Rats with extended access to cocaine exhibit increased stress reactivity and sensitivity to the anxiolytic-like effects of the mGluR 2/3 agonist LY379268 during abstinence.
Metabotropic glutamate 2/3 receptors (mGluR2/3) are emerging targets for the reduction of stress that contributes to drug relapse. The effect of a history of cocaine escalation on stress reactivity during abstinence and the role of mGlu2/3 receptors in stress in these animals were tested. Experiment 1-Rats trained to self-administer cocaine, under short (ShA, 1-h) or long (LgA, 6-h) access conditions, or noncaloric food pellets (Ctrl, 1-h), were tested for stress reactivity in the shock-probe defensive burying test following 1, 14, 42, or 84 days of abstinence. Experiment 2-Experimentally naive rats receiving the mGlu2/3 receptor agonist LY379268 (0, 0.3, 1.0, or 3.0 mg/kg) were tested in the defensive burying test to establish the anxiolytic efficacy of this compound in this model. Experiment 3-Rats with a history of ShA vs LgA cocaine self-administration, or a history of operant responding reinforced by noncaloric food pellets, were tested in the defensive burying test, following administration of LY379268 (0.3, 1.0, or 3.0 mg/kg) at 14 days of abstinence. LgA rats exhibited a two- to threefold increase in defensive burying at 1, 14, and 42 days of abstinence compared to ShA or control animals. LY379268 (3.0 mg/kg) reduced burying in all groups, whereas the 1.0-mg/kg dose reduced burying only in the LgA group. A robust and enduring increase in stress reactivity developed in rats with a history of daily 6-h access to cocaine. The anxiolytic-like effects of LY379268 identify mGlu2/3 receptors as targets for ameliorating stress-associated relapse risk, and point toward the possibility that a history of cocaine escalation in rats may modify glutamatergic function.
Aujla
Harinder
H
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA 92037, USA. haujla@scripps.edu
Martin-Fardon
Rémi
R
Weiss
Friedbert
F
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000523:psychology*; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005502:Food; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012054:Reinforcement, Psychology; D013315:Stress, Psychological / Q000523:psychology*; D013375:Substance Withdrawal Syndrome / Q000523:psychology*
D000596:Amino Acids; D014151:Anti-Anxiety Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018690:Excitatory Amino Acid Agonists; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3