Approximately 10 million persons a=use marijuana on a monthly or more frequent basis making it the most commonly used illicit drug. 2% of 12th graders use marijuana on a daily basis. Moreover, marijuana use at even younger ages (eight graders) increased a full percentage point in 1992. Healthy People 2000 refers to marijuana use as typifying the age-at-first- use phenomenon whereby its use prior to age 15 relates to its greater abuse and that of other drugs after 15. These facts coupled with the knowledge that psychoactive cannabinoids produce a myriad of behavioral effects and alterations in information processing within the CNS through actions at endogenous cannabinoid receptors requires that substantial efforts should be made to understand its effects on central nervous system function. The overall goal of these studies is to determine the mechanism(s) of action of the psychoactive cannabinoid, delta-9-tetrahydrocannabinol (delta-9-THC) on those dopamine containing systems thought to be pivotally involved in the reinforcing and psychotomimetic properties of drugs of abuse. Specifically, the effects of acute and chronic administration of delta-9- THC, and the endogenous brain constituent anandamide, on midbrain dopamine neurons (A9 & A10) have been selected for study. In the proposed experiments we will use single neuron extracellular recordings to determine the effects of various cannabinoids (psychoactive and non-psychoactive) on the rate and patterns of action potential generation, and importantly the effects of prolonged exposure to delta-9-THC on these parameters. In addition, intracellular recording from neurons in the in vitro midbrain slice preparation will be used to analyze the effects of acute and chronic delta-9-THC administration on neuronal membrane properties and excitability. These projects should enable us to characterize the consequences of delta-9-THC exposure on midbrain dopamine neurophysiology. The data derived from these experiments will provide information relevant to delta-9-THC's pharmacological effects on those dopamine neurons implicated in the emotional, cognitive and sensorimotor changes occurring with marijuana use.
