piperidines and atipamezole

Prevention of epileptogenesis is an unmet need in medicine. During the last 3 years, however, several preclinical studies have demonstrated remarkable favorable effects of novel treatments on genetic and acquired epileptogenesis. These include the use of immunosuppressants and treatments that modify cellular adhesion, proliferation, and/or plasticity. In addition, the use of antiepileptic drugs in rats with genetic epilepsy or proconvulsants in acquired epilepsy models has provided somewhat unexpected favorable effects. This review summarizes these studies, and introduces some caveats when interpreting the data. In particular, the effect of genetic background, the severity of epileptogenic insult, the method and duration of seizure monitoring, and size of animal population are discussed. Furthermore, a novel scheme for defining epileptogenesis-related terms is presented.

Topics: Animals; Anticonvulsants; Epilepsy; Epilepsy, Post-Traumatic; Humans; Imidazoles; Immunosuppressive Agents; Piperidines; Pyrazoles; Rats; Rimonabant; Sirolimus; Status Epilepticus; Terminology as Topic

Topics: Adrenergic alpha-2 Receptor Antagonists; Animals; Anticonvulsants; Axons; Body Temperature; Brain; Drug Evaluation, Preclinical; Epilepsy, Post-Traumatic; Imidazoles; Male; Motor Activity; Neuronal Plasticity; Neuroprotective Agents; Piperidines; Proof of Concept Study; Pyrazoles; Random Allocation; Rats, Sprague-Dawley; Recovery of Function; Rimonabant; Seizures; Spatial Memory

The aim of this study was to characterize the modulation of synaptic transmission in the glutamatergic corticostriatal pathway by cholinergic and adrenergic receptors. In coronal slices of mouse brain, negative-going field potentials were recorded in the dorsal striatum in response to stimulation of the overlying white matter, and their susceptibility to various pharmacological manipulations was studied. The responses were mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors, since they were augmented by aniracetam (0.5-1.5 mM), a positive modulator of AMPA-type glutamate receptors, and blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (> or = 10 microM), a selective antagonist of AMPA receptors. Carbachol (10 microM), a muscarinic agonist, reduced the size of responses and abolished paired-pulse depression; these effects being consistent with previous studies indicating that muscarinic activation inhibits release of glutamate in the corticostriatal pathway. Muscarinic antagonists could block the effect of carbachol. Their rank order was: 10 microM scopolamine (a non-selective muscarinic antagonist) > or = 1 microM 4-diphenylacetoxy-N-methyl-piperidine (M3/M1 antagonist)>1 microM pirenzepine (M1 antagonist)>10 microM methoctramine (M2 antagonist). McN-A-343 (1-10 microM), an M1 muscarinic agonist, was ineffective in this preparation. In contrast, isoproterenol (10-30 microM), a beta-adrenergic agonist, slightly increased the synaptic responses, but it did not affect paired-pulse depression. None of alpha-adrenergic agents (30 nM-1.0 microM dexmedetomidine, an alpha2-adrenergic agonist, 0.3 microM atipamezole, an alpha2-adrenergic antagonist or 30 microM phenylephrine, an alpha1-adrenergic agonist) influenced the size of the responses; neither did these drugs alter paired-pulse depression. These results indicate that the activation of striatal M3-like muscarinic receptors and beta-adrenoceptors, but not M2-like muscarinic receptors and alpha-adrenoceptors, modulates directly corticostriatal glutamatergic neurotransmission.

Topics: (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; 6-Cyano-7-nitroquinoxaline-2,3-dione; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Adrenergic beta-Agonists; Adrenergic Fibers; Animals; Carbachol; Cerebral Cortex; Cholinergic Fibers; Corpus Striatum; Diamines; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; Glutamic Acid; Imidazoles; Isoproterenol; Male; Medetomidine; Mice; Mice, Inbred DBA; Muscarinic Agonists; Muscarinic Antagonists; Phenylephrine; Piperidines; Pirenzepine; Pyrrolidinones; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Receptors, AMPA; Receptors, Muscarinic; Scopolamine; Synaptic Transmission