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. 2017 Jun 1;81(11):949-958.
doi: 10.1016/j.biopsych.2016.11.011. Epub 2016 Dec 1.

Oxytocin Acts in Nucleus Accumbens to Attenuate Methamphetamine Seeking and Demand

Brittney M Cox  1 , Brandon S Bentzley  2 , Helaina Regen-Tuero  2 , Ronald E See  3 , Carmela M Reichel  2 , Gary Aston-Jones  4
Affiliations

Oxytocin Acts in Nucleus Accumbens to Attenuate Methamphetamine Seeking and Demand

Brittney M Cox et al. Biol Psychiatry. .

Abstract

Background: Evidence indicates that oxytocin, an endogenous peptide well known for its role in social behaviors, childbirth, and lactation, is a promising addiction pharmacotherapy. We employed a within-session behavioral-economic (BE) procedure in rats to examine oxytocin as a pharmacotherapy for methamphetamine (meth) addiction. The BE paradigm was modeled after BE procedures used to assess motivation for drugs in humans with addiction. The same BE variables assessed across species have been shown to predict later relapse behavior. Thus, the translational potential of preclinical BE studies is particularly strong.

Methods: We tested the effects of systemic and microinfused oxytocin on demand for self-administered intravenous meth and reinstatement of extinguished meth seeking in male and female rats using a BE paradigm. Correlations between meth demand and meth seeking were assessed.

Results: Female rats showed greater demand (i.e., motivation) for meth compared with male rats. In both male and female rats, meth demand predicted reinstatement of meth seeking, and systemic oxytocin decreased demand for meth and attenuated reinstatement to meth seeking. Oxytocin was most effective at decreasing meth demand and seeking in rats with the strongest motivation for drug. Finally, these effects of systemic oxytocin were mediated by actions in the nucleus accumbens.

Conclusions: Oxytocin decreases meth demand and seeking in both sexes, and these effects depend on oxytocin signaling in the nucleus accumbens. Overall, these data indicate that development of oxytocin-based therapies may be a promising treatment approach for meth addiction in humans.

Keywords: Addiction; Behavioral economics; Methamphetamine; Oxytocin; Reinstatement; Self-administration.

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Conflict of interest statement

