Title:Molecular and Cellular Mechanisms of Rapid-Acting Antidepressants Ketamine and Scopolamine
Volume: 15
Issue: 1
Author(s): Eric S. Wohleb, Danielle Gerhard, Alex Thomas and Ronald S. Duman
Affiliation:
Keywords:
Acetylcholine, antidepressant, BDNF, depression, GABA, glutamate, ketamine, mTORC1, scopolamine, synapse.
Abstract: Major depressive disorder (MDD) is a prevalent neuropsychiatric disease
that causes profound social and economic burdens. The impact of MDD is
compounded by the limited therapeutic efficacy and delay of weeks to months of
currently available medications. These issues highlight the need for more efficacious
and faster-acting treatments to alleviate the burdens of MDD. Recent breakthroughs
demonstrate that certain drugs, including ketamine and scopolamine, produce rapid
and long-lasting antidepressant effects in MDD patients. Moreover, preclinical work
has shown that the antidepressant actions of ketamine and scopolamine in rodent
models are caused by an increase of extracellular glutamate, elevated BDNF, activation
of the mammalian target of rapamycin complex 1 (mTORC1) cascade, and increased
number and function of spine synapses in the prefrontal cortex (PFC). Here we review studies showing
that both ketamine and scopolamine elicit rapid antidepressant effects through converging molecular and
cellular mechanisms in the PFC. In addition, we discuss evidence that selective antagonists of NMDA
and muscarinic acetylcholine (mACh) receptor subtypes (i.e., NR2B and M1-AChR) in the PFC produce
comparable antidepressant responses. Furthermore, we discuss evidence that ketamine and scopolamine
antagonize inhibitory interneurons in the PFC leading to disinhibition of pyramidal neurons and increased
extracellular glutamate that promotes the rapid antidepressant responses to these agents. Collectively,
these studies indicate that specific NMDA and mACh receptor subtypes on GABAergic interneurons are
promising targets for novel rapid-acting antidepressant therapies.
