Developmental Pharmacology of Cannabinoids

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DESCRIPTION (provided by applicant): Adolescence represents a developmental time point during which substance abuse often begins. Although the most prevalently used illicit drug during adolescence is marijuana, little is known about short- or long-term effects of its use during development. The major hypotheses of this proposal are that (1) developing animals will be more sensitive to the effects of delta9-tetrahydrocannabinol (delta9-THC), the primary psychoactive constituent of marijuana, than are adult animals and (2) chronic dosing with delta9-THC during development will produce long-term changes in response to challenges with cannabinoids in later life such that animals are less sensitive to the effects of cannabinoids. In order to test the first hypothesis, rats of different ages (postnatal day 22 to adult) will be administered acute doses of delta9-THC; subsequently, they will be evaluated in vivo procedures designed to measure cannabinoid activity (locomotion, body temperature, antinociception, and catalepsy). In addition, we will investigate the role of metabolism in any observed age differences in pharmacological effects. In order to test the second hypothesis, rats will be chronically injected with delta9-THC during development. After reaching adulthood, these animals will be evaluated in behavioral procedures to evaluate cannabinoid sensitivity, cognition, timing ability, and the reinforcing efficacy of food. In addition to baseline activity in these procedures, the effects of challenges with delta9-THC and other cannabinoids will also be assessed in the rats. In order to determine possible underlying changes in cannabinoid (CB1) receptor binding and distribution, autoradiography of the brains of rats that received identical chronic injection regimens will be performed using [3H]SR141716A as a radioligand. In addition, functioning of these receptors will be measured through use of [35S]GTPgammaS binding. The proposed studies will provide empirical information on acute and long-term effects of delta9-THC on the developing brain and behavior. This information may also help to provide a more rational basis for making treatment decisions concerning adolescents who abuse marijuana.