The narcotic antagonist naltrexone has a biphasic effect on the nicotinic acetylcholine receptor

AbstractIt is known that narcotic antagonists interact with many cholinergic pathways but less in known about specific mechanisms. Using neonatal rat myoballs to study single channel behaviour of the acetylcholinegated nicotinic receptor, it was found that micromolar concentrations of naltrexone had no effect on channel conductance but caused open channel blockade by increasing the flickering from the open to the closed state in a concentration-dependent manner. At micromolar concentrations of naltrexone, the frequency of channel opening was decreased and bursts were grouped in clusters, whereas at nanomolar levels the frequency of opening was increased. The sequential model for ion-channel blockade cannot explain these effects, and an alternative allosteric mechanism of action is proposed.Narcotic antagonistNaltrexoneNicotinic receptorElectrophysiologySingle channel recordingChannel activationChannel blockad

Phencyclidine (PCP) blocks glutamate-activated postsynaptic currents

AbstractPhencyclidine (PCP) was tested on the metathoracic tibialis muscles of Locusta migratoria. In physiological solution, the peak amplitude of the excitatory postsynaptic currents (EPSCs) evoked by nerve stimulation was linearly related to membrane potential between −50 and −150 mV. The decay time constant of the EPSC (τEPSC) was exponentially dependent on voltage and decreased with hyperpolarization. The membrane potential change required to produce an e-fold change in τEPSC was 315 mV. PCP (5–40 μM) produced a concentration-dependent depression of both EPSC peak amplitude and τEPSC. A slight nonlinearity in the current-voltage relationship could be discerned at high concentrations of PCP. The shortening of the decay time constant of EPSC (τEPSC) occurred without significant change in the voltage sensitivity observed under control conditions. Under all experimental conditions, the decay of the EPSCs remained a single exponential of time. Fluctuation analysis indicated that 5 μM PCP shortens the lifetime of the glutamate-activated channels by 25.7 ± 3%. PCP (10–80 μM) did not induce desensitization of the glutamate receptors. These results suggest that PCP interacts with the open conformation of ion channels activated by the glutamate receptor.PhencyclidineGlutamate receptorLocustNeuromuscular transmissionExcitatory postsynaptic currentChannel blacke

Zanos et al. reply

Clinical data have demonstrated rapid and sustained antidepressant effects of ketamine, a noncompetitive NMDAR (N-methyl-daspartate receptor) antagonist. Recently, Zanos et al.2 claimed that the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) is essential for the antidepressant effects of ketamine in mice in an NMDAR-independent manner, although no alternative mechanism was proposed, beyond unspecific activation of AMPAR (α -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor). Here we report that (2R,6R)-HNK blocks synaptic NMDARs in a similar manner to its parent compound, and we show that the effects of (2R,6R)-HNK on intracellular signalling are coupled to NMDAR inhibition. These data demonstrate that (2R,6R)-HNK inhibits synaptic NMDARs and subsequently elicits the same signal transduction pathway previously associated with NMDAR inhibition by ketamine