Ketamine and Zinc: Treatment of Anorexia Nervosa Via Dual NMDA Receptor Modulation

Abstract

Anorexia nervosa is a disorder associated with serious adverse health outcomes, for which there is currently considerable treatment ineffectiveness. Characterised by restrictive eating behaviours, distorted body image perceptions and excessive physical activity, there is growing recognition anorexia nervosa is associated with underlying dysfunction in excitatory and inhibitory neurometabolite metabolism and signalling. This narrative review critically explores the role of N-methyl-D-aspartate receptor-mediated excitatory and inhibitory neurometabolite dysfunction in anorexia nervosa and its associated biomarkers. The existing magnetic resonance spectroscopy literature in anorexia nervosa is reviewed and we outline the brain region-specific neurometabolite changes that have been reported and their connection to anorexia nervosa psychopathology. Considering the proposed role of dysfunctional neurotransmission in anorexia nervosa, the potential utility of zinc supplementation and sub-anaesthetic doses of ketamine in normalising this is discussed with reference to previous research in anorexia nervosa and other neuropsychiatric conditions. The rationale for future research to investigate the combined use of low-dose ketamine and zinc supplementation to potentially extend the therapeutic benefits in anorexia nervosa is subsequently explored and promising biological markers for assessing and potentially predicting treatment response are outlined.

Fig. 1

N-methyl-d-aspartate (NMDA) receptor and its ligand binding sites. Note: zinc binds to the GluN2/3 subunit allosteric sites, whilst ketamine binds at the deep channel blocker site within the receptor pore. Created on BioRender.com with Publication and Licensing Rights obtained

Fig. 2

a Acute anorexia nervosa (AN): a hyperglutamatergic state is promoted due to decreased zinc-mediated N-methyl-d-aspartate receptor (NMDAr) inhibition and pro-inflammatory cytokines induced inhibition of astrocyte-mediated glutamate uptake and recycling, resulting in decreased synaptic cleft clearance. Serotonin (5-HT) and dopamine (DA) signalling are altered in AN, and this may influence pre-synaptic neurotransmitter glutamate release. The resulting hyperglutamatergic state increases calcium conductance into the post-synaptic neuron, contributing to calcium-induced excitotoxicity. Decreased nutrient signals (insulin/insulin-like growth factor-1) and zinc deficiency may promote increased silent mating type information regulation 2 mammalian homologue (SIRT1) activity, suppressing mammalian target of rapamycin (mTOR)-mediated protein synthesis, and promoting dysfunctional NMDAr-mediated synaptic plasticity via downregulation of GluN2A expression. b Chronic AN: decreased zinc-mediated inhibition of GABAergic neurons (via NMDA and GABA_A receptors) inhibits glutamate release, and downregulates BDNF and CREB expression (via the GPR39 receptor). Increased SIRT1 expression leads to a higher NMDAr GluN2B subunit ratio, which coupled with decreased zinc-mediated NMDAr inhibition, decreased glutamate clearance, and increased expression of calcium permeable (CP) AMPAr, promotes dysfunctional activity and connectivity in brain regions implicated in AN. (c) Ketamine and zinc: ketamine binds to NMDArs on GABAergic interneurons in the prefrontal cortex, disinhibiting pyramidal glutamatergic neurons and consequently increasing extracellular glutamate. Increased zinc similarly inhibits GABAergic interneurons. At the post-synaptic neuron, ketamine and zinc inhibit NMDAr activity, leading to decreased NMDAr-mediated calcium influx and reduced NMDAr expression. Synaptic and extra-synaptic NMDAr ketamine inhibition promotes protein (AMPA) synthesis and membrane insertion. The combined AMPAr insertion and increased excitatory PFC firing drives synaptic remodelling. Zinc and ketamine increase 5-HT and DA signalling; however, the specific effects on pre-synaptic firing are not known. Increased zinc levels may downregulate SIRT1 and pro-inflammatory cytokine activity, promoting increased synaptic protein synthesis and astrocyte-mediated glutamate clearance, respectively. The resulting changes in pre-synaptic firing, post-synaptic NMDAr and AMPR expression and composition, and synaptic glutamate clearance may stimulate region-specific synaptic remodelling. (d) The healthy state: ketamine and zinc-induced changes in pre-synaptic neurotransmitter release, post-synaptic receptor expression and glutamate clearance may be sustained by zinc’s regulatory action. Sustained zinc-mediated NMDAr inhibition and reduction in pro-inflammatory signalling prevents relapse of the hyperglutamatergic state, and normalises GABAergic and 5-HT activity. AMPAr alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, BDNF brain-derived neurotrophic factor, CREB cAMP-response element binding protein, EAAT excitatory amino acid transporter, GPR-39 G protein-coupled receptor 39, GABA gamma-aminobutyric acid, GABAr GABA receptor, IL interleukin, TNF-α tumor necrosis factor-alpha. Created on BioRender.com with Publication and Licensing Rights obtained