Pharmacological Modulation of Long-Term Potentiation-Like Activity in the Dorsolateral Prefrontal Cortex.

Bahar Salavati,Daniel M Blumberger,Bruce G Pollock,Tarek K Rajji,Zafiris J Daskalakis,Robert Chen,Reza Zomorrodi

doi:10.3389/fnhum.2018.00155

Abstract

Background: Long-term potentiation (LTP) depends on glutamatergic neurotransmission and is modulated by cholinergic, dopaminergic and GABAergic inputs. Paired associative stimulation (PAS) is a neurostimulation paradigm that, when combined with electroencephalography (EEG), assesses LTP-like activity (PAS-induced LTP) in the dorsolateral prefrontal cortex (DLPFC). Thus, we conducted a study to assess the role of cholinergic, dopaminergic, GABAergic and glutamatergic neurotransmission on PAS-induced LTP in the DLPFC. We hypothesized that increasing the dopaminergic tone with L-DOPA and the cholinergic tone with rivastigmine will enhance PAS-induced LTP, while increasing the GABAergic tone with baclofen and inhibiting glutamatergic neurotransmission with dextromethorphan will reduce it compared to placebo.Methods: In this randomized controlled, double-blind cross-over within-subject study, 12 healthy participants received five sessions of PAS to the DLPFC in a random order, each preceded by the administration of placebo or one of the four active drugs. PAS-induced LTP was assessed after each drug administration and compared to PAS-induced LTP after placebo.Results: As predicted, L-DOPA and rivastigmine resulted in enhanced PAS-induced LTP in the DLPFC and dextromethorphan inhibited it compared to placebo. In contrast, baclofen did not significantly suppress PAS-induced LTP compared to placebo.Conclusions: This study provides a novel approach to study DLPFC neuroplasticity and its modulation in patients with brain disorders that are associated with abnormalities in these neurochemical systems. This study was based on a single dose administration of each drug. Given that these drugs are typically administered chronically, future studies should assess the effects of chronic administration.

Highlights

Neuroplasticity refers to the ability of the brain to change and adapt in response to experiences (Pascual-Leone et al, 2005)
Paired associative stimulation (PAS) simulates a spike-timing dependent plasticity protocol by combining singlepulse transcranial magnetic stimulation (TMS) to a cortical area with contralateral peripheral nerve stimulation (PNS) such as the two stimulations arrive contemporaneously at the targeted cortical area and in turn strengthen the cortical output in response to single-pulse TMS
Using well-established methods of combining TMS with electroencephalography (EEG), our group has shown that PAS results in Long-term potentiation (LTP)-like activity in the human dorsolateral prefrontal cortex (DLPFC) as captured by EEG as the potentiation of TMS-induced cortical evoked activity (CEA; Rajji et al, 2013; Kumar et al, 2017; Loheswaran et al, 2017)

Summary

Introduction

Neuroplasticity refers to the ability of the brain to change and adapt in response to experiences (Pascual-Leone et al, 2005). Using well-established methods of combining TMS with electroencephalography (EEG), our group has shown that PAS results in LTP-like activity in the human DLPFC as captured by EEG as the potentiation of TMS-induced cortical evoked activity (CEA; Rajji et al, 2013; Kumar et al, 2017; Loheswaran et al, 2017). This PAS-induced LTP-like activity only simulates cellular LTP and will be referred to hereafter as PAS-induced LTP merely for simplicity. We hypothesized that increasing the dopaminergic tone with L-DOPA and the cholinergic tone with rivastigmine will enhance PAS-induced LTP, while increasing the GABAergic tone with baclofen and inhibiting glutamatergic neurotransmission with dextromethorphan will reduce it compared to placebo

Methods

Discussion

Conclusion