ABSTRACT Rearing is an exploratory behavior induced by novelty, such as exposure to an open field. Stimulation of certain brain regions, including the hippocampus, induces both rearing and clonic convulsions. Brain excitability is controlled by gamma-aminobutyric acid (GABA) inhibitory neurotransmission through its ionotropic GABAA/allosteric benzodiazepine site. Drugs that decrease GABAA receptor fast inhibitory neurotransmission induce clonic convulsions and rearing when injected into the hippocampus. Therefore, individual differences in rearing behavior may be related to the susceptibility to clonic convulsions, which could involve differences in brain excitability controlled by GABAA/allosteric benzodiazepine site receptors. Adult, male Wistar rats were divided into high- (HR) and low-rearing (LR) groups based on the number of rearings in the open field test. Groups of HR and LR rats were challenged with convulsant drugs that antagonize GABA neurotransmission via different mechanisms of action (3-mercaptopropionic acid, a glutamate decarboxilase inhibitor; bicuculline, a GABAA receptor antagonist; pentylenetetrazol and picrotoxin, both GABAA receptor chloride channel blockers and DMCM, a benzodiazepine inverse agonist). The convulsant doses that induced 50% of clonic convulsions were determined for each drug. The LR rats had a higher susceptibility (a lower convulsant dose 50%) to clonic convulsions induced by DMCM than the HR rats, but there were no differences between the groups in the susceptibility to tonic convulsions induced by the same drug. There were no significant differences in the convulsant dose 50% for clonic convulsions between the groups for all other drugs injected. In another experiment, additional HR and LR rats were injected with a sedative-hypnotic dose of diazepam, which caused a significantly higher hypnotic effect (sleeping-time) in the LR rats than in the HR rats. The LR group was also shown to have a significantly lower density of [3H]-Flunitrazepam bound to the GABAA receptor in hippocampal membranes. Our data suggest that inter-individual differences in rearing are related, at least in part, to the GABA inhibitory neurotransmission controlled by the benzodiazepine allosteric site in the GABAA receptor.
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R. Alves, J. Carvalho and M. Venditti, "High- and Low-Rearing Rats Differ in the Brain Excitability Controlled by the Allosteric Benzodiazepine Site in the GABAA Receptor," Journal of Behavioral and Brain Science, Vol. 2 No. 3, 2012, pp. 315-325. doi: 10.4236/jbbs.2012.23036.
 W. E. Crusio, “Genetic Dissection of Mouse Exploratory Behavior,” Behavioural Brain Research, Vol. 125, No. 1-2, 2001, pp. 127-132.
 J. H. F. van Abeelen, “Genetic Analysis of Behavioural Responses to Novelty in Mice,” Nature, Vol. 254, No. 5497, 1975, pp. 239-241. doi:10.1038/254239a0
 J. H. F. van Abeelen, “Rearing Responses and Locomotor Activity in Mice: Single-Locus Control,” Behavioral Biology, Vol. 19, No. 3, 1977, pp. 401-404.
 H. van Lier, W. H. Drinkenburg and A. M. L. Coenen, “Strain Differences in Hippocampal EEG Are Related to Strain Differences in Behaviour in Rats,” Physiology & Behavior, Vol. 78, No. 1, pp. 91-97.
 D. K. Hannesson, J. Howland, M. Pollock, P. Mohapel, A. E. Wallace and M. E. Corcoran, “Dorsal Hippocampal Kindling Produces a Selective and Enduring Disruption of Hippocampally Mediated Behavior,” The Journal of Neuroscience, Vol. 21, No. 12, 2001, pp. 4443-4450.
 J. Ma, S. M. Brudzynski and L. W S. Leung, “Involvement of the Nucleus Accumbens-Ventral Pallidal Pathway in Posictal Behavior Induced by a Hippocampal after Discharge in Rats,” Brain Research, Vol. 739, No. 1-2, 1996, pp. 26-35. doi:10.1016/S0006-8993(96)00793-7
 J. Ma, S. M. Brudzynski and L. W. S. Leung, “A Role of Subicular and Hippocampal after Discharges in Initiation of Locomotor Activity in Rats,” Brain Research, Vol. 193, No. 1-2, 1998, pp. 112-118.
 R. J. Racine, “Modification of Seizure Activity by Electrical Stimulation: II. Motor Seizure,” Electroencephlography and Clinical Neurophysiol, Vol. 32, No. 3, 1972, pp. 281-294. doi:10.1016/0013-4694(72)90177-0
 H. van Lier, H. I. Drinkenburg, Y. J. W. van Eeten and A. M. L. Coenen AML, “Effects of Diazepam and Zolpidem on EEG Beta Frequencies Are Behavior-Specific in Rats,” Neuropharmacology, Vol. 47, No. 2, 2004, pp. 163-174. doi:10.1016/j.neuropharm.2004.03.017
 C. Belzung, “Hippocampal Mossy Fibres: Implication in Novelty Reactions or in Anxiety Behaviors?” Behavioral Brain Research, Vol. 51, No. 2, 1992, pp. 149-155.
