Role of GABAA receptors in dorsal raphe nucleus in stress-induced reinstatement of morphine-conditioned place preference in rats

• Published in: Psychopharmacology Vol. 230; no. 4; pp. 537 - 545
• Main Authors: Li, Chen, Staub, Daniel R., Kirby, Lynn G.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2013
• Subjects: Animals; Behavior, Animal - drug effects; Bicuculline - pharmacology; Biomedical and Life Sciences; Biomedicine; Conditioning (Psychology) - drug effects; Extinction, Psychological - drug effects; GABA-A Receptor Agonists - pharmacology; GABA-A Receptor Antagonists - pharmacology; Male; Morphine - pharmacology; Muscimol - pharmacology; Neurons - drug effects; Neurons - metabolism; Neurosciences; Original Investigation; Pharmacology/Toxicology; Psychiatry; Raphe Nuclei - drug effects; Raphe Nuclei - metabolism; Rats; Rats, Sprague-Dawley; Receptors, GABA-A - metabolism; Serotonin - metabolism; Stress, Psychological - metabolism; Relapse; Corticotropin-releasing factor (CRF); Addiction; Conditioned place preference; Stressor; Stress-induced reinstatement; GABA; Morphine; Dorsal raphe; Swim
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-013-3182-x

Rationale The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Our data indicate that stress inhibits the dorsal raphe nucleus (DRN)-5-HT system via stimulation of GABA synaptic activity by the stress neurohormone corticotropin-releasing factor and, more recently, that morphine history sensitizes DRN-5-HT neurons to GABAergic inhibitory effects of stress. Objectives We tested the hypothesis that DRN GABA A receptors contribute to stress-induced reinstatement of morphine-conditioned place preference (CPP). Methods First, we tested if activation of GABA A receptors in the DRN would reinstate morphine CPP. Second, we tested if blockade of GABA A receptors in the DRN would attenuate swim stress-induced reinstatement of morphine CPP. CPP was induced by morphine (5 mg/kg) in a 4-day conditioning phase followed by a conditioning test. Upon acquiring conditioning criteria, subjects underwent 4 days of extinction training followed by an extinction test. Upon acquiring extinction criteria, animals underwent a reinstatement test. For the first experiment, the GABA A receptor agonist muscimol (50 ng) or vehicle was injected into the DRN prior to the reinstatement test. For the second experiment, the GABA A receptor antagonist bicuculline (75 ng) or vehicle was injected into the DRN prior to a forced swim stress, and then, animals were tested for reinstatement of CPP. Results Intraraphe injection of muscimol reinstated morphine CPP, while intraraphe injection of bicuculline attenuated swim stress-induced reinstatement. Conclusions These data provide evidence that GABA A receptor-mediated inhibition of the serotonergic DRN contributes to stress-induced reinstatement of morphine CPP.