- Ventral hippocampal corticosterone (vHipp CORT) enhances accumbal dopamine output in drug-naive rats, peaking 55 minutes post-infusion, suggesting a mechanism by which stress could enhance reward. However, in amphetamine withdrawal rats, vHipp CORT immediately reduces accumbal dopamine output, peaking at 20 and 80 minutes post-infusion, suggesting stress could contribute to dysphoric states and relapse. - The findings support an opponent-process theory of addiction where blunted dopamine and enhanced CORT stress responses drive continued drug use. Receptor mechanisms are being tested to explain the differential dopamine responses to vHipp CORT in controls versus withdrawal.

1. Ventral hippocampal corticosterone:
Linking stress, accumbal dopamine output, and reward salience
in healthy conditions and in amphetamine withdrawal
Brenna Bray, Matthew Weber, and Gina L. Forster
Center for Brain and Behavior Research, Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota
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 CORT 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 AMP WD, vHipp CORT immediately reduces accumbal dopamine
output, peaking 20 min and then 80 min post-infusion (Fig 3).
• This suggests stress-induced vHipp CORT could contribute to
dysphoric states that prompt drug-seeking and relapse during
withdrawal (Fig 4A)2-4.
• These findings support an opponent-process theory of
addiction, in which blunted dopamine reward responses and
enhanced CORT stress responses contribute to negative
reinforcement of drug-taking (Fig 4A)2.
Discussion
• CORT activation of glucocorticoid receptors (GRs) is thought to be
excitatory in the vHipp7-8,11,, implicating GRs as the underlying
mechanism for the CORT-induced dopamine output (Fig 3).
• GR expression is reduced in the vHipp during AMP WD, but vHipp
mineralocorticoid receptor (MR) expression is not altered (Fig 4B)17
• This results in vHipp MRs – which are thought to be inhibitory
– having a more pronounced effect during AMP WD.
• This suggests CORT activation of vHipp MRs may mediate the
reduction in accumbal dopamine output during withdrawal.
To uncover the underlying receptor mechanisms (of the 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 AMP WD.
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Saline
Amphetamine
HippocampalCorticosterone
(%baseline)
Ventral
Hippocampus
Time (min)
Restraint
Glutamate (+)
GABA (-)
Enhanced vHipp CORT stress response proposed to enhance accumbal dopamine output
Fig 2A5 : Rats undergoing amphetamine withdrawal (n=7) show enhanced
CORT in the vHipp in response to 20 min of restraint stress (marked by
horizontal bar), relative to saline pre-treated controls (n=6). # Significant
difference from pre-stress levels. *Significant difference from saline rats5.
Fig 2B14 : CORT 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 salience13-16.
Opponent-Process Theory of Addiction, Altered GR/MR expression in AMP WD
GROpticalDensity
GR/MRRatio
Fig 4B17: vHipp GR expression (left) and
GR/MR expression ratio (right) are reduced
during AMP WD17, resulting in MRs having
more pronounced (inhibitory) effect in WD.
Fig 4A2: 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.
-40 -20 0 20 40 60 80 100 120
-0.6
-0.4
-0.2
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 CORT 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 CORT immediately reduces accumbal
dopamine output in AMP WD (red tracing), peaking
20 min and then 80 min post infusion (n=7).
• This suggests stress-induced vHipp CORT could
contribute to dysphoric states that prompt drug-
seeking and relapse during withdrawal2-4 (Fig 4A).
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 (AMP WD) is associated with dysphoria4
and stress hypersensitivity4-10 that can prompt relapse (Fig 4A)2-4.
• In rats, AMP WD is associated with enhanced stress-induced
corticosterone (CORT) in the ventral hippocampus (vHipp), which
may contribute to stress hypersensitivity during WD (Fig 2A)5.
• CORT in the vHipp can induce glutamate release11-12 and the vHipp
sends glutamatergic projections to the nucleus accumbens13-14 to
enhance dopamine output13-15 and reward salience (Fig 2B)14,16.
• It remains unknown whether a stress-relevant concentration of
CORT in the vHipp can directly enhance accumbal dopamine output
in control conditions, and during AMP WD.
Methods
Rodent Model of AMP Withdrawal:
Adult male Sprague-Dawley rats were treated with AMP (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:
Stereotactic surgery was performed in the 2nd week of withdrawal8-9:
● A stearate-treated carbon paste electrode19 was implanted into the
nucleus accumbens shell (1.6mm AP; ±0.7mm ML; -7.0mm DV)20,21
● A 22-guage guide cannula was implanted into the vHipp (-5.2mm AP;
±4.5mm ML; -4.5mm DV)8,21
Intracranial Infusion:
A stress-relevant concentration of CORT (0.48 ng/uL)17 or vehicle (0.05% HBC)
was infused into the vHipp (1uL total at flow rate 1uL/min, ipsilateral to the
carbon paste electrode in the nucleus accumbens) of anesthetized drug-naïve
rats and rats in AMP WD to mimic the vHipp CORT 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 working electrode (implanted into the
nucleus accumbens shell), resulting in dopamine oxidation19,22.
The oxidation current was recorded by an electrometer and plotted as a function of
time (min) before, during, and after the vHipp CORT infusion19,22.
http://www.strictly-stress-management.com/types_of_stress.html
Fig 1: Optimal levels of stress motivate goal-oriented behavior.
Differential effects of vHipp CORT on accumbal dopamine output in controls and in AMP WD