 W. E. Crusio, H. Schwegler, I. Brust and J. H. van Abeelen, “Genetic Selection for Novelty-Induced Rearing Behavior in Mice Produces Changes in Hippocampal Mossy Fiber Distributions,” Journal of Neurogenetics, Vol. 5, No. 1, 1989, pp. 87-93.
 Z. Hausheer-Zarmakupi, D. P. Wolfer, M. C. Leisinger-Trigona and H. P. Lipp, “Selective Breeding for Extremes in Open-Field Activity of Mice Entails a Differentiation of Hippocampal Mossy Fibers, Behavior Genetics, Vol. 26, No. 2, 1996, pp. 167-176.
 P. Roullet and J. M. Lassalle, “Genetic Variation, Hippocampal Mossy Fibres Distribution, Novelty Reactions and Spatial Representation in Mice,” Behavioral Brain Research, Vol. 41, No. 1, 1990, pp. 61-70.
 S. J. Enna and N. G. Bowery, “GABAB Receptor Alterations as Indicators of Physiological and Pharmacological Function,” Biochemical Pharmacology, Vol. 68, No. 8, 2004, pp. 1541-1548. doi:10.1016/j.bcp.2004.06.037
 G. A. R. Johnston, “GABAA Receptor Pharmacology,” Pharmacology and Therapeutics, Vol. 69, No. 3, 1996, pp. 173-198. doi:10.1016/0163-7258(95)02043-8
 E. R. Korpi, G. Grunder and H. Luddens, “ Drug Interactions at GABAA Receptors,” Progress in Neurobiology, Vol. 37, No. 2, 2002, pp. 113-159.
 H. Mohler, J. M. Fritschy and U. Rudolph, “A New Benzodiazepine Pharmacology,” Journal of Pharmacology and Experimental Therapeutics, Vol. 300, No. 1, 2002, pp. 2-8. doi:10.1124/jpet.300.1.2
 M. Vergnes, A. Boehrer, S. Reibel, S. Simler and C. Marescaux, “Selective Susceptibility to Inhibitors of GABA Synthesis and Antagonists of GABAA Receptors in Rats with Genetic Absence Epilepsy,” Experimental Neurology, Vol. 161, No. 2, 2000, pp. 714-723.
 M. Vergnes, A. Boehrer, X. He, H. Greney, M. Dontenwill, J. Cook and C. Marescaux, “Differential Sensitivity to Inverse Agonist of GABAA/Benzodiazepine Receptors in Rats with Genetic Absence-Epilepsy,” Epilepsy Research, Vol. 47, No. 1-2, 2001, pp. 43-53.
 M. Netopilova, J. Drsata, R. Haugvicova, H. Kubova and P. Mares, “Inhibition of Glutamate Decarboxylase Activity by 3-Mercaptopropionic Acid Has Different Time Course in the Immature and Adult Rat Brains,” Neuroscience Letters, Vol. 226, No. 1, 1997, pp. 68-70.
 G. De Sarro, A. Chimirri, M. Zappala, P. Guisti, M. Lipartiti and A. De Sarro, “Azirinol[1,2-d][1,4]benzodiazepine Derivatives and Related 1,4-benzodiazepines as Anticonvulsant Agents in DBA/2 Mice,” General Pharmacology, Vol. 27, No. 7, 1996, pp. 1155-1162.
 P. Kwan, G. J. Sills and M. J. Brodie, “The Mechanisms of Action of Commonly Used Antiepileptic Drug,” Pharmacology & Therapeutics, Vol. 90, No. 1, 2001, pp. 21-34. doi:10.1016/S0163-7258(01)00122-X
 R. Alves, J. G. B. Carvalho and M. A. C. Benedito, “High and Low Rearing Subgroups of Rats Selected in the Open Field Differ in the Activity of
K+-stimulated-p-nitrophenylphosphatase in the Hippocampus,” Brain Research, Vol. 1058, No. 1-2, 2005, pp. 178-182. doi:10.1016/j.brainres.2005.08.005
 R. J. Hernández, “Na+/K+-ATPase Regulation by Neurotransmitters,” Neurochemistry International, Vol. 20, No. 1, 1992, pp. 1-10. doi:10.1016/0197-0186(92)90119-C
 J. W. Phillis, “Na+/K+-ATPase as an Effector of Synaptic Transmission,” Neurochemistry International, Vol. 20, No. 1, 1992, pp. 19-22.
