1. Stress in the Brain: Uncovering a novel neurobiological mechanism
that links stress to reward value and drug relapse
Brenna Bray, Matthew Weber, and Gina Forster, Ph.D.
Center for Brain and Behavior Research, Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota. Contact: Brenna.bray@usd.edu
References
Acknowledgements
Grant support: NIH grant RO1 DA019921. Special thanks to Jamie Scholl, Michael Watt, PhD,
Wenyu Tu, Dana Turgeon, and Raisul Rubel for their invaluable help.
Conclusions
• In drug-naive rats, vHipp corticosterone enhances accumbal
dopamine output, peaking 55 min post infusion (Fig 3).
• This suggests a novel mechanism by which stress exposure
could enhance reward value to promote goal-oriented
behavior1,14 (Fig 1).
• In amphetamine withdrawal, vHipp corticosterone immediately
reduces accumbal dopamine output (Fig 3).
• This suggests stress-induced vHipp corticosterone could
contribute to dysphoric states that prompt drug-seeking and
relapse during withdrawal (Fig 4)2-4.
• These findings support an opponent-process theory of
addiction, in which blunted dopamine reward responses and
enhanced corticosterone stress responses contribute to
negative reinforcement of drug-taking (Fig 4)2.
Discussion
• Corticosterone activation of glucocorticoid receptors (GRs) is
thought to be excitatory in the vHipp7-8,11,, implicating GR activation
as mediating dopamine output in control conditions (Fig 3).
• GR expression is reduced in the vHipp during amphetamine
withdrawal, but vHipp mineralocorticoid receptor (MR) expression
is not altered17.
• This may result in inhibitory vHipp MRs having a more
pronounced effect during amphetamine withdrawal.
• This suggests vHipp MRs may mediate the reduction in
accumbal dopamine output during withdrawal.
To uncover the underlying receptor mechanisms (of findings in Fig 3),
we are currently testing whether these differential stress responses
can be inhibited by separate infusions of GR and MR antagonists.
Significance
Overall, findings suggest the neural corticosterone system could play
an important role in driving positive stress coping mechanisms in
healthy conditions, with dysregulation of this system potentially
contributing to relapse during amphetamine withdrawal.
1. Hollon, N.G. et al. (2015). Nature Neuroscience, 18(10).
2. Koob, G.F. (2015). Eur J Pharmacol, 753.
3. Cleck, J.N & Blendy, J.A. (2008). J Clinical Investivation, 118(2).
4. Shoptaw, S.J. et al. (2009). Cochrane Database Syst Rev, (2).
5. Bray et al. (2016). Brain Res, 1644(C).
6. Barr, J. L., et al. (2010). Neuropharmacology, 59(6).
7. Li, H. et al. (2014). Eur J Neurosci, 40(11).
8. Tu, W. et al. (2014). Neuroscience, 281c.
9. Vuong, S. M., et al. (2010). Behav Brain Res, 208(1).
10. Russig, H. et al. (2006). Brain Res, 1084(1).
11. Wang, C.C. & Wang, S.J. (2009). Synapse, 63(9).
12. Karst, H. et al. (2005). Proc of Nat Acad Sci USA, 102(52).
13. Blaha, C.D. et al. (1997). Eur J Neurosci, 9(5).
14. Floresco, S.B. (2014). Ann Rev Psych.
15. Barr, J.L. et al. (2014). J Neurochemistry, 130(4).
16. Taepavarapruk, P. et al. (2014). Int J Neurospchypharm, 18(1).
17. Barr, J.L. & Forster, G.L. (2011). Neuroscience, 182.
18. Droste, S.K. et al. (2008). Endocrinology, 149(7).
19. Novick, A.M. et al. (2015). Neuropharmacol, 97.
20. Miller et al. (2005). Neurosci, 136(2).
21. Paxinos, G.W.C. (1998). Rat Brain in Stereotaxic Coordinates, 4e.
22. Borland, L. & Michael A., (2007). Electrochem Met Neurosci.
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0.0
0.2
0.4
0.6
0.8
1.0
SAL + VEH (n=6)
AMP + VEH (n=6)
AMP + CORT (n=7)
SAL + CORT (n=7)
Time (min)
DopamineOxidationCurrent(nA)
Infusion
Fig 3: vHipp corticosterone enhances accumbal
dopamine output in drug-naïve rats (green tracing),
peaking 55 min post infusion (n=7).
