Animal Study Suggests Marijuana May Affect Future Offspring's Susceptibility to Heroin

Animal Study Suggests Marijuana May Affect
Future Offspring’s Susceptibility to Heroin
February 03, 2015
By Sarah Webb, Ph.D., NIDA Notes Contributing Writer
Can marijuana use put offspring at heightened risk for opiate addiction, even if the
use stops before the offspring are conceived? Recent animal research by NIDA-
supported scientists suggests that the answer may be yes.

Dr. Yasmin L. Hurd and colleagues at the Icahn School of Medicine at Mount Sinai in
New York City showed that rats whose parents had been exposed as adolescents to
the main psychoactive ingredient in marijuana sought heroin more vigorously than
the offspring of unexposed animals. Although more research is needed to confirm
and explain the findings, they are consistent with other studies suggesting that a
parent’s history of drug use, even preconception, may affect a child’s brain function
and behavior.

Lasting Imprint
Scientists have known for a while that drugs of abuse produce some of their effects
epigenetically—that is, by increasing or decreasing the rates at which the body’s
genetic machinery produces certain proteins. Researchers recently reported that
some epigenetic changes produced by cocaine appear to be inherited and affect the
behavior of subsequent generations. In that experiment, rats whose parents had
been exposed to cocaine responded differently when introduced to the drug than did
rats whose parents had not been exposed.
Dr. Hurd and colleagues hypothesized that rats whose parents were exposed as
adolescents to the main psychoactive ingredient in marijuana (delta-9
tetrahydrocannabinol, or THC) would inherit epigenetic changes that would alter
their responses to heroin. To test the hypothesis, the researchers injected
adolescent male and female rats with THC for 3 weeks on an intermittent schedule
(1.5 milligram per kilogram of body weight every 3 days) that corresponds to the
amounts consumed by a typical recreational marijuana user. They waited 2 to 4
weeks for the drug to wash out of the rats’ bodies, then paired and mated them.

Figure 1. Offspring of THC-Exposed Parents Work
Harder To Get Heroin When only a single press of a lever was required to obtain a dose
of heroin, the offspring of THC-exposed and unexposed rats self-administered similar
amounts of the drug. However, when the researchers raised the work requirement to 5 lever
presses for a single dose, the rats whose parents had been exposed to THC pressed almost 3
times as often as the offspring of unexposed rats.
Text Description of Graphic
When the offspring of these matings reached adulthood, the researchers presented
them with a lever that, when pressed, delivered heroin (30 micrograms per kilogram
of body weight). At first, the animals self-administered the drug at roughly the same
rates as a group of control animals whose parents had not been exposed to THC.
However, when the researchers made the animals work harder for the drug—
requiring them to press the active lever at least 5 times to receive a dose—those
whose parents had been exposed to the drug pressed on average nearly 3 times as
often as the control rats (see Figure 1).

When the researchers removed the animals’ access to heroin, the THC-exposed rats’
offspring exhibited more pronounced withdrawal symptoms, such as increased
locomotion and repetitive behaviors. Also during withdrawal, the two groups of rats
differed in their readiness to approach a novel stimulus in their environment.

                                Figure 2. Offspring of THC-Exposed Rats Show
Long-Term Depression of Synaptic Activity in the Striatum Medium spiny neurons
in the dorsal striatum of rats whose parents had been exposed to THC responded less to
electrophysiological stimulation than the neurons in rats whose parents had not been exposed

to THC.
Text Description of Graphic
Using electrophysiology, the researchers also demonstrated that the offspring of the
THC-exposed rats had altered neuronal functioning (see Figure 2). The specific
alteration that they observed—enhanced long-term synaptic depression of medium
spiny neurons in the dorsal striatum—has been associated with addiction in previous
studies. The neurons are less responsive to stimulation, which inhibits an individual’s
ability to adjust to experience and results in habitual and compulsive behaviors
rather than adaptive ones.

To identify the epigenetic factors that might underlie the differences they had
observed in the offspring of the THC-exposed animals, the researchers assayed
concentrations of messenger RNA (mRNA) for key proteins in the brain. The
formation of mRNA is the first step in the process of protein production, and mRNA
levels indicate how much protein is being produced at a given time. The researchers’
analysis showed that, during adolescence, the THC-exposed animals’ offspring had
higher levels of mRNA for glutamate receptors and for the cannabinoid 1 receptor in
the ventral striatum. During adulthood, the offspring of the THC-exposed rats had
less mRNA for N-methyl-D-aspartate (NMDA)-type glutamate receptors in the dorsal
striatum (see Figure 3). Reduced production of glutamate receptors could underlie
the reduced responsiveness to stimulation researchers observed in that brain region.

                                                             Figure 3. Offspring of
THC-Exposed Parents Show Decreased Expression of Genes for Key Receptor
Genes in the Brain Expression of genes for the glutamate-responsive receptors NMDA
(Grin1 and Grin2A) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) (Gria1)

and for the endocannabinoid receptor CB1 (CNR1) was lower in the dorsal striatum of adult
rats whose parents had been exposed to THC. These changes in gene expression suggest an
epigenetic effect of THC on glutamate and endocannabinoid signaling in the brain.
Text Description of Graphic
Is It Real?
The Mount Sinai researchers took pains to rule out potential nonepigenetic
explanations for the differences they observed between their groups of rats. One
concern was that the THC-exposed rats’ pups might themselves be exposed to the
drug during gestation, resulting in altered brain development. To preclude this
possibility, the researchers postponed mating their THC-exposed animals until
sensitive gas chromatography and mass spectrometry confirmed that no drug
remained in the animals’ blood or brain tissue. Another concern was that the THC-
exposed animals might parent differently than the unexposed animals, potentially
altering their offspring’s responses to heroin. To prevent this, the researchers
removed the THC-exposed animals’ pups from their parents immediately after birth
and had unexposed dams raise both groups of offspring in mixed litters.

Despite these careful controls, Dr. Hurd and colleagues say that they cannot
completely rule out nonepigenetic explanations for the alterations they observed in
their THC-exposed rats’ offspring until they see what happens in the next two
generations of their germ line. The researchers are proceeding with this work.

“The idea of cross-generational transmission of complex traits such as drug
responses without alterations to the genome is contentious,” says Dr. John
Satterlee, Project Officer at NIDA’sGenetics and Molecular Neurobiology Research
Branch. “Is it real? And if it’s real, how is it transmitted?” he asks.
Dr. Satterlee agrees with Dr. Hurd that studies on future generations are needed to
definitively rule out the possibility that nonepigenetic factors led to the observed
effects in the offspring. Previous exposure to THC theoretically could affect the
womb or placental formation, he says, or lead to changes in the parents’
microbiome—the assemblage of microorganisms in the gut controlling a variety of
conditions and behaviors—that were then transmitted to their offspring.

“If the effect is real, it’s important,” Dr. Satterlee says. “If studies show that
marijuana use also shows cross-generational effects in people, those results would
add to the known dangers of the drug and amplify the importance of prevention
efforts, especially those aimed at youth,” he adds.

This study was supported by NIH grants DA030359 and DA033660.

Source

Szutorisz, H.; DiNieri, J.A.; Sweet, E. et al. Parental THC exposure leads to
compulsive heroin-seeking and altered striatal synaptic plasticity in the subsequent
generation.Neuropsychopharmacology. 39(6):1315-1323, 2014. Abstract
Tags

   Heroin
   Marijuana
   Addiction Science
   Basic Science
   Genetics

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