0 13 Abnormalities abnormality NNS 14 16 of of IN 17 23 cyclic cyclic JJ 24 33 adenosine adenosine NN 34 47 monophosphate monophosphate NN 48 57 signaling signaling NN 58 60 in in IN 61 70 platelets platelet NNS 71 75 from from IN 76 85 untreated untreated JJ 86 94 patients patient NNS 95 99 with with IN 100 107 bipolar bipolar JJ 108 116 disorder disorder NN 116 117 . . . 119 129 BACKGROUND background NN 129 130 : : : 131 144 Abnormalities abnormality NNS 145 147 in in IN 148 151 the the DT 152 158 cyclic cyclic JJ 159 168 adenosine adenosine NN 169 182 monophosphate monophosphate NN 183 184 ( ( ( 184 199 cAMP)-dependent camp)-dependent JJ 200 215 phosphorylation phosphorylation NN 216 222 system system NN 223 227 have have VBP 228 232 been be VBN 233 241 recently recently RB 242 250 reported report VBN 251 253 in in IN 254 262 patients patient NNS 263 267 with with IN 268 275 bipolar bipolar JJ 276 284 disorder disorder NN 284 285 . . . 286 288 We we PRP 289 298 evaluated evaluate VBD 299 302 the the DT 303 319 immunoreactivity immunoreactivity NN 320 322 of of IN 323 326 the the DT 327 337 regulatory regulatory JJ 338 341 and and CC 342 351 catalytic catalytic JJ 352 360 subunits subunit NNS 361 363 of of IN 364 378 cAMP-dependent camp-dependent JJ 379 386 protein protein NN 387 393 kinase kinase NNP 394 395 ( ( ( 395 402 protein protein NN 403 409 kinase kinase NNP 410 411 A A NNP 411 412 ) ) ) 413 416 and and CC 417 418 1 1 CD 419 421 of of IN 422 425 its its PRP$ 426 436 substrates substrate NNS 436 437 , , , 438 442 Rap1 Rap1 NNP 442 443 , , , 444 446 in in IN 447 456 platelets platelet NNS 457 461 from from IN 462 471 untreated untreated JJ 472 480 euthymic euthymic JJ 480 481 , , , 482 487 manic manic JJ 487 488 , , , 489 492 and and CC 493 502 depressed depressed JJ 503 511 patients patient NNS 512 516 with with IN 517 524 bipolar bipolar JJ 525 533 disorder disorder NN 534 537 and and CC 538 545 healthy healthy JJ 546 554 subjects subject NNS 554 555 . . . 556 563 METHODS methods NNS 563 564 : : : 565 574 Platelets Platelet NNPS 575 579 were be VBD 580 589 collected collect VBN 590 594 from from IN 595 598 112 112 CD 599 608 drug-free drug-free JJ 609 617 patients patient NNS 618 622 with with IN 623 630 bipolar bipolar JJ 631 639 disorder disorder NN 640 641 ( ( ( 641 643 52 52 CD 644 652 euthymic euthymic JJ 652 653 , , , 654 656 29 29 CD 657 666 depressed depress VBD 666 667 , , , 668 671 and and CC 672 674 31 31 CD 675 680 manic manic JJ 680 681 ) ) ) 682 685 and and CC 686 688 62 62 CD 689 696 healthy healthy JJ 697 705 subjects subject NNS 705 706 . . . 707 710 The the DT 711 717 levels level NNS 718 720 of of IN 721 735 cAMP-dependent camp-dependent JJ 736 743 protein protein NN 744 750 kinase kinase NNP 751 754 and and CC 755 759 Rap1 Rap1 NNP 760 764 were be VBD 765 773 assessed assess VBN 774 776 by by IN 777 784 Western western JJ 785 789 blot blot NN 790 798 analysis analysis NN 798 799 , , , 800 814 immunostaining immunostaining NN 814 815 , , , 816 819 and and CC 820 837 computer-assisted computer-assisted JJ 838 845 imaging imaging NN 845 846 . . . 