This topic involves gene-environment interactions. The environmental signal is Δ9-tetrahydrocannabinol exposure (THC) to the male rat prior to mating; response in the offspring’s brain to the signal represents changes in phenotype, probably reflecting epigenetic effects caused by the THC. Authors [see attached article] exposed males for 28 days to THC at “doses commensurate with moderate cannabis use in humans,” mated them to drug-naïve females, and then assessed biomarkers of acetylcholine (ACh) synaptic function in the offspring; evaluations were conducted longitudinally from adolescence through adulthood — so as to capture early and late stages of brain development and function; assessments were carried out in brain regions comprising all the major ACh projections and their corresponding cell bodies. Authors specifically focused on ACh systems — which provide essential inputs for learning, memory, reward, and mood.
Authors measured presynaptic high-affinity choline transporter SLC5A7 (hemicholinium-3, or HC3-binding), choline acetyl-transferase (ChAT) activity, and α4β2 nicotinic ACh receptor (nAChR) concentrations. SLC5A7 and ChAT are both constitutive components of ACh nerve terminals, but they differ in regulatory mechanisms and hence in their functional significance. ChAT is the enzyme that synthesizes ACh, but it is not regulated by nerve impulse activity, so that its presence provides an index of the density of ACh innervation. In contrast, HC3-binding to SLC5A7 directly affects neuronal activity. Thus, comparative effects on HC3-binding and ChAT enable characterization of both the concentration of ACh terminals and presynaptic impulse activity.
Authors then calculated the HC3/ChAT ratio as an index of presynaptic activity, relative to the number of cholinergic nerve terminals. Finally, the α4β2 nAChR is the most abundant subtype in mammalian brain and regulates the ability of ACh systems to release other neurotransmitters involved in reward, cognition, and mood. These indices have been used successfully to characterize the impact of diverse neurotoxicants and diseases on ACh systems: neuroactive pesticides, nicotine or tobacco smoke, polycyclic aromatic hydrocarbons and glucocorticoids — as well as terminal stages of Alzheimer disease.
Authors [see attached article] found that THC produces a dose-dependent deficit in HC3-binding (index of presynaptic ACh activity), superimposed on regionally-selective increases in ChAT activity (biomarker for numbers of ACh terminals). The combined effects produce persistent decreases in the HC3/ChAT ratio (index of impulse activity per nerve terminal). At the low THC dose (2 mg/kg/day), decreased presynaptic activity was partially compensated by up-regulation of nAChRs, whereas at the high THC dose (4 mg/kg/day), nAChRs were subnormal, an effect that exacerbates the presynaptic defect. Overlaid on these effects, either dose of THC also accelerated the age-related decline in nAChRs. These data provide evidence for adverse effects of paternal THC administration on neurodevelopment in subsequent offspring and further demonstrate that adverse impacts of drug exposure on brain development are not limited to effects mediated by the in utero chemical environment, but rather that vulnerability can even be created by exposures occurring prior to conception, and involving the father as well as the mother [wa-a-a-ay too cool, man]. 😉
Toxicol Sci Apr 2020; 174: 210-217