rTMS-Induced Changes in Glutamatergic and Dopaminergic Systems: Relevance to Cocaine and Methamphetamine Use Disorders

Abstract

Cocaine use disorder and methamphetamine use disorder are chronic, relapsing disorders with no US Food and Drug Administration-approved interventions. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation tool that has been increasingly investigated as a possible therapeutic intervention for substance use disorders. rTMS may have the ability to induce beneficial neuroplasticity in abnormal circuits and networks in individuals with addiction. The aim of this review is to highlight the rationale and potential for rTMS to treat cocaine and methamphetamine dependence: we synthesize the outcomes of studies in healthy humans and animal models to identify and understand the neurobiological mechanisms of rTMS that seem most involved in addiction, focusing on the dopaminergic and glutamatergic systems. rTMS-induced changes to neurotransmitter systems include alterations to striatal dopamine release and metabolite levels, as well as to glutamate transporter and receptor expression, which may be relevant for ameliorating the aberrant plasticity observed in individuals with substance use disorders. We also discuss the clinical studies that have used rTMS in humans with cocaine and methamphetamine use disorders. Many such studies suggest changes in network connectivity following acute rTMS, which may underpin reduced craving following chronic rTMS. We suggest several possible future directions for research relating to the therapeutic potential of rTMS in addiction that would help fill current gaps in the literature. Such research would apply rTMS to animal models of addiction, developing a translational pipeline that would guide evidence-based rTMS treatment of cocaine and methamphetamine use disorder.

Non-invasive High Frequency Repetitive Transcranial Magnetic Stimulation (hfrTMS) Robustly Activates Molecular Pathways Implicated in Neuronal Growth and Synaptic Plasticity in Select Populations of Neurons

“…Some of these forms of synaptic plasticity are considered as NMDA-R mediated (for a review, see Müller-Dahlhaus and Vlachos, 2013). Also, previous studies have documented that different patterns of TMS can activate immediate early gene (IEG) expression (c-fos and zif268) in select populations of neurons (Aydin-Abidin et al, 2008;Gersner et al, 2011;Volz et al, 2013), cause both increases and decreases in levels of different neuronal proteins involved in neurotransmitter function (Müller-Dahlhaus and Vlachos, 2013;Moretti et al, 2020), and activate expression of GFAP in astrocytes (Fujiki and Steward, 1997). Nevertheless, our understanding of consequences of different patterns of TMS is incomplete, both in terms of the molecular and cellular mechanisms that are activated and especially in terms of the populations of neurons in which TMS-induced molecular events occur.…”

Psychostimulant use disorder emphasizing methamphetamine and the opioid -dopamine connection: Digging out of a hypodopaminergic ditch

“…Interestingly, treatment targets now include specific neurotransmitters like glutamate, endocannabinoids, and GABA. These include glutamate-enhancers like N-acetylcysteine and modafinil, and GABAergic medications, like topiramate, which target endocannabinoids, and transcranial magnetic stimulation (TMS) [133][134][135].…”

Targeting neuroplasticity in patients with neurodegenerative diseases using brain stimulation techniques

“…1 b). Also, rTMS stimulation seems to evoke glutamate/GABA release [ 23 , 24 ] and to facilitate calcium-mediated signaling, thereby modulating synaptic plasticity [ 25 ] (Fig. 1 b).…”