Opiate withdrawal-induced hyperactivity of locus coeruleus neurons is substantially mediated by augmented excitatory amino acid input.
Single-cell activity was recorded in the locus coeruleus (LC) of morphine-dependent, halothane-anesthetized rats. Systemic administration of the opiate antagonist naloxone (0.1 mg/kg, i.v.) robustly increased the activity of LC neurons. Local microinjection of naloxone or of its hydrophilic derivative, naloxone methiodide, into LC (10 mM, 20-40 nl) did not activate LC neurons in dependent rats. Intracerebroventricular or intracoerulear injection of kynurenate, a broad-spectrum antagonist of excitatory amino acids (EAAs), substantially but incompletely attenuated the activation of LC cells induced by intravenous naloxone-precipitated withdrawal (more than 50% blockade). Intracoerulear microinjections of the non-NMDA-receptor antagonist 6-cyano-7-dinitroquinoxaline-2,3-dione (CNQX) or the selective NMDA-receptor antagonist AP5 significantly reduced the withdrawal-induced excitation. AP5 was the least effective among all antagonists tested. Similar microinjections of kynurenate or CNQX almost completely suppressed the excitation of LC neurons induced by electrical stimulation of a rear footpad. LC responses to footpad stimulation (mediated by endogenous EAAs) or iontophoretically applied glutamate were not modified by the chronic morphine treatment. These results indicate that a substantial part of LC hyperactivity during opiate withdrawal is mediated by an augmented EAA input to LC.
Department of Mental Health Sciences, Hahnemann University, Philadelphia, Pennsylvania 19102.
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D000596:Amino Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001927:Brain Diseases / Q000139:chemically induced; D004558:Electric Stimulation; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D015918:Infusion Pumps, Implantable; D007736:Kynurenic Acid / Q000494:pharmacology; D008125:Locus Coeruleus / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008845:Microinjections; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D009270:Naloxone / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology
D000596:Amino Acids; D005971:Glutamates; D009270:Naloxone; D018698:Glutamic Acid; D009020:Morphine; D007736:Kynurenic Acid