One of the most salient cognitive effects of THC is the impairment of learning and memory, a cognitive domain that is particularly important during adolescence given the academic and social demands experienced during that developmental period. It has recently become clear that adolescence is a period of unique neurobehavioral sensitivity to some drugs of abuse, though studies of this type with THC exposure during adolescence are conspicuously limited. This has been studied most extensively with ethanol, a drug that, like THC, powerfully impairs learning and learning-related CNS activity. Using animal models, we have shown that spatial learning, hippocampal long-term potentiation (LTP), and n-methyl-d-aspartate (NMDA) receptor-mediated synaptic activity are all inhibited by ethanol more potently in adolescence than in adulthood. Moreover, we have shown that chronic exposure to ethanol during adolescence produces enduring changes in the sensitivity of animals to the amnestic effects of ethanol, while no such long-lasting changes were observed after identical chronic exposure in adulthood. We have now collected preliminary data that strongly suggest similar developmental sensitivities to THC (see Section C, below). The first study indicates that adolescent rats may be more sensitive than adults to the acute effects of THC on spatial learning. The second study indicates that chronic exposure to THC during adolescence results in a long lasting compromise of spatial learning ability that is manifested well into adulthood. These preliminary data are strikingly consistent with the pattern of developmental effects that we have observed with ethanol. Therefore, our central hypothesis is that adolescent animals are more sensitive to the effects of both acute and chronic THC exposure, and that this sensitivity will be manifested in both behavioral learning and hippocampal function.
Specific Aim 1 of this application has two components that will extend our behavioral preliminary studies. We will first assess the acute effects of THC on spatial learning and memory in adolescent and adult rats of both genders. The second study will assess the effects of chronic THC exposure during adolescence or adulthood on subsequent spatial learning and memory, in the absence of acute drug treatment.
Specific Aims 2 &3 will use electrophysiological and biochemical techniques to test specific mechanisms that may underlie the behavioral effects we have observed in our preliminary data.
