OPPOSING PERSISTENT BEHAVIORAL EFFECTS OF PHYTO- AND ENDOCANNABINOIDS FOLLOWING CHRONIC DEVELOPMENTAL , BUT NOT ADULT , TREATMENTS

"The rate of adolescent Cannabis abuse is increasing for recreational purposes and it is thought to be linked to a range of developmental and social problems. Many studies have demonstrated effects of early Cannabis exposure to produce behavioral effects that persist through adulthood. However , the physiological changes in the CNS that must be responsible for this altered behavior remain poorly understood. Delta-9-tetrahydrocannabinol (THC) is a psychoactive cannabinoid isolated from Cannabis that exerts its effect by partially-activating cannabinoid receptors. Adolescence is a critical period for brain development and maturation. Zebra finches are songbirds that learn vocal patterns during a sensitive period of development that approximates adolescence. Exposure of these animals to a cannabinoid agonist during their period of sensorimotor vocal learning alters song patterns produced in adulthood. Thus , songbirds have unique value in studying developmental effects of drug exposure on a naturally learned behavior. We have adapted place preference methods to study cocaine reinforcement of behavior. Moreover , we pharmacologically manipulated 2- arachidonoyl glycerol (2-AG) levels using JLZ-184 (a selective inhibitor of MAG lipase , the enzyme responsible for degradation of 2-AG) to determine if augmentation of the endogenous cannabinoid signaling produced THC-like increased cocaine sensitivity. We have found that cocaine dose-dependently reinforces both place preference and aversion at potencies consistent with those observed in mammalian species. THC persistently increases sensitivity to cocaine through adulthood. However , developmental exposure to JZL-184 induced aversion. These effects were not observed following treatment of adults. Moreover , the expression of c-Fos (a marker of neuronal activity) was increased in Area X of striatum in THC-treated animals and nucleus taeniae of amygdala in JZL-184-treated animals. Also , elevated dopamine (DA) and 3 , 4-Dihydroxyphenylacetic acid (DOPAC) levels were observed in Area X and VTA only in animals that developmentally treated with THC. On the other hand , we have found that developmental chronic THC and JZL-184 exposure resulted in alteration of the song phonology that persist through adulthood. This indicates that normal endocannabinoid signaling is important to vocal learning , and agonism or antagonism of these processes disrupts this learning , indicating that a ""normal tone"" of cannabinoid signaling is required.