaction between time and treatment (F4,32 = 0.35; p = 0.87). Despite that result indicated no difference in the effect of the two conditions (active vs. sham) along time, a decreasing trend in cocaine consumption in active TMS group (F3,23 = 3.42; p = 0.04) vs. sham (F3,15 = 1.88; p = 0.20) was observed when we performed exploratory analysis with time as factor. Indeed, Post hoc comparisons showed a significant reduction in the amount of cocaine detected from the onset to 3 months later (T0–T2; p = 0.02) and to the end of treatment (T0–T3; p = 0.01) in addicts from the active group.ConclusionBilateral rTMS of PFC at 10 Hz did not show a significant effect on cocaine intake compared to sham. However, a long-term reduction on cocaine intake in active TMS-treated patients was observed when we considered the time as factor. Further studies are required to confirm these encouraging but preliminary findings, in order to consolidate rTMS as a valid tool to treat cocaine addiction.

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Background Aβ 1-42 peptide abnormal production is associated with the development and maintenance of neuroinflammation and oxidative stress in brains from Alzheimer disease (AD) patients. Suppression of neuroinflammation may then represent a suitable therapeutic target in AD. We evaluated the efficacy of IFNβ1a in attenuating cognitive impairment and inflammation in an animal model of AD. Methods A rat model of AD was obtained by intra-hippocampal injection of Aβ 1-42 peptide (23 μg/2 μl). After 6 days, 3.6 μg of IFNβ1a was given subcutaneously (s.c.) for 12 days. Using the novel object recognition (NOR) test, we evaluated changes in cognitive function. Measurement of pro-inflammatory or anti-inflammatory cytokines, reactive oxygen species (ROS), and SOD activity levels was performed in the hippocampus. Data were evaluated by one-way ANOVA with Fisher’s Protected Least Significant Difference (PLSD) test. Results We showed that treatment with IFNβ1a was able to reverse memory impairment and to counteract microglia activation and upregulation of pro-inflammatory cytokines (IL-6, IL-1β) in the hippocampus of Aβ 1-42 -injected rats. The anti-inflammatory cytokine IL-10, significantly reduced in the Aβ 1-42 animals, recovered to control levels following IFNβ1a treatment. IFNβ1a also reduced ROS and lipids peroxidation and increased SOD1 protein levels in the hippocampus of Aβ 1-42 -injected rats. Conclusion This study shows that IFNβ1a is able to reverse the inflammatory and cognitive effects of intra-hippocampal Aβ 1-42 in the rat. Given the role played by inflammation in AD pathogenesis and the established efficacy of IFNβ1a in the treatment of inflammatory diseases of the central nervous system such as multiple sclerosis, its use may be a viable strategy to inhibit the pro-inflammatory cytokine and oxidative stress cascade associated with Aβ deposition in the hippocampus of AD patients.

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