Group III metabotropic glutamate receptor agonists selectively suppress excitatory synaptic currents in the rat prefrontal cortex induced by 5-hydroxytryptamine2A receptor activation
2006
Activation and blockade of prefrontal cortical 5-hydroxytryptamine2A (5-HT2A) receptors have been linked to the action of hallucinogenic and antidepressant/antipsychotic drugs; these effects may involve modulation of glutamate release from thalamocortical afferents. Although activation of metabotropic glutamate 2 (mGlu2) receptors may suppress 5-HT-induced excitatory postsynaptic currents (EPSCs), group III mGlu receptors (mGlu4/7/8) also are expressed in the thalamus and may suppress 5-HT-induced EPSCs. We have found by intracellular recordings from layer V pyramidal cells of the medial prefrontal cortex (mPFC) that group III mGlu receptor agonists ( R , S )-4-phosphonophenylglycine (PPG), l-4-phosphono-2-aminobutyric acid (l-AP4), l-serine- O -phosphate (l-SOP), and ( S )-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4) preferentially suppress 5-HT-induced EPSCs compared with excitatory postsynaptic potentials evoked by electrical stimulation of the white matter. A number of pharmacological features [e.g., the rank order of agonist potency; MAP4 partial agonist action; differential potency for the group III mGlu receptor antagonist ( R , S )-α-cyclopropyl-4-phosphonophenylglycine (CPPG) in blocking the suppressant action of PPG or MAP4; and a relatively low potency of 2 S -2-amino-2-(1 S ,2 S -2-carboxycycloprop-1-yl)-3(xanthy-9-yl)propanoic acid (LY341495) in blocking the suppressant action of PPG or l-SOP] suggest that activation of both mGlu4 and mGlu8 receptors may play a role in suppressing 5-HT-induced EPSCs. Furthermore, l-SOP did not alter the synaptic currents or steady-state inward current induced by α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid. Thus, although both group III and group II mGlu receptor agonists suppress the frequency of 5-HT-induced EPSCs in the mPFC, they differ in that the group III mGlu receptor agonists appear to have relatively minimal effects on glutamate released by sources other than thalamocortical afferents.
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