Pharmacokinetic and pharmacodynamic properties of aerosolized ("vaped") THC in adolescent male and female rats.

RATIONALE: Adolescent exposure to ∆9-tetrahydrocannabinol (THC), the psychotropic constituent of cannabis, might affect brain development, and in rodent models leads to long-term behavioral and physiological alterations. Yet, the basic pharmacology of this drug in adolescent rodents, especially when ingested via ecologically relevant routes like aerosol inhalation, commonly referred to as "vaping," is still poorly characterized. Moreover, sex differences exist in THC metabolism, kinetics, and behavioral effects, but these have not been rigorously examined after vapor dosing in adolescents. OBJECTIVES: We investigated the pharmacokinetics and pharmacodynamics of aerosolized THC (30 min inhalation exposure, 25 or 100 mg/ml) in adolescent Wistar rats of both sexes. METHODS: Liquid chromatography/mass spectrometry analysis of THC and its major metabolites was conducted on blood plasma and brain tissue at 5, 30, 60, and 120 min following a 30-min aerosol dosing session. Effects on activity in a novel environment for 120 min after aerosol, and temperature, were measured in separate rats. RESULTS: We found sex-dependent differences in the pharmacokinetics of THC and its active (11-OH-THC) and inactive (11-COOH-THC) metabolites in the blood and brain, along with dose- and sex-dependent effects on anxiety-like and exploratory behaviors; namely, greater 11-OH-THC levels accompanied by greater behavioral effects in females at the low dose but similar hypothermic effects in both sexes at the high dose. CONCLUSIONS: These results provide a benchmark for dosing adolescent rats with aerosolized (or "vaped") THC, which could facilitate adoption by other labs of this potentially human-relevant THC exposure model to understand cannabis effects on the developing brain.

Differential expression of vasopressin, oxytocin and corticotrophin-releasing hormone messenger RNA in the paraventricular nucleus of the prairie vole brain following stress.

Forced swimming, as an effective stressor, has been found to facilitate the development of pair bonds in male but to interfere with this behaviour in female prairie voles (Microtus ochrogaster). In the present study, we found that forced swimming differentially influenced the expression of messenger RNA for vasopressin, oxytocin and corticotrophin-releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN) in the prairie vole brain. Forced swimming did not alter vasopressin mRNA labelling, but did induce a sustained decrease in oxytocin mRNA labelling and a progressive increase in CRH mRNA labelling in the PVN. The elevated CRH mRNA labelling appeared to be due to an increased number of cells synthesizing CRH mRNA and an enhanced ability of individual cells to produce CRH mRNA. Male and female prairie voles did not differ in the vasopressin, oxytocin or CRH mRNA expression either at the basal levels or in response to swimming stress. Together, these data indicate that the hypothalamic response of vasopressin, oxytocin and CRH messenger RNAs to swimming stress is regulated by distinct transcriptional factors. In addition, it seems unlikely that these changes are involved directly in the sex differences in pair bond formation.

Ontogeny of brain-derived neurotrophic factor gene expression in the forebrain of prairie and montane voles.

Brain-derived neurotrophic factor (BDNF) plays an important role in normal brain development. In the present study, we examined the ontogenetic pattern of BDNF gene expression in both monogamous prairie voles (Microtus ochrogaster) and promiscuous montane voles (M. montanus); two closely related microtine rodents that differ in life strategy and social behavior. In both species, BDNF mRNA showed an early appearance and a transient expression in a regionally specific manner. In the dentate gyrus and CA3 region of the hippocampus, BDNF mRNA was found neonatally, increased gradually during development, and reached a peak at weaning, followed by a subsequent decline to the adult level. In the paraventricular nucleus of the hypothalamus, levels of BDNF mRNA persisted until weaning, followed by a significant increase to the adult levels at 3 months of age. BDNF mRNA also demonstrated a species-specific developmental pattern. In the cingulate cortex, BDNF mRNA labeling displayed a transient increase in the second and third postnatal weeks followed by a subsequent decrease to the adult level in prairie voles, but persisted throughout the course of development in montane voles. In general, montane voles achieved an adult pattern of BDNF mRNA expression earlier than did prairie voles. Together, these data indicate that BDNF may function differently in infant and adult brains, and that the two species of voles differ in the ontogenetic pattern of BDNF mRNA expression in a regional-specific manner, which may be associated with their different life strategy and brain and behavioral development.

Expression and estrogen regulation of brain-derived neurotrophic factor gene and protein in the forebrain of female prairie voles.

Brain-derived neurotrophic factor (BDNF) has been linked to the development, differentiation, and plasticity of the central nervous system. In the present study, we first used a highly specific affinity-purified antibody and a cRNA probe to generate a detailed mapping of BDNF immunoreactive (BDNF-ir) staining and mRNA labeling throughout the forebrain of female prairie voles. Our data revealed that (1) BDNF-ir cells were present essentially in the brain regions in which BDNF mRNA-labeled cells were found; (2) BDNF-ir fibers were distributed extensively throughout many forebrain regions; and (3) BDNF mRNA was also detected in some thalamic regions in which BDNF-ir fibers, but not immunostained cells, were present. With few exceptions, the distribution pattern of BDNF in the vole brain generally resembled the pattern found in rats. In a second experiment, we examined the effects of estrogen on BDNF expression. Ovariectomized prairie voles that were treated with estradiol benzoate had a higher level of BDNF mRNA labeling in the dentate gyrus and CA3 region of the hippocampus, as well as in the basolateral nucleus of the amygdala, than did ovariectomized voles that were treated with vehicle. In addition, estrogen treatment increased the density of BDNF-ir fibers in the lateral septum, dorsolateral area of the bed nucleus of the stria terminalis, and lateral habenular nucleus. These data suggest that estrogen may regulate BDNF at the level of gene and protein expression, and thus, BDNF may be in a position to mediate the effects of estrogen on the brain of the prairie vole.