Among drugs that act on serotonergic neurotransmission, selective
serotonin (5-HT) reuptake inhibitors (
SSRIs) are now the gold standard for the treatment of
anxiety disorders. The precise mechanisms of the
anxiolytic actions of
SSRIs are unclear. We reviewed the literature related to the effects of
SSRIs and the neurochemical changes of
5-HT in conditioned fear. Acute
SSRIs and
5-HT(1A) receptor agonists reduced the acquisition and expression of contextual conditioned fear. Chronic SSRI administration enhanced
anxiolytic-like effects. Microinjection studies revealed the amygdala as the target brain region of both classes of
serotonergic drugs, and the hippocampus as the target of
5-HT(1A) receptor agonists. These findings highlight the contribution of post-synaptic
5-HT receptors, especially 5-HT(1A) receptors, to the
anxiolytic-like effects of
serotonergic drugs. These results support the new
5-HT hypothesis of fear/anxiety: the facilitation of
5-HT neurotransmission ameliorates fear/anxiety. Furthermore, these behavioral data provide a new explanation of neurochemical adaptations to contextual conditioned fear: increased
5-HT transmission seems to decrease, not increase, fear.