NMDAR inhibition-independent antidepressant actions of ketamine metabolites

Major depressive disorder afflicts ~16 percent of the world population at some point in their lives. Despite a number of available monoaminergic-based antidepressants, most patients require many weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), exerts rapid and sustained antidepressant effects following a single dose in depressed patients. Here we show that the metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant actions in vivo. Notably, we demonstrate that these antidepressant actions are NMDAR inhibition-independent but they involve early and sustained α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activation. We also establish that (2R,6R)-HNK lacks ketamine-related side-effects. Our results indicate a novel mechanism underlying ketamine’s unique antidepressant properties, which involves the required activity of a distinct metabolite and is independent of NMDAR inhibition. These findings have relevance for the development of next generation, rapid-acting antidepressants

X.: Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons. I. Pharmacological and functional evidence for distinct structural subtypes

ABSTRACT ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; CNS, central nervous system; ML.A, methyllycaconitine; BGT, bungarotoxin; DHI3E, dihydro-f3-erythroidine; lm ,, maximum obtainable peak whole-cell current; ACh, acetylcholine; DMPP, 1 ,1 -dimethyl-4-phenyl-piperazinium

A Single in Vivo Application of Cholinesterase Inhibitors Has Neuron Type-Specific Effects on Nicotinic Receptor Activity in Guinea Pig Hippocampus

The present study was designed to test the hypothesis that an acute in vivo treatment with reversible or irreversible acetylcholinesterase (AChE) inhibitors modifies the activities of nicotinic receptors (nAChRs) in hippocampal neurons. Here, whole-cell nicotinic responses were recorded from CA1 interneurons in hippocampal slices obtained from male guinea pigs at 1, 7, or 14 days after treatment with the irreversible AChE inhibitor, soman (1× LD50 s.c.), and/or the reversible AChE inhibitor, galantamine (8 mg/kg i.m.). Naive animals were used as controls. Three types of nAChR responses, namely types IA, II, and III, which were mediated by α7, α4β2, and α3β2β4 nAChRs, respectively, could be recorded from the interneurons. The magnitude of α7 nAChR currents was neuron-type dependent. Stratum radiatum interneurons (SRIs) with thick initial dendrites had the largest α7 nAChR currents. Acute challenge with soman caused sustained reduction of type IA current amplitudes recorded from stratum oriens interneurons and increased the ratio of acetylcholine- to choline-evoked current amplitudes recorded from SRIs. In guinea pigs that developed long-lasting convulsions after the soman challenge, there was a sustained reduction of α3β2β4 nAChR responses. Acute treatment with galantamine had no effect on type IA or III responses, whereas it decreased the incidence of type II currents. Pretreatment of the guinea pigs with galantamine prevented the suppressive effect of soman on type III responses. The neuron type-specific changes in nAChR activity induced by soman, some of which could be prevented by galantamine, may contribute to the maintenance of pathological rhythms in the hippocampal neuronal network