Research report Muscimol prevents NMDA antagonist neurotoxicity by activati GABA A receptors in several brain regions Nuri B.Farber * , Xiaoping Jiang, Krikor Dikranian, Brian Nemmers Department of Psychiatry, Washington University, Campus Box 8134, 660 S. Euclid Ave. St.Louis,MO 63110-1093, USA Accepted 4 September 2003 Abstract N-Methyl- D-aspartate (NMDA) glutamate receptor antagonists are being developed as therapeutic agents for several cli However, the ability of these agents to produce neurotoxicity and psychosis can compromise their clinical usefulness. In receptor hypofunction (NRHypo) state may play a role in neurodegenerative and psychotic disorders. A betterunderstanding of the mechanism underlying these adverse effects should allow for the safer use of these agents and might clarify mechanism clinicaldisorders. NRHypo neurotoxicity is mediated by a complex disinhibition mechanism in which NMDA antagonists abolish GABAergic inhibition, resulting in the simultaneous excessive release of acetylcholine and glutamate onto the vulnerable (RSC) neurons. Systemically administered GABAergic agents are potent protectors against NRHypo neurotoxicity. To determine where in brain GABAergic agents could be acting to protect against NRHypo neurotoxicity, we injected the GABAergic agonist, muscimol, into different brain regions of rats treated systemically with a neurotoxic dose of the potent NMDA antagonist, MK-801. We re injections into the anterior thalamus or diagonal band of Broca provide substantial protection, suggesting that disinhibition of neurons in these regions underlies NRHypo neurotoxicity. Muscimol injections into the RSC also provide substantial protection possibly by directly inhibiting the vulnerable RSC neuron. Injections of muscimol into other areas known to project to the RSC (ventral orbita cingulate cortex and subiculum) provide only minimal protection. We conclude that GABAergic agents prevent NRHypo neurotoxicity mainly by activating GABA receptors in the anterior thalamus, diagonal band of Broca and RSC. D 2003 Elsevier B.V. All rights reserved. Theme: Disorders of the nervous system Topic: Neurotoxicity Keywords: Neurotoxicity; Dizocilpine maleate; GABA agonist; Dissociative anesthetic; Alzheimer disease; Psychose 1. Introduction Antagonists of the N-methyl- D-aspartate (NMDA) gluta- mate (Glu)receptor, including phencyclidine, ketamine, MK-801, CPP, CPP-ene, nitrous oxide, and memantine, have anesthetic-like properties and are of potential therapeutic benefit in clinical situations such as status epilepticus, stroke, trauma, neuropathic pain, and the development of tolerance to opiates [26,29,30,40,42]. Unfortunately, these agents injure neurons [1,9,28,43,44,51], induce a wide variety of CNS changes [3,7,8,19,24,31,34,37], and produce cognitive and behavioral symptoms including psychosis [6,32,38]. The ability of these agents to injure neurons and produce a w range ofcognitive and behavioral effectshasdampened enthusiasm for their clinical use. In addition, NMDA recep torhypofunction (NRHypo), the condition induced in the brain by NMDA antagonist drugs, might be involved in th pathophysiology of psychotic disorders and Alzheimer’s disease [41,45]. Finally, the abuse of these agents is an going problem for society. A betterunderstanding of the mechanism underlying these NRHypo-induced effects po tentially could lead to increased clinical utility of these d and an improved understanding and better treatment of several neuropsychiatric conditions. The pathomorphological changes induced by NRHypo can be either reversible or irreversible, depending on how long NMDA receptorblockade ismaintained. Changes induced by alow dose of an NMDA antagonistare reversible, are regionally selective for neurons in the retro- 0006-8993/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2003.09.002 * Corresponding author.Tel.: +1-314-362-2459; fax: +1-314-362- 9902. E-mail address: farbern@psychiatry.wustl.edu (N.B. Farber). www.elsevier.com/locate/brainres Brain Research 993 (2003) 90 – 100