Oxycodone decreases anxiety-like behavior in the elevated plus-maze test in male and female rats

Adriaan W. Bruijnzeel, Azin Behnood-Rod, Wendi Malphurs, Ranjithkumar Chellian, Robert M. Caudle, Marcelo Febo, Barry Setlow, John K. Neubert

Preprint posted on 3 December 2021

Article now published in Behavioural Pharmacology at

Oxycodone-induced anxiolysis in rats: sex matters

Selected by Nándor Lipták


Addiction to prescription-required opioids is a regrettably common problem in the United States (Kertesz & Gordon 2019). Oxycodone is a derivative of the opium alkaloid thebaine, which can be extracted from Papaver somniferum and other species of the Papaver genus (Aceto et al. 1999). Oxycodone, under the brand name of Oxycontin, was one the most frequently prescribed and misused opioid in the United States, between 2015-2019 (Khouja et al. 2021). Similarly to thebaine, oxycodone can bind to mu, kappa and delta opioid receptors (Nielsen et al. 2007) and may alter a wide range of physiological functions, including stress, anxiety, pain or reward.

Oxycodone self-administration methods in rats were used for modelling human usage in previous studies. Pretreatment with D3 dopamine partial agonists/antagonist decreased oxycodone self-intake in males (You et al. 2017). Significant differences between sexes were revealed in further studies: female rats were more susceptible to oxycodone addiction than males (Zanni et al. 2020; Sharp et al. 2021).

Oxycontin was also prescribed for patients with anxiety disorder (Martins et al. 2009), but the effect of oxycodone on anxiety in rats has not been revealed so far.

The main goal of this preprint was to study the effect of oxycodone on anxiety-like behavior and locomotor activity in rats, using two behavioral assays, small open-field and elevated plus maze (EPM).

Key findings

Female and male Sprague Dawley rats were injected with different doses of oxycodone (0 to 1 mg/kg, intraperitoneal, i.p.), after which EPM and small open-field tests were conducted.

Less time spent in the open arms and less entries into the open arms are associated with anxiety in the EPM. The locomotor activity of rats was also monitored during both tests.


Locomotor activity

Neither horizontal nor vertical activity were affected by oxycodone in the small open-field test. Females traveled a greater distance compared with the males in EPM, indicating a sex-specific response, in line with a previous study with Wistar rats by the same research group (Knight et al. 2021). Oxycodone also increased the total distance in the EPM, but the sex-treatment interaction was not significant.


Anxiety-like behavior

In the EPM, oxycodone induced a greater increase in the percentage of open arm entries in the males, compared to the females. In this parameter, the sex-treatment interaction was significant.

In contrast to these results, the open arm time percentage was significantly increased by oxycodone, but sex-treatment interaction was not significant.


Why I liked this preprint

It is a concise preprint about a very important topic with far-reaching impact: oxycodone addiction. In addition, the statistical probes were chosen appropriately.




Questions for the authors

  1. I.p. injection of oxycodone is not a widely spread route of administration in humans. Why did you choose this type of administration instead of self-administration, like in the previous studies? (please see references)
  2. Open-field is an accepted method for studying anxiety in rats, but usually in a bigger open-field arena, e.g., 60 cm x 60 cm x 60 cm (width x length x height) (Carlini et al. 2002); 57 cm x 57 cm x 39 cm (Liebsch et al. 1998), etc. What were the advantages of the utilization of the small open-field?
  3. Total activity (total number of entries into any arm) is a conventional parameter for measuring locomotor activity in the EPM. Were the statistics of total activity in the EPM similar as you observed in total distance traveled parameter?




Aceto M.D., Harris L.S., Abood M.E. & Rice K.C. (1999) Stereoselective mu- and delta-opioid receptor-related antinociception and binding with (+)-thebaine. Eur J Pharmacol 365, 143-7.

Carlini V.P., Monzon M.E., Varas M.M., Cragnolini A.B., Schioth H.B., Scimonelli T.N. & de Barioglio S.R. (2002) Ghrelin increases anxiety-like behavior and memory retention in rats. Biochemical and Biophysical Research Communications 299, 739-43.

Kertesz S.G. & Gordon A.J. (2019) A crisis of opioids and the limits of prescription control: United States. Addiction 114, 169-80.

Khouja T., Tadrous M., Matusiak L. & Suda K. (2021) Opioid Prescribing in United States Health Systems, 2015 to 2019. Value Health 24, 1279-84.

Knight P., Chellian R., Wilson R., Behnood-Rod A., Panunzio S. & Bruijnzeel A.W. (2021) Sex differences in the elevated plus-maze test and large open field test in adult Wistar rats. Pharmacology Biochemistry and Behavior 204.

Liebsch G., Montkowski A., Holsboer F. & Landgraf R. (1998) Behavioural profiles of two Wistar rat lines selectively bred for high or low anxiety-related behaviour. Behav Brain Res 94, 301-10.

Martins S.S., Storr C.L., Zhu H. & Chilcoat H.D. (2009) Correlates of extramedical use of OxyContin (R) versus other analgesic opioids among the US general population. Drug and Alcohol Dependence 99, 58-67.

Nielsen C.K., Ross F.B., Lotfipour S., Saini K.S., Edwards S.R. & Smith M.T. (2007) Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain. Pain 132, 289-300.

Sharp B.M., Fan X., Redei E.E., Mulligan M.K. & Chen H. (2021) Sex and heredity are determinants of drug intake in a novel model of rat oral oxycodone self-administration. Genes Brain Behav 20, e12770.

You Z.B., Gao J.T., Bi G.H., He Y., Boateng C., Cao J., Gardner E.L., Newman A.H. & Xi Z.X. (2017) The novel dopamine D3 receptor antagonists/partial agonists CAB2-015 and BAK4-54 inhibit oxycodone-taking and oxycodone-seeking behavior in rats. Neuropharmacology 126, 190-9.

Zanni G., DeSalle M.J., Deutsch H.M., Barr G.A. & Eisch A.J. (2020) Female and male rats readily consume and prefer oxycodone to water in a chronic, continuous access, two-bottle oral voluntary paradigm. Neuropharmacology 167, 107978.


Posted on: 7 February 2022


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