ABSTRACT
In the present paper, we analyzed the effects of hippocampal mGluR1 on the consolidation of a fear-conditioned response and on hippocampal glutamate and GABA concentration in rats subjected to the chemically-induced kindling of seizures. We hypothesized the important role of this glutamate receptor subpopulation in behavioural disturbances accompanying epilepsy. To this end, the behavioural and biochemical effects of selective mGluR1 and 5 receptor ligands were compared in sham and kindled animals (pentylenetetrazol-induced seizures). It was found that despite the fact that the freezing response to the aversively conditioned context was not changed by kindling itself, post-training intrahippocampal (dentate gyrus) injection of AIDA (a mGluR1 antagonist) oppositely influenced rat freezing behaviour in the non-kindled and kindled animals (i.e. the receptor ligand increased and decreased duration of the fear reaction, respectively). Kindling of seizures also enhanced the Glutamate/GABA ratio in the dorsal hippocampus (in vivo microdialysis), indicating an enhancement of excitatory processes in the brain. Altogether, the results showed that kindling of seizures led the potentiation of excitatory processes in the hippocampus, changing the role of the local mGluRs1 population in the conditioned fear learning.
Subject(s)
Conditioning, Psychological/physiology , Epilepsy/metabolism , Fear/physiology , Hippocampus/metabolism , Kindling, Neurologic/metabolism , Receptors, Metabotropic Glutamate/metabolism , Animals , Brain Chemistry/drug effects , Brain Chemistry/physiology , Conditioning, Psychological/drug effects , Convulsants , Epilepsy/chemically induced , Epilepsy/physiopathology , Excitatory Amino Acid Antagonists/pharmacology , Extracellular Fluid/metabolism , Fear/drug effects , Glutamic Acid/analysis , Glutamic Acid/metabolism , Hippocampus/drug effects , Hippocampus/physiopathology , Kindling, Neurologic/drug effects , Learning/physiology , Male , Microdialysis , Rats , Rats, Wistar , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , gamma-Aminobutyric Acid/analysis , gamma-Aminobutyric Acid/metabolismABSTRACT
The aim of the present study was to analyze biochemical effects of a neurosteroid, pregnenolone sulfate (PS), which accompany changes in the threshold of seizures, and to establish the contribution of local, hippocampal monoaminergic and amino acid systems, to the control of convulsive activity. Pretreatment of mice with PS (intracerebroventricularly) selectively enhanced the potency of peripherally (intraperitoneally) administered NMDA at the LD16 (88.0 mg/kg) to induce clonic-tonic convulsions (PS, LD84 = 184.7 nM; 95% CL = 181.4-188.1). The proconvulsive actions of picrotoxin and bicuculline, the GABA-A receptor antagonists, were not modified by pretreatment of mice with PS. Administration of PS alone (up to 240 nM icv) did not show any seizure-like activity. PS given at LD84, together with NMDA (at the LD16), increased the hippocampal concentration of alanine, and enhanced local metabolism of dopamine in a period immediately preceding the onset of seizures significantly stronger than did NMDA alone. These and other data indicate that the enhancement by PS of hippocampal levels of alanine may contribute to the seizures development as this amino acid is a precursor of glutamate, and a co-agonist of the NMDA receptors. On the other hand, simultaneously occurring stimulation of hippocampal dopaminergic system may be considered a compensatory phenomenon, limiting seizures propagation through the limbic forebrain. Summarizing, our results show that PS-induced potentiation of NMDA seizures is accompanied by selective changes in hippocampal dopamine turnover and alanine concentration.
Subject(s)
Alanine/metabolism , Dopamine/metabolism , Excitatory Amino Acid Agonists/pharmacology , Hippocampus/metabolism , N-Methylaspartate/pharmacology , Pregnenolone/pharmacology , Amino Acids/metabolism , Animals , Bicuculline/administration & dosage , Bicuculline/pharmacology , Convulsants/administration & dosage , Convulsants/pharmacology , Dose-Response Relationship, Drug , Hippocampus/drug effects , Male , Mice , Microinjections , Picrotoxin/administration & dosage , Picrotoxin/pharmacology , Seizures/physiopathologyABSTRACT
The present study was aimed at determining the changes in the 5-HT transporter activity, in different brain structures after pentylenetetrazol induced kindling of seizures. We examined [3H]-citalopram binding in the rat brain structures, and the neurodegenerative effects in the hippocampal formation using autoradiographic and immunohistochemical methods. A statistically significant and selective reduction in the binding of [3H]-citalopram was found in the CA3 field of the hippocampus (P=0.009), and a similar tendency, close to the significance level, in the dentate gyrus (P=0.05). This effect was accompanied by a loss of neurons and activation of microglia in the hippocampal formation. The present data suggest the important role for CA3- serotonergic innervation in pentylenetetrazol induced kindling of seizures.
