Prenatal Delta(9)-tetrahydrocannabinol exposure modifies proenkephalin gene expression in the fetal rat brain: sex-dependent differences.

Perinatal Delta(9)-tetrahydrocannabinol (Delta(9)-THC) exposure in rats resulted in enhanced morphine self-administration behavior, naloxone-precipitated withdrawal signs or changes in pain sensitivity, which have been related to changes in micro-opioid receptor binding and/or proenkephalin mRNA levels in several brain regions. However, despite exposure of these animals to Delta(9)-THC from fetal ages, the effects were studied only when animals matured, whereas there is no study on possible changes caused by this cannabinoid during the prenatal ontogeny of opioidergic neurons. The purpose of the present study was to examine the changes in proenkephalin mRNA levels, measured by using in situ hybridization, in several brain nuclei of rat fetuses that had been daily exposed to Delta(9)-THC from the 5th day of gestation. Results were as follows. Prenatal Delta(9)-THC exposure altered proenkephalin mRNA levels in most of the brain areas studied at different fetal ages, but the effects were different between sexes. Thus, proenkephalin mRNA levels increased in females, but decreased in males that had been prenatally exposed to Delta(9)-THC. This was observed in the caudate-putamen, hypothalamic paraventricular and ventromedial nuclei and cerebral cortex. No changes were observed, however, in the subventricular zones of the caudate-putamen, neocortex and nucleus accumbens. In summary, prenatal Delta(9)-THC exposure produced a sex-dependent effect in proenkephalin mRNA levels in several brain structures of rat fetuses.