https://www.repository.cam.ac.uk/bitstream/1810/267142/1/Milton---Everitt-open-access.pdf

The persistence of maladaptive memory: Addiction, drug memories and anti-relapse treatments

Aberrant Learning and Memory in Addiction

Relapse processes after the extinction of instrumental learning: renewal, resurgence, and reacquisition.

An increasingly compelling literature points to a major role for the glutamate system in mediating the effects of alcohol on behavior and the pathophysiology of alcoholism. Preclinical studies indicate that glutamate signaling mediates certain aspects of ethanol's intoxicating and rewarding effects, and undergoes adaptations following chronic alcohol exposure that may contribute to the withdrawal, craving and compulsive drug-seeking that drive alcohol abuse and alcoholism. We discuss the potential for targeting the glutamate system as a novel pharmacotherapeutic approach to treating alcohol use disorders, focusing on five major components of the glutamate system: the N-methyl-d-aspartate (NMDA) receptor and specific NMDA subunits, the glycineB site on the NMDA receptors (NMDAR), l-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid ionotropic (AMPA) and kainate (KAR) receptors, metabotropic receptors (mGluR), and glutamate transporters. Chronic alcohol abuse produces a hyperglutamatergic state, characterized by elevated extracellular glutamate and altered glutamate receptors and transporters. Pharmacologically manipulating glutamatergic neurotransmission alters alcohol-related behaviors including intoxication, withdrawal, and alcohol-seeking, in rodents and human subjects. Blocking NMDA and AMPA receptors reduces alcohol consumption in rodents, but side-effects may limit this as a therapeutic approach. Selectively targeting NMDA and AMPA receptor subunits (e.g., GluN2B, GluA3), or the NMDAR glycineB site offers an alternative approach. Blocking mGluR5 potently affects various alcohol-related behaviors in rodents, and mGluR2/3 agonism also suppresses alcohol consumption. Finally, glutamate transporter upregulation may mitigate behavioral and neurotoxic sequelae of excess glutamate caused by alcohol. Despite the many challenges that remain, targeting the glutamate system offers genuine promise for developing new treatments for alcoholism.

/pdf/glutamatergic-targets-for-new-alcohol-medications-4ltohag5sv.pdf

Glutamatergic targets for new alcohol medications

Glutamate Receptors in Extinction and Extinction-Based Therapies for Psychiatric Illness

Aims: The aim of the present study was to examine the influence of partial NMDA receptor agonist D-cycloserine (DCS) on the extinction of conditioned alcohol-seeking behaviour. Methods: For this purpose, rats were administered with DCS 60 min before each successive extinction session. Resumption of alcohol responding was carried out 1 day after the final extinction session. Results: We demonstrate that treatment of rats with 5 mg/kg of DCS was capable in facilitating extinction of conditioned alcohol-seeking behaviour, which subsequently reduced the resumption of extinguished operant responding. Conclusions: Our study suggests a good rationale for the development of new add-on medications for exposure-based psychotherapy so as to extinguish drug-conditioned appetitive memories in alcohol-dependent patients. lated sound-attenuating cubicles. The chambers were equipped with a response lever on each side panel of the chamber. Re- sponses at the appropriate lever activated a syringe pump that delivered an ∼30-µl drop of fluid into a liquid receptacle next to it. A light stimulus (house light) was mounted above the right response lever and a loudspeaker (65 dB, 'beep') was po- sitioned above the left response lever of the self-administration chamber. All animal training and extinction sessions were per- formed during the active dark phase. Eight-week-old Wistar rats (Charles River, Sulfeld, Germany) were trained to self-administer 10% (v/v) ethanol in daily 30-min sessions using a fixed-ratio 1 (FR 1) sched- ule preceded by a saccharine-fading procedure. Throughout the training phase, responses at the opposite lever resulted in the delivery of a drop of water. The purpose of the condition- ing phase was to train the animals to discriminate between the availability of ethanol (reward) and water (non-reward). Note that non-reward sessions were included in the study in order to see the selectivity of DCS towards the extinction of ethanol related stimuli. The conditioning phase started after the completion of the training phase. Discriminative stimuli pre- dicting 10% ethanol or water availability was presented during each ethanol or water self-administration session (one 30-min session/day). During these sessions, the opposite lever was in- active (i.e. the presses on this lever did not have any con- sequences). An orange flavour extract served as the S+ for ethanol, whereas water availability was signalled by an anise extract (S−). These olfactory stimuli were generated by de- positing six drops of the respective extract into the bedding of the operant chamber before each session. In addition, each lever press resulting in alcohol delivery was accompanied by a 5-s auditory stimulus ('beep', CS+), whereas a 5-s light stimulus (CS−) was presented with water delivery. The 5-s period served as a 'time-out', during which responses were recorded but not reinforced. Alcohol and water sessions were conducted in a ran- dom manner until the animals received a total of 10 alcohol and 10 water sessions. After completing the conditioning phase, the rats were subjected to daily 30-min extinction sessions for 12 consecutive days. Extinction sessions began by extending the

PHARMACOLOGY AND CELL METABOLISM D-Cycloserine Facilitates Extinction of Conditioned Alcohol-Seeking Behaviour in Rats

It has recently been demonstrated that pharmacological blockade of the glycine transporter 1 (GlyT1) reduced alcohol intake and relapse in rats. The aim of the present study was to further explore the role of GlyT1 in alcohol relapse-like behavior. For this purpose we used three different GlyT1 blockers—SSR504734, A-1246399, and RO4993850—and tested their effect on alcohol-seeking and relapse-like consumption. Two behavioral models, the alcohol deprivation effect model and the cue-induced reinstatement model, were used. Our data show that all three GlyT1 blockers reduce relapse-like alcohol consumption and cause either minimal or no side effects, measured as changes in home-cage activity, water intake, and body weight. In the reinstatement test, GlyT1 blockers completely abolished alcohol-seeking responses. Furthermore, we tested other drug/cue associations and found that cocaine-seeking responses were also abolished by GlyT1 blockade. Our data confirm that GlyT1 can be used as a target to develop novel anticraving and antirelapse drugs.

https://jpet.aspetjournals.org/content/jpet/365/1/202.full.pdf

Targeting Glycine Reuptake in Alcohol Seeking and Relapse.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Rainer Spanagel

Author Tools

Chat about Author

Papers

PHARMACOLOGY AND CELL METABOLISM D-Cycloserine Facilitates Extinction of Conditioned Alcohol-Seeking Behaviour in Rats

Targeting Glycine Reuptake in Alcohol Seeking and Relapse.