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At proximal synapses from layer V pyramidal neurons from the rat prefrontal cortex, activation of group II metabotropic glutamate receptors (group II mGlu) by (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl) glycine (DCG IV) induced a long-lasting depression of excitatory postsynaptic currents. Paired-pulse experiments suggested that the depression was expressed presynaptically. Activation of type 1 cannabinoid receptors (CB1) by WIN 55,212-2 occluded the DCG IV-induced depression in a mutually occlusive manner. At the postsynaptic level, WIN 55,212-2 and DCG IV were also occlusive for the activation of extracellular signal-regulated kinase. The postsynaptic localization of active extracellular signal-regulated kinase was confirmed by immunocytochemistry after activation of CB1 receptors. However, phosphorylation of extracellular signal-regulated kinase in layer V pyramidal neurons was dependent on the activation of N-methyl-d-aspartate receptors, consequently to a release of glutamate in the local network. Group II mGlu were also shown to be involved in long-term changes in synaptic plasticity induced by high frequency stimulations. The group II mGlu antagonist (RS)-alpha-methylserine-O-phosphate monophenyl ester (MSOPPE) favoured long-term depression. However, no interaction was found between MSOPPE, WIN 55,212-2 and the CB1 receptor antagonist SR 141716A on the modulation of long-term depression or long-term potentiation and the effects of these drugs were rather additive. We suggest that CB1 receptor and group II mGlu signalling may interact through a presynaptic mechanism in the induction of a DCG IV-induced depression. Postsynaptically, an indirect interaction occurs for activation of extracellular signal-regulated kinase. However, none of these interactions seem to play a role in synaptic plasticities induced with high frequency stimulations.

Cannabinoids receptors have been reported to modulate synaptic transmission in many structures of the CNS, but yet little is known about their role in the prefrontal cortex where type I cannabinoid receptor (CB-1) are expressed. In this study, we tested first the acute effects of selective agonists and antagonist of CB-1 on glutamatergic excitatory postsynaptic currents (EPSCs) in slices of rat prefrontal cortex (PFC). EPSCs were evoked in patch-clamped layer V pyramidal cells by stimulation of layer V afferents. Monosynaptic EPSCs were strongly depressed by bath application (1 microM) of the cannabinoid receptors agonists WIN55212-2 (-50.4 +/- 8.8%) and CP55940 (-42.4 +/- 10.9%). The CB-1 antagonist SR141716A reversed these effects. Unexpectedly, SR141716A alone produced a significant increase of glutamatergic synaptic transmission (+46.9 +/- 11.2%), which could be partly reversed by WIN55212-2. In the presence of strontium in the bath, the frequency but not the amplitude of asynchronous synaptic events evoked in layer V pyramidal cells by stimulating layer V afferents, was markedly decreased (-54.2 +/- 8%), indicating a presynaptic site of action of cannabinoids at these synapses. Tetanic stimulation (100 pulses at 100 Hz, 4 trains) induced in control condition, no changes (n = 7/18), long-term depression (LTD; n = 6/18), or long-term potentiation (LTP; n = 5/18) of monosynaptic EPSCs evoked by stimulation of layer V afferents. When tetanus was applied in the presence of WIN 55,212-2 or SR141716-A (1 microM) in the bath, the proportion of "nonplastic" cells were not significantly changed (n = 7/15 in both cases). For the plastic ones (n = 8 in both cases), WIN 55,212-2 strongly favored LTD (n = 7/8) at the apparent expense of LTP (n = 1/8), whereas the opposite effect was observed with SR141716-A (7/8 LTP; 1/8 LTD). These results demonstrate that cannabinoids influence glutamatergic synaptic transmission and plasticity in the PFC of rodent.

Tetanic stimuli to layer I-II afferents in rat prefrontal cortex induced long-term depression (LTD) of layer I-II to layer V pyramidal neuron glutamatergic synapses when tetani were coupled to bath application of dopamine. This LTD was blocked by the following metabotropic glutamate receptor (mGluR) antagonists coapplied with dopamine: (S)-alpha-methyl-4-carboxyphenylglycine (MCPG; group I and II antagonist), (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA; group I antagonist), or (RS)-alpha-methylserine-O-phosphate monophenyl ester (MSOPPE; group II antagonist). This suggests that the dopamine-facilitated LTD requires synaptic activation of groups I and II mGluRs during tetanus. LTD could also be induced by coupling tetani to bath application of groups I and II mGluR agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD). In the next series of experiments, coapplication of dopamine and 1S,3R-ACPD, but not application of either drug alone, consistently induced LTD without tetani or even single test stimuli during drug application, suggesting that coactivation of dopamine receptors and the mGluRs is sufficient for LTD induction. Immunoblot analyses with anti-active mitogen-activated protein kinases (MAP-Ks) revealed that D1 receptors, D2 receptors, group I mGluRs, and group II mGluRs all contribute to MAP-K activation in prefrontal cortex, and that combined activation of dopamine receptors and mGluRs synergistically or additively activate MAP-Ks. Consistently, LTD by dopamine + 1S, 3R-ACPD coapplication, as well as the two other forms of LTD (LTD by dopamine + tetani and LTD by 1S,3R-ACPD + tetani), was blocked by bath application of MAP-K kinase inhibitor PD98059. LTD by dopamine + 1S,3R-ACPD coapplication was also blocked by postsynaptic injection of synthetic MAP-K substrate peptide. Our results suggest that dopamine receptors and groups I and II mGluRs cooperate to induce LTD through converging postsynaptic activation of MAP-Ks.