Vincent N. Marty

Long-Lasting Alterations in Membrane Properties, K+ Currents, and Glutamatergic Synaptic Currents of Nucleus Accumbens Medium Spiny Neurons in a Rat Model of Alcohol Dependence

Chronic alcohol exposure causes marked changes in reinforcement mechanisms and motivational state that are thought to contribute to the development of cravings and relapse during protracted withdrawal. The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system. Although the NAcc plays an important role in mediating alcohol-seeking behaviors, little is known about the molecular mechanisms underlying alcohol-induced neuroadaptive changes in NAcc function. The aim of this study was to investigate the effects of chronic intermittent ethanol (CIE) treatment, a rat model of alcohol withdrawal and dependence, on intrinsic electrical membrane properties and glutamatergic synaptic transmission of medium spiny neurons (MSNs) in the NAcc core during protracted withdrawal. We show that CIE treatment followed by prolonged withdrawal increased the inward rectification of MSNs observed at hyperpolarized potentials. In addition, MSNs from CIE-treated animals displayed a lower input resistance, faster action potentials (APs), and larger fast afterhyperpolarizations (fAHPs) than MSNs from vehicle-treated animals, all suggestive of increases in K+-channel conductances. Significant increases in the Cs+-sensitive inwardly rectifying K+-current accounted for the increased input resistance, while increases in the A-type K+-current accounted for the faster APs and increased fAHPs in MSNs from CIE rats. We also show that the amplitude and the conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated mEPSCs were enhanced in CIE-treated animals due to an increase in a small fraction of functional postsynaptic GluA2-lacking AMPARs. These long-lasting modifications of excitability and excitatory synaptic receptor function of MSNs in the NAcc core could play a critical role in the neuroadaptive changes underlying alcohol withdrawal and dependence.

Effects of alcohol on the membrane excitability and synaptic transmission of medium spiny neurons in the nucleus accumbens

Chronic and excessive alcohol drinking lead to alcohol dependence and loss of control over alcohol consumption, with serious detrimental health consequences. Chronic alcohol exposure followed by protracted withdrawal causes profound alterations in the brain reward system that leads to marked changes in reinforcement mechanisms and motivational state. These long-lasting neuroadaptations are thought to contribute to the development of cravings and relapse. The nucleus accumbens (NAcc), a central component of the brain reward system, plays a critical role in alcohol-induced neuroadaptive changes underlying alcohol-seeking behaviors. Here we review the findings that chronic alcohol exposure produces long-lasting neuroadaptive changes in various ion channels that govern intrinsic membrane properties and neuronal excitability, as well as excitatory and inhibitory synaptic transmission in the NAcc that underlie alcohol-seeking behavior during protracted withdrawal.

Plasticity of GABAA receptor-mediated neurotransmission in the nucleus accumbens of alcohol-dependent rats

Chronic alcohol exposure-induced changes in reinforcement mechanisms and motivational state are thought to contribute to the development of cravings and relapse during protracted withdrawal. The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system and plays an important role in mediating alcohol-seeking behaviors. Here we describe the long-lasting alterations of γ-aminobutyric acid type A receptors (GABA(A)Rs) of medium spiny neurons (MSNs) in the NAcc after chronic intermittent ethanol (CIE) treatment, a rat model of alcohol dependence. CIE treatment and withdrawal (>40 days) produced decreases in the ethanol and Ro15-4513 potentiation of extrasynaptic GABA(A)Rs, which mediate the picrotoxin-sensitive tonic current (I(tonic)), while potentiation of synaptic receptors, which give rise to miniature inhibitory postsynaptic currents (mIPSCs), was increased. Diazepam sensitivity of both I(tonic) and mIPSCs was decreased by CIE treatment. The average magnitude of I(tonic) was unchanged, but mIPSC amplitude and frequency decreased and mIPSC rise time increased after CIE treatment. Rise-time histograms revealed decreased frequency of fast-rising mIPSCs after CIE treatment, consistent with possible decreases in somatic GABAergic synapses in MSNs from CIE rats. However, unbiased stereological analysis of NeuN-stained NAcc neurons did not detect any decreases in NAcc volume, neuronal numbers, or neuronal cell body volume. Western blot analysis of surface subunit levels revealed selective decreases in α1 and δ and increases in α4, α5, and γ2 GABA(A)R subunits after CIE treatment and withdrawal. Similar, but reversible, alterations occurred after a single ethanol dose (5 g/kg). These data reveal CIE-induced long-lasting neuroadaptations in the NAcc GABAergic neurotransmission.

Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation

ABSTRACT Chemotherapy‐induced peripheral neuropathy (CIPN) is a severe and dose‐limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy‐induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)‐mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin‐induced peripheral neuropathy. Results show that local or systemic administration of 4‐{2‐[‐(1E)‐1[(4‐propylnaphthalen‐1‐yl)methylidene]‐1H‐inden‐3‐yl]ethyl}morpholine (PrNMI) dose‐dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose‐dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co‐administration with selective cannabinoid receptor subtype blockers revealed that PrNMIs anti‐allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMIs anti‐allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose‐dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms. HIGHLIGHTSFirst demonstration of effective mechanical and cold allodynia suppression by peripherally‐restricted PrNMI in male and female CIPN rats.No significant CNS side‐effects of PrNMI before or after CIPN.Two week daily oral PrNMI treatment shows no significant tolerance to allodynia suppression.Potent, long‐lasting suppression of CIPN behaviors by systemic PrNMI in an operant task.Decreased CB2R mRNA, unchanged mRNAs of CB1R and endocannabinoid‐related enzymes in CIPN sensory ganglia.

Introduction to Young Investigator Award Symposium: Symposium XII: Young Investigator Award

The growing health burdens of alcohol addiction and stressrelated disorders demand novel treatment strategies and new advances in biomedical research. Alcoholism and Stress: A Framework for Future Treatment Strategies is an international meeting dedicated to developing preventive strategies and pharmacotherapeutic remedies for stressand alcohol-related disorders. This was the second conference on this topic hosted by Drs. Roberto and Koob in May 2011, and like the inaugural conference, the meeting was held in Volterra, Italy. This conference is the only international meeting of its kind. Its primary purpose is to establish an international effort between both basic researchers and clinicians to develop prevention strategies and pharmacotherapeutic remedies for alcohol disorders. The meeting provided a platform for the world’s preeminent scientists in alcoholism and stress research to present their latest findings through plenary lectures, symposia, posters, and roundtable discussions. Presentations represented research in molecular and cellular biology, epidemiology, behavioral, and clinical alcohol research. To promote the work of young researchers and highlight their outstanding achievements in the fields of addiction medicine and stress disorders, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) conferred a Young Investigator Award. This is the second Young Investigator Award to be sponsored and funded by the NIAAA (AA017581). This award is intended to facilitate innovative research opportunities and support young alcohol investigators. Applications were received from scientists throughout the United States. Applications were reviewed by the conference organizers, Drs. Marisa Roberto and George Koob of The Scripps Research Institute (La Jolla, CA). The main criteria for selecting awardees was: 1) scientific merit of the submitted abstract, 2) previous publication record, 3) current work in the alcohol research field, and 4) potential for development and contribution to alcohol and stress research. Those judged to be outstanding in quality were selected to be recipients of the Young Investigator Award and invited to give a presentation during the Young Investigator Symposium, chaired by Dr. Fulton Crews (University of North Carolina at Chapel Hill) and Dr. Antonio Noronha (NIH/NIAAA). Awardees also received a waiver of the meeting registration fee as well as an official certificate of merit from the meeting organizers. Dr. Thomas L. Kash (University of North Carolina at Chapel Hill) provided an overview of stress and alcohol modulation of Kappa opioid receptor signaling in the bed nucleus of the stria terminalis (BNST). Dr. Patrick Mulholland (University of South Carolina) showed that SK channels regulate ethanol-associated plasticity