Developmental treatments with Δ9- tetrahydrocannabinol and the MAGL inhibitor JZL184 persistently alter adult cocaine conditioning in contrasting ways

Using a songbird, zebra finches, as a developmental drug abuse model we found previously that cannabinoid agonists administered during the sensorimotor period of vocal learning (50-75 days of age) persistently alter song patterns and cocaine responsiveness in adulthood. However, these effects were not produced in adults exposed to similar treatment regimens. Currently, we have used the MAGL inhibitor, JZL184, to test whether enhanced endocannabinoid signaling may similarly alter cocaine responsiveness. We found that, as expected and consistent with prior results, repeated developmental (but not adult) treatments with Δ⁹-tetrahydrocannabinol (THC, 3 mg/kg QD IM) resulted in increased time spent in cocaine-paired chambers. Unexpectedly and in contrast, repeated developmental JZL184 (4 mg/kg QD IM) treatments decreased time spent in cocaine-conditioned chambers. That is, young finches repeatedly treated with JZL184 avoided cocaine-paired chambers later in adulthood, while similar development treatments with THC had the opposite effect. To begin to identify brain regions that may underly this differential responsiveness we used c-Fos expression as a marker of neuronal activity. Differences in c-Fos expression patterns following placement of cocaine-conditioned finches into vehicle- vs. cocaine-paired chambers suggest distinct involvement of circuits through striatal and amygdaloid regions in respective effects of THC and JZL184. Results demonstrate that, like exogenous cannabinoid exposure, inhibition of MAGL activity during late post-natal development persistently alters behavior in adulthood. Contrasting effects of THC vs. MAGL inhibition with JZL184 suggests the latter alters development of brain regions to favor promotion of aversive rather than appetitive cocaine responsiveness later in adulthood.