The pathophysiological mechanisms underlying depression are still poorly understood. An initial hypothesis postulated to explain
the substrates of depression was based on the involvement of monoaminergic systems. This early theory was proposed from different
findings obtained using pharmacological tools and can explain the mechanism of action of the drugs currently used to treat depression.
However, more recent studies have revealed that other neurobiological processes different from monoamines also participate in the
substrates of depression. These mechanisms include the participation of several neuromodulatory systems, stress-related circuits and neuroplastic
changes that could represent a direct substrate for these pathophysiological processes. The lack of selective pharmacological
tools for several of these potential targets of depression represents an important limitation to study their potential involvement. In the last
two decades, different lines of genetically modified mice have been generated with selective deletions in specific genes related to the control
of emotional responses. This review summarizes the main findings that have been obtained with these novel genetic tools to clarify
the neurobiological substrates of depression. A particular focus has been devoted to the advances obtained with mice deficient in specific
components of the monoaminergic, opioid and cannabinoid system and those with mutations in elements of the hypothalamic-pituitaryadrenal
Keywords: Knockout mice, mutants, behavioural models, mood disorders, dopamine, serotonin, noradrenaline, endocannabinoids, opioids,
HPA, GABA, glutamate, CRF.
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