Since the first report that the mechanism of action of antidepressants involves the facilitation of monoaminergic
neurotransmission in the brain in the 1960s, the leading hypothesis about the neurobiology of depression has been the so
called “monoaminergic hypothesis”. However, a growing body of evidence from the last two decades also supports
important involvement of non-monoaminergic mechanisms in the neurobiology of depression and antidepressant action.
The discovery of nitric oxide (NO) and endocannabinoid signaling in the brain during the 1990s challenged the wellestablished
criteria of classical neurotransmission. These transmitters are synthesized and released on demand by the postsynaptic
neurons, and may act as a retrograde messenger on the presynaptic terminal, modulating neurotransmitter release.
These unconventional signaling mechanisms and the important role as neural messengers have classified NO and
endocannabinoids as atypical neurotransmitters. They are able to modulate neural signaling mediated by the main
conventional neurotransmitters systems in the brain, including the monoaminergic, glutamatergic and GABAergic
This review aims at discussing the fundamental aspects of NO- and endocannabinoid-mediated signaling in the brain, and
how they can be related to the neurobiology of depression. Both preclinical and clinical evidence supporting the
involvement of these atypical neurotransmitters in the neurobiology of depression, and in the antidepressant effects are
presented here. The evidence is discussed on basis of their ability to modulate different neurotransmitter systems in the
brain, including monoaminergic and glutamatergic ones. A better comprehension of NO and endocannabinoid signaling
mechanisms in the neurobiology depression could provide new avenues for the development of novel non-monoamine