847 854 RESULTS results NNS 854 855 : : : 856 859 The the DT 860 874 immunolabeling immunolabeling NN 875 877 of of IN 878 881 the the DT 882 891 catalytic catalytic JJ 892 899 subunit subunit NN 900 902 of of IN 903 917 cAMP-dependent camp-dependent JJ 918 925 protein protein NN 926 932 kinase kinase NNP 933 936 was be VBD 937 950 significantly significantly RB 951 960 different different JJ 961 966 among among IN 967 973 groups group NNS 974 975 ( ( ( 975 981 P<.001 P<.001 NNP 981 982 ) ) ) 982 983 , , , 984 988 with with IN 989 995 higher high JJR 996 1002 values value NNS 1003 1005 in in IN 1006 1015 untreated untreated JJ 1016 1025 depressed depressed JJ 1026 1029 and and CC 1030 1035 manic manic JJ 1036 1044 patients patient NNS 1045 1049 with with IN 1050 1057 bipolar bipolar JJ 1058 1066 disorder disorder NN 1067 1075 compared compare VBN 1076 1080 with with IN 1081 1090 untreated untreated JJ 1091 1099 euthymic euthymic JJ 1100 1108 patients patient NNS 1109 1113 with with IN 1114 1121 bipolar bipolar JJ 1122 1130 disorder disorder NN 1131 1134 and and CC 1135 1142 healthy healthy JJ 1143 1151 subjects subject NNS 1151 1152 . . . 1153 1155 No no DT 1156 1167 significant significant JJ 1168 1179 differences difference NNS 1180 1184 were be VBD 1185 1190 found find VBN 1191 1193 in in IN 1194 1197 the the DT 1198 1212 immunolabeling immunolabeling NN 1213 1215 of of IN 1216 1219 the the DT 1220 1230 regulatory regulatory JJ 1231 1239 subunits subunit NNS 1240 1241 ( ( ( 1241 1245 type type NN 1246 1247 I i CD 1248 1251 and and CC 1252 1256 type type NN 1257 1259 II ii CD 1259 1260 ) ) ) 1261 1263 of of IN 1264 1278 cAMP-dependent camp-dependent JJ 1279 1286 protein protein NN 1287 1293 kinase kinase NNP 1293 1294 . . . 1295 1298 The the DT 1299 1313 immunolabeling immunolabeling NN 1314 1316 of of IN 1317 1321 Rap1 Rap1 NNP 1322 1325 was be VBD 1326 1339 significantly significantly RB 1340 1346 higher high JJR 1347 1348 ( ( ( 1348 1354 P<.001 p<.001 NN 1354 1355 ) ) ) 1356 1358 in in IN 1359 1368 untreated untreated JJ 1369 1377 euthymic euthymic JJ 1377 1378 , , , 1379 1388 depressed depressed JJ 1388 1389 , , , 1390 1393 and and CC 1394 1399 manic manic JJ 1400 1408 patients patient NNS 1409 1413 than than IN 1414 1416 in in IN 1417 1424 healthy healthy JJ 1425 1432 persons person NNS 1432 1433 . . . 1434 1445 CONCLUSIONS conclusions NNS 1445 1446 : : : 1447 1453 Levels level NNS 1454 1456 of of IN 1457 1461 Rap1 Rap1 NNP 1462 1465 and and CC 1466 1469 the the DT 1470 1479 catalytic catalytic JJ 1480 1487 subunit subunit NN 1488 1490 of of IN 1491 1505 cAMP-dependent camp-dependent JJ 1506 1513 protein protein NN 1514 1520 kinase kinase NNP 1521 1524 are be VBP 1525 1532 altered alter VBN 1533 1535 in in IN 1536 1539 the the DT 1540 1549 platelets platelet NNS 1550 1552 of of IN 1553 1560 bipolar bipolar JJ 1561 1569 patients patient NNS 1569 1570 . . . 1571 1576 These these DT 1577 1585 findings finding NNS 1586 1589 may may MD 1590 1597 provide provide VB 1598 1603 clues clue NNS 1604 1610 toward toward IN 1611 1624 understanding understand VBG 1625 1628 the the DT 1629 1640 involvement involvement NN 1641 1643 of of IN 1644 1648 cAMP camp NN 1649 1658 signaling signaling NN 1659 1661 in in IN 1662 1665 the the DT 1666 1678 pathogenesis pathogenesis NN 1679 1681 of of IN 1682 1689 bipolar bipolar JJ 1690 1698 disorder disorder NN 1698 1699 . . .