 E. S. Vizi and F. Oberfrank, “Na+/K+-ATPase, Its Endo-genous Ligands and Neurotransmitter Release,” Neurochemistry International, Vol. 20, No. 1, 1992, pp. 11-17. doi:10.1016/0197-0186(92)90120-G
 C. Vaillend, S. E. Mason, M. F. Cuttle and B. E. Alger, “Mechanisms of Neuronal Hyperexcitability Caused by Partial Inhibition of Na+-K+-ATPases in the Rat CA1 Hippocampal Region,” Journal of Neurophysiology, Vol. 88, No. 6, 2002, pp. 2963-2978.
 D. S. Eidman, M. A. C. Benedito and J. R. Leite, “Daily Changes in Pentylenetetrazol-Induced Convulsions and Open-Field Behavior in Rats,” Physiology & Behavior, Vol. 47, No. 5, 1990, pp. 853-856.
 J. T. Litchfield Jr. and F. Wilcoxon, “A Simplified Method of Evaluating Dose-Effect Experiments,” Journal of Pharmacology and Experimental Therapeutics, Vol. 96, No. 2, 1949, pp. 99-113.
 M. B. Contó, D. C. Hipólide, J. G. de Carvalho and M. A. C. Venditti, “Rats with Different Thresholds for DMCM-Induced Clonic Convulsions Differ in the Sleep-Time of Diazepam and [3H]-Ro 15-4513 Binding,” Epilepsy Research, No. 2-3, 2011, pp. 216-222.
 R. Rupprecht, “Neuroactive Steroids: Mechanism of Action and Neuropsychopharmacological Properties,” Psychoneuroendocrinology, Vol. 28, No. 2, 2003, pp. 139-168. doi:10.1016/S0306-4530(02)00064-1
 M. L. Andersen, P. J. F. Martins, V. D’ Almeida, M. Bignotto and S. Tufik, “Endocrinological and Catecholaminergic Alterations during Sleep Deprivation and Recovery in Male Rats,” Journal of Sleep Research, Vol. 14, No. 1, 2005, pp. 83-90.
 D. Suchecki, P. A. Tiba and S. Tufik, “Paradoxical Sleep Deprivation Facilitates Subsequent Corticosterone Response to a Mild Stressor in Rats,” Neuroscience Letters, Vol. 320, No. 1-2, 2002, pp. 45-48.
 M. S. Kafka, M. A. Benedito, J. A. Blendy and N. S. Tokola, “Circadian Rhythms in Neurotransmitter Receptors in Discrete Rat Brain Regions,” Chronobiology International, Vol. 3, No. 2, 1986, pp. 91-100.
 O. H. Lowry, N. J. Rosebrough, A. L. Farr and R. J. Randall, “Protein Measurement with the Folin Phenol Reagent,” Journal of Biological Chemistry, Vol. 193, No. 1, 1951, pp. 265-275.
 C. Braestrup, M. Nielsen and T. Honoré, “Binding of [3H]DMCM, a Convulsive Benzodiazepine Ligand, to Rat Brain Membranes: Preliminary Studies,” Journal of Neurochemistry, Vol. 41, No. 2, 1983, pp. 454-465.
 R. F. Squires, E. Saederup, J. N. Crawley, P. Skolnick and S. M. Paul, “Convulsant Potencies of Tetrazoles Are Highly Correlated with Actions on GABA/Benzodiaze-pine/Picrotoxin Receptor Complexes in Brain,” Life Sciences, Vol. 35, No. 14, 1984, pp. 1439-1444.
 A. Borta and R. W. Schwarting, “Post-Trial Treatment with the Nicotinic Agonist Metanicotine: Differential Effects in Wistar Rats with High Versus Low Rearing Activity,” Pharmacology Biochemistry and Behavior, Vol. 80, No. 4, 2005, pp. 541-548.
 M. Orchinik, N. G. Weiland and B. S. McEwen, “Chronic Exposure to Stress Levels of Corticosterone Alters GABAA Receptor Subunit mRNA Levels in Rat Hippocampus,” Molecular Brain Research, Vol. 34, No. 1, 1995, pp. 29-37. doi:10.1016/0169-328X(95)00118-C
 A. Islam, B. Henriksson, A. Mohammed, B. Winblad and A. Adem, “Behavioural Deficits in Adult Rats Following Long-Term Adrenaletomy,” Neuroscience Letters, Vol. 194, No. 1-2, 1995, pp. 49-52.
