title: Availability of N-Methyl-d-Aspartate Receptor Coagonists Affects Cocaine-Induced Conditioned Place Preference and Locomotor Sensitization: Implications for Comorbid Schizophrenia and Substance Abuse.
abstract: Schizophrenia is associated with high prevalence of substance abuse. Recent research suggests that dysregulation of N-methyl-d-aspartate receptor (NMDAR) function may play a role in the pathophysiology of both schizophrenia and drug addiction, and thus, may account for this high comorbidity. Our laboratory has developed two transgenic mouse lines that exhibit contrasting NMDAR activity based on the availability of the glycine modulatory site (GMS) agonists d-serine and glycine. Glycine transporter 1 knockdowns (GlyT1(+/-)) exhibit NMDAR hyperfunction, whereas serine racemase knockouts (SR(-/-)) exhibit NMDAR hypofunction. We characterized the behavior of these lines in a cocaine-induced (20 mg/kg) conditioned place preference (CPP) and locomotor sensitization paradigm. Compared with wild-type mice, GlyT1(+/-) mice displayed hastened extinction of CPP and robust cocaine-induced reinstatement. SR(-/-) mice appeared to immediately "forget" the learned preference, because they did not exhibit cocaine-induced reinstatement and also displayed attenuated locomotor sensitization. Treatment of GlyT1(+/-) mice with gavestinel (10 mg/kg on day 1; 5 mg/kg on days 2-17), a GMS antagonist, attenuated cocaine-induced CPP and caused them to immediately "forget" the learned preference. Treatment of SR(-/-) mice with d-serine (300 mg/kg on day 1; 150 mg/kg on days 2-17) to normalize brain levels caused them to avoid the cocaine-paired side of the chamber during extinction. These results highlight NMDAR dysfunction as a possible neural mechanism underlying comorbid schizophrenia and substance abuse. Also, these findings suggest drugs that directly or indirectly activate the NMDAR GMS could be an effective treatment of cocaine abuse.
authors: Department of Psychiatry, Harvard Medical School (M.D.P., A.R.B., A.J.B., J.T.C.), and Laboratory for Psychiatric and Molecular Neuroscience (M.D.P., A.R.B., J.T.C.) and Behavioral Genetics Laboratory (A.J.B.), McLean Hospital, Belmont, Massachusetts.
authors: Matthew D
authors: MD
authors: Puhl
authors: Department of Psychiatry, Harvard Medical School (M.D.P., A.R.B., A.J.B., J.T.C.), and Laboratory for Psychiatric and Molecular Neuroscience (M.D.P., A.R.B., J.T.C.) and Behavioral Genetics Laboratory (A.J.B.), McLean Hospital, Belmont, Massachusetts.
authors: Alexandra R
authors: AR
authors: Berg
authors: Department of Psychiatry, Harvard Medical School (M.D.P., A.R.B., A.J.B., J.T.C.), and Laboratory for Psychiatric and Molecular Neuroscience (M.D.P., A.R.B., J.T.C.) and Behavioral Genetics Laboratory (A.J.B.), McLean Hospital, Belmont, Massachusetts.
authors: Anita J
authors: AJ
authors: Bechtholt
authors: Department of Psychiatry, Harvard Medical School (M.D.P., A.R.B., A.J.B., J.T.C.), and Laboratory for Psychiatric and Molecular Neuroscience (M.D.P., A.R.B., J.T.C.) and Behavioral Genetics Laboratory (A.J.B.), McLean Hospital, Belmont, Massachusetts joseph_coyle@hms.harvard.edu.
authors: Joseph T
authors: JT
authors: Coyle
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000523:psychology; D003216:Conditioning, Operant / Q000187:drug effects; D055785:Gene Knockdown Techniques; D050487:Glycine Plasma Membrane Transport Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D019998:Racemases and Epimerases / Q000172:deficiency / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D012559:Schizophrenia / Q000150:complications*; D019966:Substance-Related Disorders / Q000188:drug therapy; D000099300:Serine Racemase
chemical_list: D003042:Cocaine; D050487:Glycine Plasma Membrane Transport Proteins; D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D000099300:Serine Racemase