Financial Disclosures

All authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1
Figure 1. Validation of within-session BE paradigm
Male and female rats were trained on a traditional BE paradigm (multiple days at each fixed ratio (FR) value) and subsequently stabilized on the within-session BE paradigm. Meth demand (α) and preferred levels of intake (Q0) were assessed from both paradigms to test whether individual variability in these variables predicted reinstatement behavior. A&B) Timeline and description of the behavioral paradigm. C&D) α and Q0 values for males and females during the multi-day BE paradigm. E&F) α and Q0 values during the within-session BE paradigm. In both paradigms, females (grey bars) had lower α values (higher motivation) and higher Q0 values (higher free consumption) than males (black bars) (*p<0.05). G&H) Demand elasticity (α) calculated from the traditional BE paradigm correlated significantly with the same variables assessed during the within-session BE paradigm in both sexes (males r=0.44, p<0.05; Females r=0.51, p<0.05; for all data: males: n=22; females n=21).
Figure 2
Figure 2. Demand elasticity predicts meth seeking behaviors
A&B) Demand elasticity predicts meth seeking in both males (panel A) and females (panel B) on the first day of extinction (males: r= −0.49, p<0.05; females: r= −0.51, p<0.05). C&D) Following extinction, α predicted cue-induced reinstatement of meth seeking in both sexes (males: r= −0.56, p<0.05; females: r= −0.44, p<0.05). For all data: males n=22; females n=21.
Figure 3
Figure 3. Oxytocin decreases meth seeking similarly in both sexes
Male and female rats were stabilized on the within-session BE paradigm to generate baseline demand elasticity (α) and free consumption (Q0) values for meth, and then these were were measured again after vehicle (saline, sal) or oxytocin administration (oxy, 1 mg/kg i.p.). Subsequently, responding was extinguished and tested on cue-induced reinstatement of meth seeking after vehicle or oxytocin administration. For A–C, significant treatment effects are noted, *p<0.05. A) Percent change in α from baseline after vehicle or oxytocin administration. In both sexes (male n=22, female n=21), oxytocin robustly increased α (decreased motivation). B) Percent change in Q0 from baseline after vehicle or oxytocin administration. Oxytocin did not significantly affect Q0 in either sex (male n=22, female n=21). C) Number of active lever presses during cue-induced reinstatement of meth seeking after vehicle or oxytocin administration. Oxytocin decreased cue-induced reinstatement responding in both sexes (male n=21, female n=23). Overall, a two-way ANOVA showed no effects of sex in any of these measures. D&E) Baseline demand elasticity (α) predicted the efficacy of oxytocin to reduce cue-induced reinstatement (change in cue reinstatement from saline test) in both sexes (males n=21: r= −0.45, p<0.05; female n=20: −0.50, p<0.05).
Figure 4
Figure 4. Central oxytocin antagonist blocks systemic oxytocin effects on meth demand
Rats stabilized on the within-session BE paradigm for meth were tested with either ICV microinfusions of OXA or aCSF immediately followed by administration of i.p. oxytocin or saline in a counterbalanced manner. A) α values assessed during the within-session BE paradigm. Systemic oxytocin (aCSF/oxy, white bar) increased α (decreased motivation) compared to controls (aCSF/sal, black bar). ICV administration of OXA blocked this effect of systemic oxytocin (OXA/oxy, light grey bar), although it did not affect behavior when administered with i.p. saline vehicle (OXA/sal, dark grey bar). *p<0.05 compared with aCSF/oxy. B) Q0 values assessed during the within-session BE paradigm. There were no effects on Q0 for any of the treatments.
Figure 5
Figure 5. Oxytocin decreases reinstatement-induced Fos in NAc core
A) Number of active lever presses during extinction (EXT, black bar) or cue-induced reinstatement of meth seeking with pretreatment of saline (CUE SAL, white bar) or oxytocin (1 mg/kg i.p.; CUE OXY, grey bar). Oxytocin attenuated cue-induced reinstatement of meth seeking (*p<0.05). B) Rats were sacrificed immediately after the session to examine Fos expression in the NAc core after extinction (black hashed bar), cue-induced reinstatement with saline (white hashed bar), or with oxytocin (grey hashed bar). Rats treated with oxytocin prior to cue-induced reinstatement had fewer Fos-positive neurons in the NAc core than saline controls (one way ANOVA *p<0.05). C) Example of Fos staining in each treatment group (AC: anterior commissure; scale bar= 100 µm)
Figure 6
Figure 6. Microinfusions of oxytocin into NAc core decreases meth demand and seeking
A) Demand elasticity (α) was increased (decreased motivation) following oxytocin microinfusions into NAc as compared to aCSF in NAc. B) Oxytocin microinfusions in NAc had no effect on Q0 compared to aCSF in NAc. C) Oxytocin in NAc decreased the number of active lever presses during cue-induced reinstatement of meth seeking (*p<0.05).
Figure 7
Figure 7. Oxytocin antagonist infused into NAc core blocks effect of systemic oxytocin on meth demand
Rats stabilized on the within-session BE paradigm were tested with either microinfusions of OXA or aCSF into the NAc core immediately followed by i.p. administration of oxytocin or saline in a counterbalanced manner. A) α values assessed during the within-session BE paradigm. Systemic oxytocin (aCSF/oxy, white bar) increased α (decreased motivation) compared to controls (aCSF/sal, black bar). Intra-NAc administration of OXA blocked this effect of systemic oxytocin (OXA/oxy, light grey bar), although it did not affect behavior when administered with systemic saline vehicle (OXA/sal, dark grey bar). *p<0.05 compared with aCSF/oxy. B) Q0 values assessed during the within-session BE paradigm. There were no significant effects on Q0.
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