This article is a collaboration between MedPage Today and:

SAN DIEGO -- Metabolic and behavioral effects of cannabis in rats during adolescence were passed down to multiple generations of male offspring, even though these animals were not themselves exposed to the drug, a researcher said here.

Male rats born to parents who had received injections of tetrahydrocannabinol (THC) when young -- but reared by drug-naive surrogate rat mothers -- weighed more than otherwise similar rats whose parents received saline injections, yet showed less motivation to seek highly tasty foods, said Yasmin Hurd, PhD, of Mount Sinai School of Medicine in New York City.

Action Points Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Preliminary results from a follow-up study indicated that third-generation male offspring did not put on extra weight through their first 2 months of life, but did show differences in motivation to seek highly tasty food, as was seen in the second-generation rats, Hurd told attendees at the Society for Neuroscience's annual meeting.

Epigenetic analyses revealed numerous alterations induced by THC exposure in the founder rats (F0 generation), which might have passed down to offspring, Hurd suggested, although those studies have not been completed.

Hurd and colleagues were exploring the mechanisms that account for apparently permanent effects of temporary cannabis exposure seen in animals, which persist long after the exposure stops. Earlier studies in her lab had shown, for example, that dosing rats with THC during adolescence increased their interest in heroin self-administration during their adulthood.

Given the likelihood that epigenetics are involved, Hurd said the question naturally arose as to whether such changes may be heritable.

Her group gave intraperitoneal injections of 1.5 mg/kg of THC, translating to a low to moderate human dose, Hurd said, every 3 days to adolescent male and female Long-Evans rats. Another group of male and female rats were injected with saline on the same schedule.

When these rats were old enough for mating, they were paired within each group to produce an F1 generation of offspring. The pups were nursed by untreated female rats in case the cannabis exposure made the biological mothers poor parents, which might contaminate the study results, Hurd said.

The F1 rats and their offspring were never exposed to THC -- thus, any differences between the two groups of offspring must result from inheritance of changes induced in the F0 parents, Hurd said.

From early adolescence into adulthood (postnatal days 33 to 57), the F1 male offspring of THC-exposed parents weighed significantly (P<0.05) more on average than F1 offspring of saline-treated rats -- by approximately 10-15 grams at each weighing. At day 57, the difference in the male F1 rats was about 14 grams.

No weight difference was seen in F1 females. However, those born to THC-exposed parents showed other differences from those born to the F0 controls, including reduced motivation to seek a favored food (chocolate) and a lower movement activity when placed in a novel environment.

F1 males born to THC F0 parents showed a similar reduction in interest in chocolate, but were more inclined to self-administer heroin compared with F1 males from the control group. No difference between the F1 groups in novelty-seeking was seen in males, as opposed to females. F1 males in the THC group did show "an unusual avoidance behavior" when a bright light was flashed in their spaces.

Analysis of mRNA expression in male F1 rats born to THC-exposed parents versus controls indicated a downregulation in glutamatergic receptors, including NMDA as well as AMPA receptor types. This downregulation was seen only in adulthood and manifested as reductions in membrane-bound receptor proteins.

Another effect of the F0 THC exposure on male offspring was to increase long-term depression in the dorsal (but not ventral) striatum following electrical stimulation. This region is involved with habit formation and obsessive behaviors, Hurd said.

Finally, she said her lab had started to look into the specific epigenetic alternations that may be responsible for these findings.

"We're nowhere close to figuring out how it is that these mechanisms are passed on across generations," Hurd said.

However, analyses of the F0 animals indicated that more than 1,000 genomic regions were differentially methylated in the THC-exposed group versus the controls. About 40% were hypermethylated in the THC group and 60% showed diminished methylation. Approximately half of these loci were within gene bodies, Hurd said, and from 8% to 14% were in promoter regions.

Several of the specific genes affected were involved in excitatory pathways, which would dovetail with the differential expression and activity in the glutamatergic system. Since the latter appeared to be inherited, it seems probable that the epigenetic changes were as well, but that remains to be confirmed.

Hurd said her group had examined body weight and some behavioral parameters in F2 and F3 offspring -- that is, the great-grandkids of the original F0 mates. F3 males in the THC line weighed the same as their control-line counterparts, but their interest in seeking chocolate was impaired.