Pharmacological effect of 2-oxo-PCMe on hippocampal synaptic activity

Abstract

The dissociative anaesthetics are a classification of drugs including ketamine and phencyclidine which induce hallucinogenic and psychomimetic effects by antagonism of the N-methyl D-aspartate receptor (NMDA-R). In recent years synthetic psychoactive substances have been designed with a similar structure to ketamine such as methoxetamine. The NMDA-R is an ionotropic glutamate receptor that has various functions in the central nervous system including synaptic plasticity and pain modulation. The non-competitive antagonism of ketamine at the NMDA-R is believed to be a key mechanism in the expression of its rapid-acting antidepressant effects. The new ketamine derivative 2-oxo-PCMe has been developed as a possible alternative to ketamine with a potential reduction in the psychomimetic effects. The hypothesis is that 2-oxo-PCMe will inhibit NMDA-R mediated synaptic transmission.

In-vitro electrophysiological recording from the stratum radiatum of CA1 region in the hippocampal slice preparation was used to investigate the effect of 2-oxo-PCMe on NMDA-R mediated synaptic transmission. The results demonstrated that 2-oxo-PCMe has a dose dependent effect on inhibition of NMDA-R mediated field excitatory post-synaptic potentials. Furthermore, long-term potentiation (LTP) induction by theta burst stimulation was blocked by application of 10 µM 2-oxo-PCMe in the hippocampus. The data suggests that 2-oxo-PCMe has antagonist action on the NMDA-R which is more potent than ketamine at the same concentration. Furthermore, the blockade of LTP by 10 µM 2-oxo-PCMe illustrates the ability of 2-oxo-PCMe to inhibit LTP without full block of the NMDA-R mediated response.

These results are the first investigation of the mechanism of action of 2-oxo-PCMe on hippocampal synaptic activity mediated by the NMDA-R. Further investigations should be conducted to outline the full pharmacological properties and therapeutic potential of 2-oxo-PCMe.

Date of Award	24 Jan 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	Zafar I Bashir (Supervisor), Zuner A Bortolotto (Supervisor) & Stephen M Fitzjohn (Supervisor)