The neurochemical basis of depression focuses on alterations in the monoaminergic and amino acid neurotransmitter systems. Moreover, decreases in serum levels of the neurotrophin brain-derived neurotrophic factor (BDNF) have led to the more recent neurotrophic hypothesis of depression. Chronic stress is one of the major predisposing factors to developing the disorder and thus we investigated the impact of chronic restraint stress on the levels of several neurotransmitters and their metabolites in a genetic animal model of depression, the Wistar Kyoto (WKY) rat. Behavioural analysis of WKY rats indicated both a depressive and anxiety-like phenotype compared to their Sprague Dawley (SD) controls. WKY animals showed similar stress-induced decreases in hippocampal GABA, noradrenaline and dopamine as their SD counterparts while exhibiting a divergent decrease in 5-HT, 5-HIAA and DOPAC. WKY rats also showed a stress-dependent increase in GABA concentrations in the amygdala compared to the SD animals. Moreover, WKY but not SD rats had a chronic stress-induced decrease in serum BDNF levels. Together these data show that there are specific strain-dependent changes in neurotransmitter and neurotrophin levels in response to chronic stress which may predispose WKY animals to a depressive-like phenotype.