An initial series of studies will investigate basic physiological actions of norephrine (NE) and serotonin (5-HT) in the somatosensory and visual areas of the rat cerebral cortex. The goal of these studies is to establish a basis for assessing noradrenergic and serotonergic function in two animal models of epilepsy; cortically kindled and genetically epilepsy prone (GEPR) rats. Furthermore, tests used to examine biogenic amine function can be employed to clarify the mode of anticonvulsant drug action at synaptic levels within central neuronal circuits. A combination of microiontophoretic techniques, stimulation of biogenic amine, visual and somatosensory afferent pathways and computer assisted analysis of peri-event histograms will be employed to quantitatively assess the effects of NE, 5-HT and several anti-epileptic agents on cerebrocortical neuronal responsiveness to synaptic inputs and putative transmitter substances. The primary concept to be tested is that NE and 5-HT exert modulatory influences on synaptic efficacy within the cerebral cortex. Specific studies in seizure prone animals will use the same protocols to assay for an alteration in cerebrocortical biogenic amine function which might correlate with increased susceptibility for convulsive episodes. Anticonvulsant drug effects on synaptically mediated and transmitter induced cortical neuronal responses will be compared with NE/5-HT actions to determine if these compounds share in common mechanisms to modify transmission of information through neocortical circuits. Additional studies will use the 14C-2-deoxy-D-glucose (2-DG) technique in conjunction with a computer-based neuroanatomical image analysis system to determine glucose utilization patterns in the brains of normal and seizure susceptible animals before and after presentation of seizure-inducing stimuli and anticonvulsant drug administration.
The aim of these studies will be to correlate regional differences in glucose metabolism, particularly in the monoamine nucleii and their target structures in the CNS, with seizure susceptibility and anti-epileptic drug efficacy. The proposed research will contribute to a basic understanding of noradrenergic and serotonergic function in the cerebral cortex and clarify the role of these biogenic amines in seizure disorders and mechanisms of anticonvulsant drug action.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS018081-05
Application #
3398135
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1982-01-01
Project End
1987-01-31
Budget Start
1986-07-01
Budget End
1987-01-31
Support Year
5
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Mouradian, R D; Sessler, F M; Waterhouse, B D (1991) Noradrenergic potentiation of excitatory transmitter action in cerebrocortical slices: evidence for mediation by an alpha 1 receptor-linked second messenger pathway. Brain Res 546:83-95
Woodward, D J; Moises, H C; Waterhouse, B D et al. (1991) Modulatory actions of norepinephrine on neural circuits. Adv Exp Med Biol 287:193-208
Waterhouse, B D; Azizi, S A; Burne, R A et al. (1990) Modulation of rat cortical area 17 neuronal responses to moving visual stimuli during norepinephrine and serotonin microiontophoresis. Brain Res 514:276-92
Sessler, F M; Mouradian, R D; Cheng, J T et al. (1989) Noradrenergic potentiation of cerebellar Purkinje cell responses to GABA: evidence for mediation through the beta-adrenoceptor-coupled cyclic AMP system. Brain Res 499:27-38
Sessler, F M; Cheng, J T; Waterhouse, B D (1988) Electrophysiological actions of norepinephrine in rat lateral hypothalamus. I. Norepinephrine-induced modulation of LH neuronal responsiveness to afferent synaptic inputs and putative neurotransmitters. Brain Res 446:77-89
Smith, S S; Waterhouse, B D; Woodward, D J (1988) Locally applied estrogens potentiate glutamate-evoked excitation of cerebellar Purkinje cells. Brain Res 475:272-82
Cheng, J T; Sessler, F M; Azizi, S A et al. (1988) Electrophysiological actions of norepinephrine in rat lateral hypothalamus. II. An in vitro study of the effects of iontophoretically applied norepinephrine on LH neuronal responses to gamma-aminobutyric acid (GABA). Brain Res 446:90-105
Smith, S S; Waterhouse, B D; Woodward, D J (1987) Sex steroid effects on extrahypothalamic CNS. I. Estrogen augments neuronal responsiveness to iontophoretically applied glutamate in the cerebellum. Brain Res 422:40-51
Smith, S S; Waterhouse, B D; Woodward, D J (1987) Sex steroid effects on extrahypothalamic CNS. II. Progesterone, alone and in combination with estrogen, modulates cerebellar responses to amino acid neurotransmitters. Brain Res 422:52-62
Smith, S S; Waterhouse, B D; Woodward, D J (1987) Locally applied progesterone metabolites alter neuronal responsiveness in the cerebellum. Brain Res Bull 18:739-47

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