The proposed research project is designed to investigate the mechanism and distribution of action of delta-9-tetrahydrocannabinol (THC - a major psychoactive constituent of marihuana) in the rodent brain. THC is a potent excitatory neuromodulator of hippocampal activity in picomolar concentrations and appears to act at membrane-active estrogen receptors in hippocampus. We propose to examine this hypothesis and determine which other brain areas display this neuromodulation. The role of membrane-acting estrogen receptors will be studied using estrogen antagonists to see if they can also block the THC effect in hippocampal slice preparations. This hypothesis will also be tested by castrating male rats and priming them with heterotypic or homotypic gonadal steroids, a treatment that alters the cellular response to applied estrogen. If the membrane-acting estrogen receptor is involved, we expect to see a THC effect only in the group primed with the heterotypic steroid. Brain localization will be determined electrophysiologically following an autoradiography uptake study to identify regions concentrating the labeled THC. This data will also allow us to evaluate the nature of the estrogen receptor hypothesis by comparing the distribution of THC neuromodulation to the known distribution of estrogen cytosol receptors. Since an estrogen receptor appears to mediate the THC effect, we shall examine the nature of the THC neuromodulation in hippocampus of female rats tested in various stages of the estrous cycle. Other localization studies will attempt to determine if cholinergic systems are preferentially affected by THC and will examine the cellular locus of THC neuromodulation. The demonstrated hippocampal THC neuromodulation may be related to the human effects of THC intoxication on learning, memory and emotionality. The role of THC in cortical regions may similarly be related to the cognitive and perceptual alterations noted in human experience with this drug.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA003755-01A1
Application #
3208362
Study Section
(DABA)
Project Start
1985-07-01
Project End
1987-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Northeast Ohio Medical University
Department
Type
Schools of Medicine
DUNS #
City
Rootstown
State
OH
Country
United States
Zip Code
44272
Fountain, S B; Teyler, T J (2001) Suppression of hippocampal slice excitability by 2-, 3-, and 4-methylpyridine. Ecotoxicol Environ Saf 48:301-5
Berry, R L; Nowicky, A; Teyler, T J (1990) A slice preparation preserving the callosal projection to contralateral visual cortex. J Neurosci Methods 33:171-8
Grover, L M; Teyler, T J (1990) Effects of extracellular potassium concentration and postsynaptic membrane potential on calcium-induced potentiation in area CA1 of rat hippocampus. Brain Res 506:53-61
Berry, R L; Teyler, T J; Han, T Z (1989) Induction of LTP in rat primary visual cortex: tetanus parameters. Brain Res 481:221-7
Teyler, T J; Perkins 4th, A T; Harris, K M (1989) The development of long-term potentiation in hippocampus and neocortex. Neuropsychologia 27:31-9
Fountain, S B; Ting, Y L; Hennes, S K et al. (1988) Triethyltin exposure suppresses synaptic transmission in area CA1 of the rat hippocampal slice. Neurotoxicol Teratol 10:539-48
Fountain, S B; Hennes, S K; Teyler, T J (1988) Aspartame exposure and in vitro hippocampal slice excitability and plasticity. Fundam Appl Toxicol 11:221-8
Perkins 4th, A T; Teyler, T J (1988) A critical period for long-term potentiation in the developing rat visual cortex. Brain Res 439:222-9
Vaknin, G; DiScenna, P G; Teyler, T J (1988) A method for calculating current source density (CSD) analysis without resorting to recording sites outside the sampling volume. J Neurosci Methods 24:131-5
Teyler, T J; Fountain, S B (1987) Neuronal plasticity in the mammalian brain: relevance to behavioral learning and memory. Child Dev 58:698-712

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