The Flinders Sensitive Line (FSL) rat is a genetic animal model of depression that displays characteristics similar to those of depressed patients including lower body weight, decreased appetite and reduced REM sleep latency. Hypothalamic neuropeptides such as orexin/hypocretin, melanin-concentrating hormone (MCH) and cocaine and amphetamine regulated transcript (CART), that are involved in the regulation of both energy metabolism and sleep, have recently been implicated also in depression. We therefore hypothesized that alterations in these neuropeptide systems may play a role in the development of the FSL phenotype with both depressive like behavior, metabolic abnormalities and sleep disturbances. In this study, we first confirmed that the FSL rats displayed increased immobility in the Porsolt forced swim test compared to their control strain, the Flinders Resistant Line (FRL), which is indicative of depressive-like behavior. We then examined the number of orexin-, MCH- and CART-immunopositive neurons in the hypothalamus using stereological analyses. We found that the total number of orexin-positive neurons was higher in the hypothalamus of female FSL rats compared to female FRL rats, whereas no changes in the MCH or CART populations could be detected between the strains. Chronic treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram reduced immobility only in the FRL rats where it also increased the number of MCH positive neurons compared to untreated rats. These findings support the view that orexin may be involved in depression and strengthen the notion that the "depressed" brain responds differently to pharmacological interventions than the normal brain.