Pharmacological Manipulation of Cortical Inhibition in the Dorsolateral Prefrontal Cortex

Cortical inhibition (CI) occurs largely through GABA receptor-mediated inhibitory neurotransmission, which can be modulated by cholinergic, dopaminergic, and glutamatergic inputs. Transcranial magnetic stimulation (TMS) can be used to index CI through a paradigm known as long-interval CI (LICI). When TMS is combined with electroencephalography (EEG), LICI can index GABA receptor-mediated inhibitory neurotransmission in the dorsolateral prefrontal cortex (DLPFC). We conducted a hypothesis-driven pharmacological study to assess the role of cholinergic, dopaminergic, GABAergic, and glutamatergic neurotransmission on LICI from the DLPFC using TMS-EEG. In this randomized controlled, double-blind crossover within-subject study, 12 healthy participants received five sessions of LICI to the DLPFC in a random order, each preceded by the administration of placebo or one of the four active drugs. LICI was assessed after each drug administration and compared to LICI after placebo. Relative to placebo, baclofen resulted in a significant increase in LICI, while rivastigmine resulted in a significant decrease in LICI. Dextromethorphan and L-DOPA did not result in a significant change in LICI relative to placebo. Our study confirms that LICI in the DLPFC is largely mediated by GABA_B receptor-mediated inhibitory neurotransmission and also suggests that cholinergic modulation decreases LICI in the DLPFC. Such findings may help guide future work examining the neurophysiological impact of these neurotransmitters in healthy and diseased states.