 S. Pirker, C. Schwarzer, A. Wieselthaler, W. Sieghart and G. Sperk, “GABAA Receptors: Immunocytochemical Distribution of 13 Subunits in the Adult Rat Brain,” Neuroscience, Vol. 101, No. 4, 2000, pp. 815-850.
 J. C. Cole, M. Hillmann, D. Seidelmann, M. Klewer and G. H. Jones, “Effects of Benzodiazepine Receptor Partial Inverse Agonists in the Elevated plus Maze Test of Anxiety in the Rat,” Psychopharmacology, Vol. 121, No. 1, 1995, pp. 118-126. doi:10.1007/BF02245598
 R. E. Grahn, B. A. Kalman, F. X. Brennan, L. R. Watkins and S. F. Maier, “The Elevated Plus-Maze Is Not Sensitive to the Effect of Stressor Controllability in Rats,” Pharmacology Biochemistry and Behavior, Vol. 52, No. 3, 1995, pp. 565-570. doi:10.1016/0091-3057(95)00141-I
 F. Crestani, R. Assandri, M. Tauber, J. R. Martin and U. Rudolph, “Contributions of the Alpha1-GABAA Receptor Subtype to the Pharmacological Actions of Benzodiazepine Site Inverse Agonists,” Neuropharmacology, Vol. 43, No. 4, 2002, pp. 679-684.
 J. M. C. Derry, S. M. J. Dunn and M. Davies, “Identification of a Residue in the Gamma-Aminobutyric Acid Type A Receptor Alpha Subunit That Differentially Affects Diazepam-Sensitive and -Insensitive Benzodiazepine Site Binding,” Journal of Neurochemistry, Vol. 88, No. 6, 2004, pp. 1431-1438.
 H. Luddens and W. Wisden, “Function and Pharmacology of Multiple GABAA Receptor Subunits,” Trends in Pharmacological Sciences, Vol. 12, No. 2, 1991, pp. 49-51. doi:10.1016/0165-6147(91)90495-E
 G. Puia, S. Vicini, P. Seeburg and E. Costa, “Influence of Recombinant Gama-Aminobutyric Acid-A Receptor Subunit Composition on the Action of Allosteric Modulators of Gamma—Aminobutyric Acid-Gated Cl-Currents,” Molecular Pharmacology, Vol. 39, No. 6, 1991, pp. 691-696.
 A. Stevenson, P. B. Wingrove, P. J. Whiting and K. A. Wafford, “Beta-Carboline Gamma-Aminobutyric AcidA Receptor Inverse Agonists Modulate Gamma-Aminobutyric Acid via the Loreclezole Binding Site as Well as the Benzodiazepine Site,” Molecular Pharmacology, Vol. 48, No. 6, 1995, pp. 965-969.
 J. E. Kralic, T. K. O’ Buckley, R. T. Khisti, C. W. Hodge, G. E. Homanics and A. L. Morrow, “GABAA Receptor Alpha-1 Subunit Deletion Alters Receptor Subtype Assembly, Pharmacological and Behavioral Responses to Benzodiazepines and Zolpidem,” Neuropharmacology, Vol. 43, No. 4, 2002, pp. 685-694.
 U. Rudolph, F. Crestani, D. Benke, I. Brunig, J. A. Benson, J. M. Fritschy, J. R. Martin, H. Bluethmann and H. Mohler, “Benzodiazepine Actions Mediated by Specific γ-Aminobutyric AcidA Receptor Subtypes,” Nature, Vol. 401, No. 6755, 1999, pp. 796-800. doi:10.1038/44579
 A. Ableitner and A. Herz, “Changes in Local Cerebral Glucose Utilization Induced by the Beta-Carbolines FG 7142 and DMCM Reveal Brain Structures Involved in the Control of Anxiety and Seizure Activity,” The Journal of Neuroscience, Vol. 7, No. 4, 1987, pp. 1047-1055.
 D. Manahan-Vaughan and K. H. Braunewell, “Novelty Acquisition Is Associated with Induction of Hippocampal Long-Term Depression,” Proceedings of the National Academy of Science USA, Vol. 96, No. 15, 1999, pp. 8739-8744. doi:10.1073/pnas.96.15.8739
 V. Lemaire, C. Aurousseau, M. Le Moal and D. N. Abrous, “ Behavioural trait of reactivity to novelty is related to hippocampal neurogenesis,” European Journal of Neuroscience, Vol. 11, No. 11, 1999, pp. 4006-4014.
 K. Gale, “Progression and Generalization of Seizure Discharge: Anatomical and Neurochemical Substrates,” Epilepsia, Vol. 29, No. 2, 1988, pp. S15-S34.