Glutamate (Glu) is an ancient compound that likely shapes conscious experience, well-being, and agency in everyday life. It is well established that Glu mediates excitatory neurotransmission, learning, memory, motor activity, is under homeostatic control and is excitotoxic when dysregulated (Magi et al, 2019). This scope would seem to argue against additional major, undiscovered roles for Glu in the brain. The evolutionary history of Glu, however, reveals rich diversity. Phylogenetically, Glu occurs at high concentrations in species that are extraordinarily distant - such as bacteria and humans - evidencing biologic roles predating divergence of prokaryotes and eukaryotes 2.7 billion years ago (Commichau et al, 2008; Cooper, 2000). Glu-like receptors occur in plants and animals, indicating common ancestry ~ 1.6 billion years ago (Chiu et al, 1999; Meyerowitz, 1999; Wang et al, 1999). Glu is thus ancient and ubiquitous, providing ample time and material for the evolution of multiple, overlapping functions in living systems. This history suggests additional undiscovered roles for Glu in healthy organisms, where rapid homeostasis readily obscures functional processes in vivo. Indeed, science over the last nine decades has repeatedly underestimated the functional diversity of Glu (Danbolt, 2021; Watkins and Jane, 2006). Glu thus very likely has further, unanticipated roles in health and well-being.
Emerging work in clinical neuroscience indicates neocortical Glu shapes the etiology and treatment of disorders of mood, motivation, and behavior. Glx, a combination of Glu and glutamate (Gln), is reduced in frontal brain in major depressive disorder (MDD) and is elevated in bipolar disorder (BPD) (Moriguchi et al, 2019; Scotti-Muzzi et al, 2021). Effective treatments for MDD such as electroconvulsive therapy, repetitive transcranial magnetic stimulation (rTMS), ketamine, and citalopram are associated with increase in Glx, Glu and Gln in frontal and temporal cortex, tracking MDD improvement (Gonsalves et al, 2022; Lener et al, 2017; Michael et al, 2003a, b; Milak et al, 2016; Pfleiderer et al, 2003). Moreover, rTMS with adjunctive D-cycloserine (100mg oral), a partial NMDA receptor agonist, yields greater alleviation of depressive symptoms than rTMS with placebo, indicating a role of Glu in recovery of positive affect (Cole et al, 2022). Euthymic states also correspond to heightened Glx, Glu and Gln in the ACC, and mood stabilizers alter Glu and Gln (Scotti-Muzzi et al, 2021; Soeiro-de-Souza et al, 2018). Further, individuals recovering from stimulant dependence report depressive symptoms that coincide with reduction in Glx in inferior frontal cortex (Bakhshinezhad et al, 2022; O'Neill et al, 2014). These data suggest contributions of neocortical glutamate to agentic states and amelioration of aversive states in clinical disorder.
Further insight is provided by drug challenge studies in healthy individuals, where phasic perturbation of neocortical Glu alters conscious experience. Here, single doses (30–40 mg oral) of memantine, an NMDA receptor antagonist, increase volunteers’ reports of feeling high, stimulated, forgetful, contented, lightheaded, detached, unreal, slow-motion, “buzzed”, and dizzy (Bisaga and Evans, 2004; Jackson et al, 2009). Single doses of D-cycloserine (50 mg oral) increase volunteers’ ratings of stimulation (Nesic et al, 2011). Low-doses of ketamine, a noncompetitive NMDA receptor antagonist, increase Gln in the ACC and reports of time distortion, dissociation, emotional blunting, cognitive disruption, excitement, and somatic activation (Coull et al, 2011; Krystal et al, 2005; Rowland et al, 2005). Conversely, the anesthetic propofol reduces Glu in motor cortex, sensory cortex, and thalamus alongside its effects on sedation (Zhang et al, 2009). These data suggest mechanistic contribution of neocortical Glu to visceral sensations, subjective states, and feelings of connection, attachment, and engagement.
Motivated by the above data and history, we here investigate contributions of neocortical glutamate to conscious experience using drug challenge in healthy volunteers. This method provides experimental manipulation of neocortical Glu in individuals who are medically and psychiatrically well (White and Gonsalves, 2020; White et al, 2018). Toward this end, d-amphetamine (AMP), methamphetamine (MA) and placebo (PBO) were administered on three separate test days to healthy participants using a within-subjects, counterbalanced, double-blinded design, with each participant serving as their own control. Using this approach, we find AMP and MA produce phasic rise in dACC Glu, an effect most apparent in females (White et al, 2018). Informed by this finding and our prior work on drug effects and positive emotion (Grodin and White, 2015; Morrone et al, 2000; Weyandt et al, 2018; White, 2011, 2017; White et al, 2020; White and Gonsalves, 2021a; White et al, 2023; White et al, 2007; White et al, 2006), we here evaluate the relationship of dACC Glu and participants’ conscious experience, assessed by a large battery of validated self-report (SR) measures of subjective states at half hour intervals over the 5.5-hour period on each session (Fig. 1). This approach provides detailed information on conscious states, mood, emotion, metacognition, and visceral/somatic sensations in each participant, suitable for evaluation with phasic change in dACC Glu.
Our hypotheses were two-fold. First, we expected drug-induced change in neocortical Glu to predict the magnitude of drug-induced change in conscious states with motivational component, i.e., perceived and reported states of subjective stimulation, excitement, enthusiasm, and vigor. Second, we expected these effects to be more readily observed in female participants, due to their heightened glutamatergic response and increased vulnerability to stimulant dependence compared to males (White et al, 2018). The study thus provides new information on experimentally-induced change in neocortical Glu and its impact on subjective experience in well individuals.