There are two main purposes of the proposed research. The first is to continue to investigate the acute effects of single isolated exposure to low concentrations of cannabinoids on central nervous system function in a behaving rat model. Research in the prior funding period has shown that the psychoactive ingredient in marijuana, delta-9-tetrahydrocannabinol (THC) produces marked changes in the sensory responses of the hippocampus in the form of suppressed auditory evoked potentials and unitary discharges to a conditioned tone stimulus following a single injection of 1.0-2.0 mg/kg of delta-9-THC. This disruption coincides with a slowing of behavioral responding and a decreased accuracy of performance in a successive two-tone frequency discrimination task. Evidence was obtained which showed that recovery of both behavior and electrophysiological responses in the hippocampus is fairly rapid occurring within 2-4 hours following initial exposure. In the current research plan these effects will be further investigated both with respect to specificity of cannabinoid action and differential effects on identified neural processes within the dentate action and differential effects on identified neural processes within the dentate gyrus of the rat hippocampus. The second purpose of the proposed research plan is to continue to investigate the effects of long-term exposure to moderate dose levels of delta-9-THC. In prior experiments it was shown that rats developed a rapid tolerance (within 5-7 days) to 10 mg/kg doses of THC in terms of the electrophysiologic and behavioral measures described above. Continued exposure to the compound at the same 10 mg/kg dose for a total of 25-30 days produced no change in tolerance. Abstinence withdrawal effected a """"""""reversal"""""""" of tone evoked potential amplitudes relative to tolerant and control levels. However, it was delayed at least 5 days and extended for at least 16 days after termination of chronic THC treatment. This """"""""residual"""""""" rebound-like effect on well characterized hippocampal mechanisms resembled closely the acute effects of the compound in terms of the directional changes produced in sensory evoked potential amplitudes. Studies are described in the current research plan to investigate more thoroughly the neurobiological and behavioral implications of these residual occurrences following long-term exposure to the psychoactive ingredient in marijuana.
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