Local application of bicuculline potentiates NMDA-receptor-mediated sensory responses of brain noradrenergic neurons.
Direct application of bicuculline methiodide (BIC) to noradrenergic locus coeruleus (LC) neurons potently enhanced their sensory responsiveness. This increased responsiveness was due to the long-lasting expression of a new, N-methyl-D-aspartate (NMDA) receptor-mediated component of the synaptic response. This enhancement only occurred when a high stimulus intensity was used to induce the sensory response. A similar increase in responsiveness was observed with stimulation of the nucleus paragigantocellularis (PGi), one of the major direct afferents to LC. This action of BIC was neither mimicked by picrotoxin, penicillin, or the GABA-B antagonist, 2-hydroxy-baclofen, nor by agents that directly depolarize LC neurons. In addition, the inverse agonist of the benzodiazepine receptor, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), did not mimic this effect of BIC. The BIC-potentiated response component was eliminated by direct application of the neurotransmitter gamma-aminobutyric acid (GABA). These results indicate that BIC, acting at a possibly novel site, unmasks NMDA receptors that can be activated by sensory stimuli. This may reflect a mechanism whereby interactions between two major neurotransmitter systems, excitatory amino acids (EAAs) and GABA, potently modulate signal transmission in the brain.
Department of Mental Health Sciences, Hahnemann University, Philadelphia, Pennsylvania 19102-1192.
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Shiekhattar
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Aston-Jones
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000344:Afferent Pathways / Q000502:physiology; D000818:Animals; D001640:Bicuculline / Q000008:administration & dosage / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D006614:Hindlimb / Q000294:innervation; D008125:Locus Coeruleus / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010812:Physical Stimulation / Q000379:methods; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000502:physiology*
D002243:Carbolines; D058787:GABA-A Receptor Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D014660:Vasoactive Intestinal Peptide; D005680:gamma-Aminobutyric Acid; D015763:2-Amino-5-phosphonovalerate; D001640:Bicuculline