MK-801 prevents the increased NMDA-NR1 and NR2B subunits mRNA expression observed in the hippocampus of rats tolerant to diazepam.
The chronic diazepam administration in rats has been show from our previous results, to produce an increased synaptic plasticity. Furthermore, this occurs with a concomitant over expression of the mRNA NR1 and NR2B N-methyl-D-aspartate receptor subunits. MK-801, a non-competitive antagonist of N-methyl-D-aspartate receptor, impairs both the development of conditioned tolerance to diazepam and the hippocampal long-term potentiation generation. In the present study, we have further investigated the hippocampal glutamatergic transmission in the development of tolerance to diazepam. Our results demonstrate that the development of tolerance to the hypolocomotive effect of diazepam, along with the increased hippocampal synaptic plasticity and the associated over expression of the mRNA NR1 and NR2B N-methyl-D-aspartate receptor subunits, were blocked by previous MK-801 administration. We suggest that the participation of hippocampal glutamatergic transmission is relevant to increased hippocampal synaptic plasticity, the latter being a neurobiological mechanism behind the development of the conditioned tolerance to diazepam.
Almirón
Romina S
RS
Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, 5000 Córdoba, Argentina.
Pérez
Mariela F
MF
Ramírez
Oscar A
OA
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002452:Cell Count / Q000379:methods; D003975:Diazepam / Q000008:administration & dosage*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004347:Drug Interactions; D004361:Drug Tolerance; D004558:Electric Stimulation / Q000379:methods; D004594:Electrophysiology / Q000379:methods; D005071:Evoked Potentials / Q000187:drug effects / Q000528:radiation effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018757:GABA Modulators / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D017403:In Situ Hybridization / Q000379:methods; D017774:Long-Term Potentiation / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
D018691:Excitatory Amino Acid Antagonists; D018757:GABA Modulators; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D003975:Diazepam