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

Abstract

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.