• This suggests a novel mechanism by which stress
exposure could enhance reward value to
promote goal-oriented behavior1,14 (Fig 1).
vHipp corticosterone immediately reduces accumbal
dopamine output in amphetamine withdrawal (red
tracing), peaking 20- and 80 min post infusion (n=7).
• This suggests stress-induced vHipp corticosterone
may contribute to dysphoria that prompts drug-
seeking and relapse in withdrawal2-4 (Fig 4).
• FIGURE LEGEND: AMP: Amphetamine pre-
treatment and withdrawal, SAL: Saline pre-
treatment (control condition, no withdrawal);
CORT: Corticosterone infusion into vHipp, VEH:
Vehicle infusion into vHipp (control condition).
Background
• Stress can motivate goal-oriented behavior (Fig 1) but can also
prompt drug use and induce relapse during withdrawal (Fig 4A)1-3.
• Amphetamine withdrawal is associated with dysphoria4 and stress
hypersensitivity4-10 that can prompt relapse (Fig 4A)2-4.
• Stress induces release of hormones (cortisol in humans,
corticosterone in rats) into the bloodstream. These hormones can
act as neurotransmitters1,11-12,18 in brain regions like the ventral
hippocampus (vHipp)5 to mediate stress responses (Fig 2).
• In rats, amphetamine withdrawal is associated with enhanced
stress-induced corticosterone in the vHipp, which may contribute to
stress hypersensitivity during withdrawal (Fig 2A)5.
• Corticosterone in the vHipp can be excitatory11-12. The vHipp sends
excitatory projections to the nucleus accumbens13-14 to enhance
dopamine output13-15 and reward value (Fig 2B)14,16.
It remains unknown whether a stress-relevant concentration of
corticosterone in the vHipp can directly enhance accumbal dopamine
output in control conditions, and during withdrawal.
Methods
Rodent Model of Amphetamine Withdrawal:
Adult male Sprague-Dawley rats were treated with d-amphetamine (2.5 mg/kg, ip) or
saline (SAL) for 2 weeks5-9, then underwent 2 weeks of withdrawal 5-9
● This protocol is known to enhance behavioral responses to stress7
Stereotactic Surgery in the 2nd week of withdrawal8-9:
● Carbon paste electrode19 implanted into the nucleus accumbens shell20,21
● Guide cannula implanted into the vHipp8,21
Intracranial Infusion:
A stress-relevant concentration of corticosterone (0.48 ng/uL)17 or vehicle (0.05%
HBC) was infused into the vHipp of anesthetized drug-naïve rats and rats in
amphetamine withdrawal (ipsilateral to the electrode in the nucleus accumbens)
to mimic the vHipp corticosterone stress response5,18.
In vivo Chronoamperometry19,22:
In vivo chronoamperometry was used to assess accumbal dopamine output:
A fixed pulse potential was applied to the electrode, resulting in dopamine oxidation19,22.
Dopamine oxidation current was recorded by an electrometer and plotted as a function of
time (min) to assess dopamine output before, during, and after the vHipp infusion19,22.
http://www.strictly-stress-management.com/types_of_stress.html
Fig 1: Optimal levels of stress motivate goal-oriented behavior.
Glutamate (+)
GABA (-)
Enhanced vHipp corticosterone stress response proposed to enhance accumbal dopamine output
Fig 2A5 : Rats undergoing amphetamine withdrawal (n=7) show enhanced
corticosterone in the vHipp in response to 20 min of restraint stress
(horizontal bar), relative to saline pre-treated controls (n=6). # Significant
difference vs. pre-stress levels. *Significant difference vs. saline rats5.
Fig 2B14 : Corticosterone in the vHipp can induce
glutamate release11-12 and the vHipp sends
glutamatergic projections to the nucleus accumbens13-14
to enhance dopamine output and reward value13-16.
Saline
Amphetamine
HippocampalCorticosterone
(%baseline)
Ventral
Hippocampus
Time (min)
Restraint
Differential effects of vHipp corticosterone on accumbal dopamine output in controls vs. withdrawal
Opponent-Process Theory of Addiction
Fig 42: In an opponent-process theory of addiction, drug-induced dopamine reward responses (a) are positively reinforcing, but become
blunted over time. Increased corticosterone stress responses in withdrawal (b) negatively reinforce drug-taking and worsen over time2,
which may contribute to relapse. DA: Dopamine, CORT: Corticosterone.