title: The effects of GABAA and NMDA receptors in the shell-accumbens on spatial memory of METH-treated rats.
abstract: Methamphetamine (METH) is a highly addictive and neurotoxic psychostimulant. Its use in humans is often associated with neurocognitive impairment and deficits in hippocampal plasticity. Striatal dopamine system is one of the main targets of METH. The dopamine neurons in the striatum directly or indirectly regulate the GABA and glutamatergic signaling in this region and thus their outputs. This is consistent with previous reports showing modification of neuronal activity in the striatum modulates the expression of hippocampal LTP and hippocampal-dependent memory tasks such as Morris water maze (MWM). Therefore, reversing or preventing METH-induced synaptic modifications via pharmacological manipulations of the shell-nucleus accumbens (shell-NAc) may introduce a viable therapeutic target to attenuate the METH-induced memory deficits. This study is designed to investigate the role of intra-shell NAc manipulation of GABAA and NMDA receptors and their interaction with METH on memory performance in MWM task. Pharmacological manipulations were performed in rats received METH or saline. We found systemic saline plus intra-shell NAc infusions of muscimol dose-dependently impaired performance, while bicuculline had no effect. Surprisingly, the intra-NAc infusions of 0.005μg/rat muscimol that has no effect on memory performance (ineffective dose) prevented METH-induced memory impairment. In the contrary, the intra-NAc infusions of bicuculline (0.2μg/rat) increased METH-induced memory impairment. However, pre-training intra-NAc infusions of D-AP5 dose-dependently impaired performance, while NMDA had no effect in rats received systemic saline (control group). The intra-NAc infusions with an ineffective dose of NMDA (0.1μg/rat) increased METH-induced memory impairment. Furthermore, intra-NAc infusions of D-AP5 with an ineffective dose (0.1μg/rat) prevented METH-induced memory impairment. Our result is consistent with the interpretation that METH-mediated learning deficit might be due to modification of hippocampus-VTA loop and that augmentation of GABAA receptor function in the shell-NAc may provide a new therapeutic target for alleviating METH-induced memory deficits.
authors.affiliation: ‍Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Soomaayeh
authors.initials: S
authors.lastname: Heysieattalab
authors.affiliation: Department of Physiology and Pharmacology, Pasteur Institute of Iran, 13164 Tehran, Iran. Electronic address: naghdi@pasteur.ac.ir.
authors.forename: Nasser
authors.initials: N
authors.lastname: Naghdi
authors.affiliation: ‍Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; School of Cognitive Sciences, Institute for Research in Fundamental Sciences, Tehran, Iran; Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: zarinmr@ams.ac.ir.
authors.forename: Mohammad-Reza
authors.initials: MR
authors.lastname: Zarrindast
authors.affiliation: Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Abbas
authors.initials: A
authors.lastname: Haghparast
authors.affiliation: Department of Pharmacology School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Shahram Ejtemaei
authors.initials: SE
authors.lastname: Mehr
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, FL 323611, United States.
authors.forename: Habibeh
authors.initials: H
authors.lastname: Khoshbouei
mesh_terms: D000818:Animals; D008297:Male; D018782:Maze Learning; D008568:Memory / Q000187:drug effects*; D008694:Methamphetamine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D008694:Methamphetamine
keywords: Methamphetamine; Muscimol; Nucleus accumbens; Spatial memory