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In four experiments we studied the impact of retrieval-extinction training on the extinction and reinstatement of alcoholic beer seeking. Experiment 1 showed that preceding daily extinction sessions with a brief (10 min) extinction session (retrieval-extinction) attenuated the context-induced reinstatement of alcoholic beer seeking, thereby replicating and extending the findings of Xue et al. (2012). Experiment 2 then showed that the retrieval-extinction manipulation could attenuate the reinstatement produced by reversible inactivation of the nucleus accumbens shell prior to test. Experiment 3 showed that a modified extinction protocol that involved a reversed retrieval (i.e., extinction then retrieval) was also able to attenuate context-induced reinstatement. Finally, experiment 4 showed that the extinction-retrieval manipulation facilitated the reacquisition of alcoholic beer seeking as evidenced by increased breakpoints and responses during tests under a progressive ratio schedule. Taken together, these findings show that retrieval-extinction training protocols can alter the propensity to reinstate extinguished drug seeking but that these alterations are not always protective. These findings are inconsistent with accounts of the retrieval-extinction manipulation in terms of memory reconsolidation and deepened extinction. Instead, they are consistent with the notion that this manipulation increases the sensitivity of animals to the contingencies in effect during testing.

Background: Prenatal alcohol exposure affects brain structure and function. This study examined brain metabolism using magnetic resonance spectroscopy (MRS) and searched for regions of specific vulnerability in adolescents and young adults prenatally exposed to alcohol.Methods: Ten adolescents and young adults with confirmed heavy prenatal alcohol exposure and a diagnosis within the fetal alcohol spectrum disorders (FASD) were included. Three of them had fetal alcohol syndrome (FAS), 3 had partial FAS (PFAS), and 4 had alcohol‐related neurobehavioral disorder (ARND). The control group consisted of 10 adolescents matched for age, sex, head circumference, handedness, and body mass. Exclusionary criteria were learning disorders and prenatal alcohol exposure. Three‐dimensional 1H magnetic resonance spectroscopic imaging (1H MRSI) was performed in the cerebrum and cerebellum. Metabolite ratios N‐acetylaspartate/choline (NAA/Cho), NAA/creatine (Cr) and Cho/Cr, and absolute metabolite intensities were calculated for several anatomic regions.Results: In patients with FASD, lower NAA/Cho and/or NAA/Cr compared with controls were found in parietal and frontal cortices, frontal white matter, corpus callosum, thalamus, and cerebellar dentate nucleus. There was an increase in the absolute intensity of the glial markers Cho and Cr but no change in the neuronal marker NAA.Conclusions: Our results suggest that prenatal alcohol exposure alters brain metabolism in a long‐standing or permanent manner in multiple brain areas. These changes are in accordance with previous findings from structural and functional studies. Metabolic alterations represent changes in the glial cell pool rather than in the neurons.

We investigated the effect of alcohol on the cervical and ocular vestibular evoked myogenic potentials (cVEMPs and oVEMPs). As alcohol produces gaze-evoked nystagmus (GEN), we also tested the effect of nystagmus independent of alcohol by recording oVEMPs during optokinetic stimulation (OKS).The effect of alcohol was tested in 14 subjects over multiple rounds of alcohol consumption up to a maximum breath alcohol concentration (BrAC) of 1.5‰ (mean 0.97‰). The effect of OKS was tested in 11 subjects at 5, 10 and 15deg/sec.oVEMP amplitude decreased from baseline to the highest BrAC level by 27% (range 5-50%, P<0.001), but there was no significant effect on oVEMP latency or cVEMP amplitude or latency. There was a significant negative effect of OKS on oVEMP amplitude (16%, P=0.006).We found a selective effect of alcohol on oVEMP amplitude, but no effect on the cVEMP. Vertical nystagmus elicited by OKS reduced oVEMP amplitude.Alcohol selectively affects oVEMP amplitude. Despite the effects of alcohol and nystagmus, both reflexes were reliably recorded in all subjects and conditions. An absent response in a patient affected by alcohol or nystagmus indicates a vestibular deficit.

Abnormal consumption of ethanol, the ingredient responsible for alcoholic drinks’ addictive liability, causes millions of deaths yearly. Ethanol’s addictive potential is triggered through activation, by a still unknown mechanism, of the mesolimbic dopamine (DA) system, part of a key motivation circuit, DA neurons in the posterior ventral tegmental area (pVTA) projecting to the ipsilateral nucleus accumbens shell (AcbSh). The present in vivo brain microdialysis study, in dually-implanted rats with one probe in the pVTA and another in the ipsilateral or contralateral AcbSh, demonstrates this mechanism. As a consequence of the oral administration of a pharmacologically relevant dose of ethanol, we simultaneously detect a) in the pVTA, a substance, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), untraceable under control conditions, product of condensation between DA and ethanol’s first by-product, acetaldehyde; and b) in the AcbSh, a significant increase of DA release. Moreover, such newly generated salsolinol in the pVTA is responsible for increasing AcbSh DA release via μ opioid receptor (μOR) stimulation. In fact, inhibition of salsolinol’s generation in the pVTA or blockade of pVTA μORs prevents ethanol-increased ipsilateral, but not contralateral, AcbSh DA release. This evidence discloses the long-sought key mechanism of ethanol’s addictive potential and suggests the grounds for developing preventive and therapeutic strategies against abnormal consumption.

Ethanol-responsive movement disorders are a group of movement disorders of which clinical manifestation could receive significant improvement after ethanol intake, including essential tremor, myoclonus-dystonia, and some other hyperkinesia. Emerging evidence supports that the sensitivity of these conditions to ethanol might be attributed to similar anatomical targets and pathophysiologic mechanisms. Cerebellum and cerebellum-related networks play a critical role in these diseases. Suppression of inhibitory neurotransmission and hyper-excitability of these regions are the key points for pathogenesis. GABA pathways, the main inhibitory system involved in these regions, were firstly linked to the pathogenesis of these diseases, and GABAA receptors and GABAB receptors play critical roles in ethanol responsiveness. Moreover, impairment of low-voltage-activated calcium channels, which were considered as a contributor to oscillation activity of the nervous system, also participates in the sensitivity of ethanol in relevant disease. Glutamate transporters and receptors that are closely associated with GABA pathways are the action sites for ethanol as well. Accordingly, alternative medicines aiming at these shared mechanisms appeared subsequently to mimic ethanol-like effects with less liability, and some of them have achieved positive effects on different diseases with well-tolerance. However, more clinical trials with a large sample and long-term follow-ups are needed for pragmatic use of these medicines, and further investigations on mechanisms will continue to deepen the understanding of these diseases and also accelerate the discovery of ideal treatment.

Baroreflex sensitivity (BRS) is reduced in humans during snoring, however the mechanisms are unknown. We used an anaesthetised rabbit induced snoring (IS) model, to test: (1) whether IS was associated with reduced BRS; and (2) if snoring related vibration transmission to peri-carotid tissues influenced BRS levels. BRS was quantified using the spontaneous sequence technique. During IS, BRS fell by 40%, without any associated change in blood pressure (BP) but accompanied by an increase in heart rate (HR). Direct application of a snore frequency and intensity matched vibratory stimulus to the peri-carotid tissues of non-snoring tracheostomised rabbits had no effect on BRS, HR or BP. In conclusion, IS induced depression of BRS is likely mediated via a HR driven change in BRS operating point that is unrelated to snoring-related vibration transmission to carotid baroreceptors. The anaesthetised IS rabbit provides a model in which mechanistic interactions between snoring and BRS can be further explored.

AbstractAlcohol use disorder (AUD) is characterized by cycles of abuse, withdrawal, and relapse. Neuroadaptations in the basal ganglia are observed in AUD; specifically in the putamen, globus pallidus (GP), and ventral pallidum (VP). These regions are associated with habit formation, drug‐seeking behaviors, and reward processing. While previous studies have shown the crucial role of glial cells in drug seeking, it remains unknown whether glial cells in the basal ganglia are altered in AUD. Glial cells in the putamen, GP, and VP were examined in human post‐mortem tissue of AUD and alcohol remission cases. Immunohistochemistry was performed to analyze cell count, staining intensity, and morphology of microglia and astrocytes, using markers Iba‐1 and GFAP. Morphological analysis revealed a significant decrease in microglia cell size and process retraction, indicating activation or a dystrophic microglia phenotype in individuals with AUD compared to controls. Microglia staining intensity was also higher in the GP and VP in AUD cases, whereas microglia staining intensity and cell size in remission cases were not different to control cases. In contrast, no astrocyte changes were observed in examined brain regions for both AUD and remission cases compared to controls. These results suggest alcohol exposure alters microglia, potentially contributing to dysfunctions in the basal ganglia that maintain addiction, and abstinence from alcohol may reverse microglia changes and associated dysfunctions. Overall, this study further characterizes AUD neuropathology and implicates microglia in the putamen, GP, and VP as a potential target for therapy.

Fetal alcohol syndrome (FAS) is a devastating disorder accompanied by numerous morphological and behavioral abnormalities. Human FAS has been modeled in laboratory animals including the zebrafish. Recently, embryonic exposure to low doses of ethanol has been shown to impair behavior without any gross morphological alterations in zebrafish. The exposed zebrafish showed reduced responses to animated conspecific images. The effect of embryonic ethanol exposure, however, has not been investigated in a real shoal and the potential mechanisms underlying the behavioral impairment are also unknown. Here we show that a 2h long immersion in 0.25% and 0.50% (vol/vol) alcohol at 24h post fertilization significantly increases the distance among members of freely swimming groups of zebrafish when measured at 70 days post fertilization. We also show that this impaired behavior is accompanied by reduced levels of dopamine, DOPAC, serotonin and 5HIAA as quantified by HPLC from whole brain extracts. Our results demonstrate that even very low concentrations of alcohol applied for a short period of time during the development of zebrafish can impair behavior and brain function. We argue that the observed behavioral impairment is not likely to be due to altered performance capabilities, e.g. motor function or perception, but possibly to social behavior itself. We also argue that our neurochemical data represent the first step towards understanding the mechanisms of this abnormality in zebrafish, which may lead to better modeling of, and ultimately perhaps better therapies for human FAS.