The effect of tetanic activation of corticostriatal glutamatergic fibers was studied in striatal slices by utilizing extracellular and intracellular recording techniques. Tetanic stimulation produced a long- term synaptic depression (LTD) (> 2 h) of both extracellularly recorded field potentials and intracellularly recorded EPSPs. LTD was not coupled with changes of intrinsic membrane properties of the recorded neurons. In some neurons, repetitive cortical activation produced a short-term posttetanic potentiation (1–3 min). Subthreshold tetanic stimulation, which under control condition did not cause LTD, induced LTD when associated with membrane depolarization. Moreover, LTD was not expressed in cells in which the conditioning tetanus was coupled with hyperpolarization of the membrane. Bath application of aminophosphonovalerate (30–50 microM), an antagonist of NMDA receptors, did not affect the amplitude of the synaptic potentials and the expression of LTD. Striatal LTD was significantly reduced by the pretreatment of the slices with 30 microM 2-amino-3-phosphonopropionic acid, an antagonist of glutamate metabotropic receptors. LTD was not blocked by bicuculline (30 microM), a GABA(A) receptor antagonist. Scopolamine (3 microM), an antagonist of muscarinic receptors, induced a slight, but significant, increase of the amplitude of LTD. Both SCH 23390 (3 microM), an antagonist of D1 dopamine (DA) receptors, and I- sulpiride (1 microM), an antagonist of D2 DA receptors, blocked LTD. LTD was also absent in slices obtained from rats in which the nigrostriatal DA system was lesioned by unilateral nigral injection of 6-hydroxydopamine. In DA-depleted slices, LTD could be restored by applying exogenous DA (30 microM) before the conditioning tetanus. In DA-depleted slices, LTD could also be restored by coadministration of SKF 38393 (3–10 microM), a D1 receptor agonist, and of LY 171555 (1–3 microM), a D2 receptor agonist. Application of a single class of DA receptor agonists failed to restore LTD. These data show that striatal LTD requires three main physiological and pharmacological conditions: (1) membrane depolarization and action potential discharge of the postsynaptic cell during the conditioning tetanus, (2) activation of glutamate metabotropic receptors, and (3) coactivation of D1 and D2 DA receptors. Striatal LTD may alter the output signals from the striatum to the other structures of the basal ganglia. This form of synaptic plasticity can influence the striatal control of motor activity.