Role of Protein Kinase C in Substance P-Induced Synaptic Depression in the Nucleus Accumbens in vitro

Objectives: This study set out to determine the roles of protein kinase A (PKA) and protein kinase C (PKC) signalling cascades in substance P- (SP-) mediated synaptic depression in the nucleus accumbens. Materials and Methods: We used whole-cell patch recording in rat forebrain slices to study the effects of excitatory and inhibitory modulators of PKA and PKC to determine their effects on SP-induced synaptic depression. Results: We showed that cAMP and PKC, but not PKA, are involved in SP-induced synaptic depression. Bath application of SP (1 μM) depressed evoked excitatory postsynaptic currents (EPSCs) by –27.50 ± 5.6% (n = 8). Pretreatment of slices with 10 μM forskolin or rolipram prevented SP (1 μM) from depressing evoked EPSCs (–0.8 ± 6.7%, n = 6; p 0.05 and 1.6 ± 5.6%, n = 8; p 0.05, respectively). Furthermore, 8-bromo cAMP (1 mM) also blocked the effect of SP (–0.5 ± 14.8, n = 4, p 0.05). However, H-89 (1 μM) did not block the SP-induced synaptic depression (–32.3 ± 4.0%, n = 4, p 0.05). By contrast, PKC inhibitors bisindolylmaleimide (1 μM; 4.0 ± 5.1%, n = 6; p 0.05) and calphostin C (400 nM; –6.7 ± 6.5%, n = 4, p 0.05) both blocked SP-induced synaptic depression. Phorbol dibutyrate caused a synaptic depression of –33.0. ± 5.0% and abolished the effect of SP (1 μM, –5.9 ± 8.6%, n = 4, p 0.05). Conclusion: Our findings demonstrate that PKC and cAMP are involved in SP-induced synaptic depression while PKA is apparently not involved. Involvement of multiple signalling pathways may reflect the fact that SP uses several intermediates to depress EPSCs.