Role of protein kinase C in substance P-induced synaptic depression in the nucleus accumbens in vitro.
OBJECTIVE
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.


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 microM) depressed evoked excitatory postsynaptic currents (EPSCs) by -27.50 +/- 5.6% (n = 8). Pretreatment of slices with 10 microM forskolin or rolipram prevented SP (1 microM) 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 microM) did not block the SP-induced synaptic depression (-32.3 +/- 4.0%, n = 4, p < 0.05). By contrast, PKC inhibitors bisindolylmaleimide (1 microM; 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 microM, -5.9 +/- 8.6%, n = 4, p > 0.05).


CONCLUSIONS
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.
Matowe
W C
WC
Department of Pharmacy Practice, Faculty of Pharmacy, Health Sciences Center, Kuwait University, Kuwait. w.matowe@hsc.edu.kw
Ananthalakshmi
K V V
KV
Kombian
S B
SB
D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013373:Substance P / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D005576:Colforsin; D013373:Substance P; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D020889:Rolipram