| Disinhibition, which enhances the excitability of neurons in the central nervoussystem, is involved in many important physiological and pathological processes, suchas learning and memory, drug addiction and chronic pain. Patients suffer much morefrom pain-related affect than from pain perception. Although a large number ofstudies, which mainly focus on the glutamatergic excitatory system, show theinvolvement of the anterior cingulate cortex (ACC) in pain-related affect,disinhibition in the ACC has been rarely reported.The present study aims to explore the functions and possible mechanisms ofdisinhibition in rat ACC, combining whole-cell patch-clamp recordings in ACC sliceswith animal behavioral tests. Main results are as follows:1. Removal of GABAA receptor mediated inhibition greatly enhanced polysynapticexcitatory transmission in rat ACC. When the slice was superfused with normalACSF, a monosynaptic response with a short and constant latency, referred as"early response", was induced in a Layer V pyramidal neuron by intracorticalstimulation at Layer II/III of the ACC. Around 4 min after blockade of GABA_Areceptors by bicuculline (10 μM), a novel response with a long and variablelatency, referred as "late response", was induced by regular stimulation at the rateof 0.04Hz. When bicuculline was continuously applied, the "late response" wasfurther enhanced to reach a steady level. The "late response" was blocked by highdivalent cation (4.2 Mg2+,7.0 Ca2+) ACSF and was sensitive to relatively higherfrequency stimuli. These two characteristics are consistent with those ofpolysynaptic response. GABAB receptor antagonist salofen (250 μM) or glycinereceptor antagonist strychnine (0.5 μM) did not affect the "early response".Pharmacological analyses revealed that both "early response" and "late response"could be completely eliminated by glutamate receptor antagonists DNQX (10 μM)and AP-V (50 μM), which indicates that removal of GABAA inhibition couldgreatly enhance excitatory transmission in the ACC.2. By using the behavioral model of formalin-induced conditioned place avoidance(F-CPA), the effect of intra-ACC microinjection of GABAA receptor agonistmuscimol on pain-related affect was examined. Rats of control group avoided theformalin-paired compartment after conditioning, and the avoidance score was191±44 s (n=8). F-CPA was blocked by intra-ACC administration of muscimol(10 mM, 0.6 μl) in the conditioning session, while formalin-induced acutenociceptive responses were not affected. These results suggest that disinhibition inACC play a role in pain aversion.3. Dopamine reduced inhibitory postsynaptic currents (IPSCs) to Layer V pyramidalneurons in the ACC via D2-like receptors and a postsynaptic mechanism. An IPSCwas induced in a Layer V pyramidal neuron by the intracortical 0.04 Hzstimulation of Layer II/III in ACC. The IPSC, which could be blocked bybicuculline (10 μM), was reduced to 70.7±7.1% (n=14) of control amplitude bysuperfusion of dopamine (50 μM). Concentration-dependent effects of dopaminewere also observed. The same reduction effects as dopamine could be induced byD2 receptor agonist quinpirole (10 μM) but not by D1 receptor agonist SKF38393(10 μM). Besides, the inhibition effects of dopamine could be reversed by D2receptor antagonist eticlopride (5 μM) but not by D1 receptor antagonistSCH23390 (10 μM). Dopamine (50 μM) inhibited currents induced by pressureinjection of GABA and amplitude ratios of paired-pulse stimulation were notaffected, which indicate the postsynaptic mechanism of dopamine effects.In conclusion, GABAergic disinhibition could greatly facilitate polysynapticexcitatory transmission in rat ACC and might be involved in pain-related aversion.One possible mechanism of disinhibition in the ACC is inhibition of IPSCs/IPSPs toLayer V pyramidal neurons by mesocortical dopaminergic activation of postsynapticD2 receptors.
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