Abstinence and Fear Experienced during This Period Produce Distinct Cortical and Hippocampal Adaptations in Alcohol-Dependent Rats.

Previous studies demonstrate that ethanol dependence induced by repeating cycles of chronic intermittent ethanol vapor exposure (CIE) followed by protracted abstinence produces significant gray matter damage via myelin dysfunction in the rodent medial prefrontal cortex (mPFC) and alterations in neuronal excitability in the mPFC and the dentate gyrus (DG) of the hippocampus. Specifically, abstinence-induced neuroadaptations have been associated with persistent elevated relapse to drinking. The current study evaluated the effects of forced abstinence for 1 day (d), 7 d, 21 d, and 42 d following seven weeks of CIE on synaptic plasticity proteins in the mPFC and DG. Immunoblotting revealed reduced expression of CaMKII in the mPFC and enhanced expression of GABAA and CaMKII in the DG at the 21 d time point, and the expression of the ratio of GluN2A/2B subunits did not change at any of the time points studied. Furthermore, cognitive performance via Pavlovian trace fear conditioning (TFC) was evaluated in 3 d abstinent rats, as this time point is associated with negative affect. In addition, the expression of the ratio of GluN2A/2B subunits and a 3D structural analysis of neurons in the mPFC and DG were evaluated in 3 d abstinent rats. Behavioral analysis revealed faster acquisition of fear responses and reduced retrieval of fear memories in CIE rats compared to controls. TFC produced hyperplasticity of pyramidal neurons in the mPFC under control conditions and this effect was not evident or blunted in abstinent rats. Neurons in the DG were unaltered. TFC enhanced the GluN2A/2B ratio in the mPFC and reduced the ratio in the DG and was not altered by abstinence. These findings indicate that forced abstinence from CIE produces distinct and divergent alterations in plasticity proteins in the mPFC and DG. Fear learning-induced changes in structural plasticity and proteins contributing to it were more profound in the mPFC during forced abstinence.

Correction to: Neuroadaptations in the dentate gyrus following contextual cued reinstatement of methamphetamine seeking.

The author reports that data for electrophysiology findings reported in Figs. 4 and 5 for control group and Meth Rst group have been published previously (Galinato MH et al., J Neurosci. 2018 Feb 21; 38(8):2029-2042.

Neuroadaptations in the dentate gyrus following contextual cued reinstatement of methamphetamine seeking.

Abstinence from unregulated methamphetamine self-administration increases hippocampal dependent, context-driven reinstatement of methamphetamine seeking. The current study tested the hypothesis that alterations in the functional properties of granule cell neurons (GCNs) in the dentate gyrus (DG) of the hippocampus in concert with altered expression of synaptic plasticity-related proteins and ultrastructural changes in the DG are associated with enhanced context-driven methamphetamine-seeking behavior. Whole-cell patch-clamp recordings were performed in acute brain slices from methamphetamine naïve (controls) and methamphetamine experienced animals (during acute withdrawal, during abstinence, after extinction and after reinstatement). Spontaneous excitatory postsynaptic currents (sEPSCs) and intrinsic excitability were recorded from GCNs. Reinstatement of methamphetamine seeking increased sEPSC frequency and produced larger amplitude responses in GCNs compared to controls and all other groups. Reinstatement of methamphetamine seeking reduced spiking capability in GCNs compared to controls, and all other groups, as indicated by reduced intrinsic spiking elicited by increasing current injections, membrane resistance and fast after hyperpolarization. In rats that reinstated methamphetamine seeking, these altered electrophysiological properties of GCNs were associated with enhanced expression of Fos, GluN2A subunits and PSD95 and reduced expression of GABAA subunits in the DG and enhanced expression of synaptic PSD in the molecular layer. The alterations in functional properties of GCNs and plasticity related proteins in the DG paralleled with no changes in structure of microglial cells in the DG. Taken together, our results demonstrate that enhanced reinstatement of methamphetamine seeking results in alterations in intrinsic spiking and spontaneous glutamatergic synaptic transmission in the GCNs and concomitant increases in neuronal activation of GCNs, and expression of GluNs and decreases in GABAA subunits that may contribute to the altered synaptic connectivity-neuronal circuitry-and activity in the hippocampus, and enhance propensity for relapse.

Platelet Endothelial Cell Adhesion Molecule-1 and Oligodendrogenesis: Significance in Alcohol Use Disorders.

Alcoholism is a chronic relapsing disorder with few therapeutic strategies that address the core pathophysiology. Brain tissue loss and oxidative damage are key components of alcoholism, such that reversal of these phenomena may help break the addictive cycle in alcohol use disorder (AUD). The current review focuses on platelet endothelial cell adhesion molecule 1 (PECAM-1), a key modulator of the cerebral endothelial integrity and neuroinflammation, and a targetable transmembrane protein whose interaction within AUD has not been well explored. The current review will elaborate on the function of PECAM-1 in physiology and pathology and infer its contribution in AUD neuropathology. Recent research reveals that oligodendrocytes, whose primary function is myelination of neurons in the brain, are a key component in new learning and adaptation to environmental challenges. The current review briefly introduces the role of oligodendrocytes in healthy physiology and neuropathology. Importantly, we will highlight the recent evidence of dysregulation of oligodendrocytes in the context of AUD and then discuss their potential interaction with PECAM-1 on the cerebral endothelium.