Unipolar depression is the most common mental health problem today. The differential reinforcement of low rate 72-second schedule of reinforcement (DRL 72-s schedule) is a sensitive and selective behavioral screen for antidepressant (AD) drugs. Drugs such as serotonin-1A (5HT1A) receptor agonists and 5HT2A receptor antagonists, as well as selective 5HT reuptake inhibitors (SSRIs), have antidepressant-like profiles on the DRL 72-s task. Rats selectively-bred for increased sensitivity to the hypothermic effects of the 5HT1A receptor agonist 8-OH-DPAT, high DPAT sensitive (HDS) rats, differ from their selectively-bred counterparts, low DPAT sensitive (LDS) rats, in baseline performance and in response to 5HT- specific ADs on the DRL. The selectively-bred rats also have different immobility times in the forced swim test (FST), another behavioral task that has been previously shown to be sensitive to ADs. The overall objective of this proposal is to more fully understand 5HT mechanisms underlying depression and the action of ADs by making use of the HDS and LDS lines of rats. The aim of the first set of studies is to compare and examine the effects of ADs from several drug classes on DRL and FST behavior; additionally, we propose to examine the effects of whole-brain and local 5HT depletions in these two behavioral paradigms, as well as investigate how the action of ADs is modified by 5HT depletions. The aim of the second set of experiments is to determine if differences exist in pre- and postsynaptic receptor function between the HDS and LDS rats using in vitro microdialysis, radioligand binding for 5HT1A and 5HT2A/C receptors, and the 5HT transporter, and second messenger assays. Taken together, these studies will determine whether these behavioral differences are regulated by the 5HT system, and will determine which components of the serotonergic system are responsible for the functional differences between the HDS and LDS lines of rats. The results of these studies will help us further understand the etiology and substrates underlying depression.