Maternal cannabis vapor exposure dose-dependently impairs behavioral flexibility in adult offspring
Hayden R. Wright, Collin R. Warrick, Jacqulyn R. Kuyat, Joshua W. Rodriguez, Janelle M. Lugo, and Ryan J. McLaughlin

235.01

Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, USA

Background

Cannabis-exposed offspring exhibit dose-dependent impairments in strategy
shifting and committed more regressive and never-reinforced errors in adulthood

o Cannabis is the most commonly used illicit drug during pregnancy. As the number of states with legal
cannabis continues to increase, there has been a concomitant rise in reported use of cannabis among
pregnant women. Rates of past-month cannabis use among pregnant women have increased 62% from
2002 to 2014 (Brown et al. 2017).
o Human studies are sparse, but longitudinal studies (OPPS & MHPCD) have revealed a negative relationship
between maternal cannabis use and performance on tests involving higher-order cognitive functions such as
abstract and visual reasoning in offspring (Fried & Smith 2001).
o However, comorbid issues such as maternal use of alcohol and other drugs, insufficient prenatal care,
malnutrition, age of pregnancy, and differences in socioeconomic status can complicate interpretation of
human data. Thus, very little is known about the enduring effects of maternal cannabis use independent of
these extraneous factors.
o The primary objective of this study was to use a translationally relevant preclinical model to
determine the long-term effects of prenatal cannabis exposure on behavioral flexibility in male and
female offspring.

Visual Cue Discrimination

Shift Task

Reversal Task

Male
Female

Methods
o Female rats were passively exposed to vaporized cannabis extract (50 or 400mg/mL; 1 puff every 2 min for 1hr,
twice daily), vehicle vapor, or no vapor beginning at the onset of mating and continuing into gestation.
o Beginning on PND 55, offspring (n=6-9/treatment/sex) were trained to press levers for food reward and tested for
behavioral flexibility in an automated attentional set-shifting task using procedures described by Floresco et al.,
2008 (see behavioral flexibility timeline below for details).
o Data collected: Trials to criterion, number of errors, type of errors (Perseverative – inability to abandon old
strategy; Regressive – inability to maintain new strategy; Never Reinforced – inability to obtain new strategy)

Perseverative Errors

Regressive Errors

Never Reinforced Errors

Vapor Delivery System

Conclusions

Behavioral Flexibility
Handling/
Food Restriction

Lever Pressing
Shaping

Cue Discrimination

Retractable
Lever Training

Side Preference
Test
(same day as last
retractable lever training
session)

First Discrimination
(Visual Cue Rule)

Strategy Shift

Strategy Shift

Strategy
Reversal

o Prenatal cannabis exposure did not significantly affect acquisition of the visual cue discrimination strategy or performance
on the reversal learning task; however rats exposed to a high (but not a low) concentration of cannabis vapor took
significantly more trials to shift to an egocentric spatial strategy when compared to rats that were not exposed to any vapor.
o Rats exposed to high-dose cannabis vapor committed significantly more never-reinforced errors and regressive errors
compared to all other groups, which suggests a difficulty learning and maintaining a new strategy, respectively.
o The error phenotype seen in cannabis-exposed offspring is similar to that observed following nucleus accumbens core
inactivation (Floresco et al., 2006).
o These results show for the first time that rodent offspring exposed to cannabis during gestation may experience deficits in
flexible responding when rules dictating reinforcer delivery suddenly change.
o Exposure to cannabis vapor in utero may cause alterations in brain development that can negatively impact cognitive
flexibility in adulthood.

Strategy Reversal

References
o
o
o
o

Press the lever that corresponds to
the illuminated cue light to receive a
food reward

Disregard the previously acquired
strategy and learn to press the lever
opposite their side preference

Press the lever opposite of the
previous task (toward side
preference)

Brown, Q. L., Sarvet, A. L., Shmulewitz, D., Martins, S. S., Wall, M. M., & Hasin, D. S. (2017). Trends in marijuana use among pregnant and nonpregnant reproductive-aged women,
2002-2014. JAMA, 317(2), 207-209.
Fried PA, Smith AM. A literature review of the consequences of prenatal marihuana exposure. An emerging theme of a deficiency in aspects of executive function. Neurotoxicol Teratol.
2001 Jan-Feb;23(1):1-11.
Floresco, S.B., Block, A.E., Tse, M.T. 2008. Inactivation of the medial prefrontal cortex of the rat impairs strategy set-shifting, but not reversal learning, using a novel, automated
procedure. Behav Brain Res, 190(1): 85-96.
Floresco, S. B., Ghods-Sharifi, S., Vexelman, C., & Magyar, O. (2006). Dissociable roles for the nucleus accumbens core and shell in regulating set shifting. Journal of Neuroscience,
26(9), 2449-2457.

This study was supported in part by funds provided for medical and biological research by the State of Washington Initiative Measure No. 171.