Synaptic plasticity at corticostraital synapses is proposed to fine tune movment and improve motor skills. We found paired-pulse plasticity at corticostriatal synapses reflected variably expressed short-term facilitation blended with a consistent background of longer-lasting depression. Presynaptic modulation via neuotransmitter receptor activation was ruled out as a mechanism for long-lasting paired-pulse depression by examining the effect of selective receptor antagonists. EPSC amplitude and paired pulse plasticity, however, was influenced by block of D2 dopamine receptors. Block of glutamate transport with L-transdicarboxylic acid (PDC) reduced EPSCs, possibly through a mechanism of AMPA receptor desensitization. Removal of AMPA receptor desensitization with cyclothiazide reduced the paired-pulse depression at long-duration interstimulus intervals (ISIs), indicating AMPA receptor desensitization participates corticostriatal paired-pulse plasticity. The low-affinity glutamate receptor antagonist cis-2,3-piperidine dicarboxylic acid (PDA) increased paired-pulse depression, suggesting a presynaptic component also exists for long lasting paired-pulse depression. Low Ca2+/ high Mg2+ or BAPTA-AM dramatically reduced the amplitude of corticostriatal EPSCs and both manipulations increased the expression of facilitation and, to a lesser extent, they reduced long-lasting paired-pulse depression. EGTA-AM produced a smaller reduction in EPSC amplitude and it did not alter paired-pulse facilitation, but in contrast to low Ca2+ and BAPTA-AM, EGTA-AM increased long-lasting paired-pulse depression. These experiments suggest facilitation and depression are sensitive to vesicle depletion, which is dependent upon changes in peak Ca2+ (ie. Low Ca2+/ high Mg2+ or BAPTA-AM). In addition, the action of EGTA-AM suggests basal Ca2+ regulates the recovery from long-lasting paired pulse depression, possibly thourgh a Ca2+ sensitive process of vesicle delivery.