Background: To evaluate whether serotonin (5-HT), 5-HT2A receptor (5-HT2AR), and 5-HT transporter (serotonin transporter [SERT]) are associated with different disease states of depression, myocardial infarction (MI) and MI co-exist with depression in Sprague-Dawley rats. Methods: After established the animal model of four groups include control, depression, MI and MI with depression, we measured 5-HT, 5-HT2AR and SERT from serum and platelet lysate. Results: The serum concentration of 5-HT in depression rats decreased significantly compared with the control group (303.25 +/- 9.99 vs. 352.98 +/- 13.73; P = 0.000), while that in MI group increased (381.78 +/- 14.17 vs. 352.98 +/- 13.73; P = 0.000). However, the depression + MI group had no change compared with control group (360.62 +/- 11.40 vs. 352.98 +/- 13.73; P = 0.036). The changes of the platelet concentration of 5-HT in the depression, MI, and depression + MI group were different from that of serum. The levels of 5-HT in above three groups were lower than that in the control group (380.40 +/- 17.90, 387.75 +/- 22.28, 246.40 +/- 18.99 vs. 500.29 +/- 20.91; P = 0.000). The platelet lysate concentration of 5-HT2AR increased in depression group, MI group, and depression + MI group compared with the control group (370.75 +/- 14.75, 393.47 +/- 15.73, 446.66 +/- 18.86 vs. 273.66 +/- 16.90; P = 0.000). The serum and platelet concentration of SERT in the depression group, MI group and depression + MI group were all increased compared with the control group (527.51 +/- 28.32, 602.02 +/- 23.32, 734.76 +/- 29.59 vs. 490.56 +/- 16.90; P = 0.047, P = 0.000, P = 0.000 in each and 906.38 +/- 51.84, 897.33 +/- 60.34, 1030.17 +/- 58.73 vs. 708.62 +/- 51.15; P = 0.000 in each). Conclusions: The concentration of 5-HT2AR in platelet lysate and SERT in serum and platelet may be involved in the pathway of MI with depression. Further studies should examine whether elevated 5-HT2AR and SERT may contribute to the biomarker in MI patients with depression.