ly-379268 and Substance-Related-Disorders

One of most formidable problems in the treatment of addiction is the high rate of relapse. The discovery of medicines to help mitigate relapse are aided by animal models that currently involve weeks of training and require surgical preparations and drug delivery devices. The present set of experiments was initiated to investigate a rapid 8-day screening method that utilizes food instead of intravenous drug administration. Male Sprague-Dawley rats were trained in a reinstatement paradigm in which every lever press produced a 45 mg food pellet concurrently paired with a light and tone. Behavior was subsequently extinguished with lever responses producing neither food nor food-associated stimuli. Reinstatement of responding was evaluated under conditions in which the first three responses of every 5 min time bin produced a food pellet along with food-associated stimuli. The mGlu

Topics: Amino Acids; Animals; Behavior, Addictive; Behavior, Animal; Bridged Bicyclo Compounds, Heterocyclic; Cannabinoid Receptor Antagonists; Conditioning, Operant; Drug Discovery; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Extinction, Psychological; Feeding Behavior; Male; Models, Animal; Pyridines; Rats; Rats, Sprague-Dawley; Recurrence; Rimonabant; Self Administration; Substance-Related Disorders; Thiazoles

Defining the drug-induced neuroadaptations specifically associated with the behavioral manifestation of addiction is a daunting task. To address this issue, we used a behavioral model that differentiates rats controlling their drug use (Non-Addict-like) from rats undergoing transition to addiction (Addict-like). Dysfunctions in prefrontal cortex (PFC) synaptic circuits are thought to be responsible for the loss of control over drug taking that characterizes addicted individuals. Here, we studied the synaptic alterations in prelimbic PFC (pPFC) circuits associated with transition to addiction. We discovered that some of the changes induced by cocaine self-administration (SA), such as the impairment of the endocannabinoid-mediated long-term synaptic depression (eCB-LTD) was similarly abolished in Non-Addict- and Addict-like rats and thus unrelated to transition to addiction. In contrast, metabotropic glutamate receptor 2/3-mediated LTD (mGluR2/3-LTD) was specifically suppressed in Addict-like rats, which also show a concomitant postsynaptic plasticity expressed as a change in the relative contribution of AMPAR and NMDAR to basal glutamate-mediated synaptic transmission. Addiction-associated synaptic alterations in the pPFC were not fully developed at early stages of cocaine SA, when addiction-like behaviors are still absent, suggesting that pathological behaviors appear once the pPFC is compromised. These data identify specific synaptic impairments in the pPFC associated with addiction and support the idea that alterations of synaptic plasticity are core markers of drug dependence.

Topics: Amino Acids; Analysis of Variance; Animals; Biophysics; Bridged Bicyclo Compounds, Heterocyclic; Cocaine; Conditioning, Operant; Disease Models, Animal; Dopamine Uptake Inhibitors; Electric Stimulation; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; In Vitro Techniques; Long-Term Synaptic Depression; Male; Patch-Clamp Techniques; Prefrontal Cortex; Psychiatric Status Rating Scales; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Self Administration; Substance-Related Disorders; Synapses