The benzodiazepine inverse agonist DMCM as an unconditional stimulus for fear-induced analgesia: implications for the role of GABAA receptors in fear-related behavior.
When the benzodiazepine inverse agonist DMCM (6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylic acid methyl ester) occupies the benzodiazepine recognition site on the GABAA receptor complex, the inhibitory action of gamma-aminobutyric acid (GABA) is attenuated. DMCM acted as an unconditional stimulus for one response associated with fear or anxiety, analgesia, as indicated by a dose-dependent (0.25-1.0 mg/kg) suppression of rats' responses to a formalin injection. This was accompanied by other fearlike responses (defecation and urination). The opioid antagonist naltrexone (1.75-14 mg/kg) did not affect these behaviors. Environmental cues associated with DMCM provoked analgesia and defecation in the absence of the drug. The conditional analgesia was reversed by naltrexone (7 mg/kg). DMCM functions as an unconditional fear stimulus by eliciting fear-related behaviors and conditioning those responses to neutral stimuli. The neural circuitry underlying fear conditioning appears to involve tonically inhibitory GABAergic synapses.
Fanselow
M S
MS
Department of Psychology, University of California, Los Angeles 90024-1563.
Kim
J J
JJ
D000818:Animals; D001143:Arousal / Q000187:drug effects*; D001245:Association Learning / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D002243:Carbolines / Q000494:pharmacology*; D003214:Conditioning, Classical / Q000187:drug effects*; D003292:Convulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects*; D005260:Female; D006120:Grooming / Q000187:drug effects; D009619:Nociceptors / Q000187:drug effects*; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects*; D012931:Social Environment
D002243:Carbolines; D003292:Convulsants; D011963:Receptors, GABA-A; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate