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

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.

Toward the establishment of neurophysiological indicators for neuropsychiatric disorders using transcranial magnetic stimulation‐evoked potentials: A systematic review

“…Specifically, five articles examined SICI, 21,45,[79][80][81]110 13 articles studied LICI, [42][43][44][82][83][84][85][86][87]103,104,108,111 four articles investigated SAI, 46,53,88,89 three articles investigated ICF, 21,45,81 and five articles investigated PAS. [90][91][92][93]109 Additionally, 11 articles examined the pharmacological effects on TEP 80,[101][102][103][104][105][106][107][108][109][110] and eight articles studied technical aspects of TMS-EEG analyses (e.g., artifact reduction). 16,111,[113][114][115][116]124,…”

“…Dextromethorphan (NMDA receptor antagonist) and levodopa (L-DOPA) did not change the DLPFC TEP of LICI compared to placebo. 109 Furthermore, Salavati et al performed a PAS paradigm on the DLPFC five times in a random order, each preceded by the administration of placebo or one of four active drugs, in a randomized controlled, doubleblind, crossover study. PAS-induced LTP was examined following the administration of each drug and compared with PAS-induced LTP after placebo.…”

Modulating Frontal Networks’ Timing-Dependent-Like Plasticity With Paired Associative Stimulation Protocols: Recent Advances and Future Perspectives

“…The neurophysiological substrates of the dlPFC-PAS were further investigated by Salavati et al (2018). Considering that synaptic LTP depends on glutamatergic neurotransmission and is modulated by cholinergic, dopaminergic, and GABAergic neurotransmission (Malenka and Bear, 2004).…”

“…Considering that synaptic LTP depends on glutamatergic neurotransmission and is modulated by cholinergic, dopaminergic, and GABAergic neurotransmission (Malenka and Bear, 2004). Salavati et al (2018) investigate whether drugs influencing these neurotransmitters could modulate the effects of the dlPFC-PAS. Results showed that PAS after-effects (i.e., dlPFC-TEPs) are enhanced by L-DOPA and rivastigmine; these two drugs increase dopaminergic and cholinergic tone.…”

“…Results showed that PAS after-effects (i.e., dlPFC-TEPs) are enhanced by L-DOPA and rivastigmine; these two drugs increase dopaminergic and cholinergic tone. Conversely, dextromethorphan intake, by blocking glutamatergic receptors, inhibits the protocol's effects (Salavati et al, 2018).…”