Abstract
Dopaminergic pathways have been recognized to play a critical role in cognition and emotion. Dopamine D2 and D4 receptors are the target for most common antipsychotics and their activation, particularly those in the medial temporal lobe structures, has been associated with their beneficial actions. The entorhinal cortex, which is the cortical area most consistently and severely affected in schizophrenia constitutes the main input to the hippocampus. Since the D4 receptor is highly concentrated in the hippocampus, and the effects of the selective activation of D4 receptors on the input/output function of the hippocampal formation are poorly understood, we sought to investigate the role of these receptors in the synaptic transmission and paired‐pulse inhibition from the perforant path to area CA1 and the dentate gyrus. The D4 receptor antagonist, clozapine, translated paired‐pulse inhibition into paired‐pulse potentiation in both perforant path targets. By contrast, the D2/D3 antagonist quinpirole had no effect. The blockade of the D2/3 receptors with sulpiride, and of D1/5 receptors with SCH‐23390, has no effect on paired‐pulse inhibition, suggesting that these receptors are not involved in feedforward inhibition in these hippocampal areas. Interestingly, the perfusion of the D4 selective antagonist, L‐745,870 (Patel et al., 1997: J Pharmacol Exp Ther 283:636–647) during the blockade of D2/3 and D1/5 receptors produces a reversible decrease in paired‐pulse inhibition in CA1, but not in the DG. Our results show that endogenous DA tonically modulates feedforward inhibition in area CA1 and the dentate gyrus through the activation of D4 receptors located in the interneuronal population of these hippocampal regions. Since activation of the D4 receptor inhibits GABA release and GABAergic synaptic transmission, we suggest that the perforant path stimulates interneurons that have the D4 receptor and that, in turn, contact other interneurons that synapse onto pyramidal cells. © 2004 Wiley‐Liss, Inc.